Title:
METHODS AND COMPOSITIONS FOR DETECTING AUTOIMMUNE DISORDERS
Kind Code:
A1


Abstract:
The invention provides methods and compositions useful for detecting autoimmune disorders.



Inventors:
Abbas, Alexander (Belmont, CA, US)
Modrek, Barmak (San Mateo, CA, US)
Townsend, Michael J. (San Jose, CA, US)
Application Number:
11/739606
Publication Date:
03/06/2008
Filing Date:
04/24/2007
Assignee:
GENENTECH, INC.
Primary Class:
Other Classes:
506/16
International Classes:
C40B40/06; C12Q1/68
View Patent Images:



Primary Examiner:
MYERS, CARLA J
Attorney, Agent or Firm:
GENENTECH, INC. (SOUTH SAN FRANCISCO, CA, US)
Claims:
1. A method comprising determining whether a subject comprises a cell that expresses at least 2 of the genes listed in Table 1, 2 and/or 3 at a level greater than the expression level of the respective genes in a normal reference sample, wherein presence of said cell indicates that the subject has an autoimmune disorder.

2. A method of predicting responsiveness of a subject to autoimmune disease therapy, said method comprising determining whether the subject comprises a cell that expresses at least 2 of the genes listed in Table 1, 2 and/or 3 at a level greater than the expression level of the respective genes in a normal reference sample, wherein presence of said cell indicates that the subject would be responsive to the autoimmune disease therapy.

3. (canceled)

4. A method for detecting an autoimmune disease state in a subject, said method comprising determining whether the subject comprises a cell that expresses at least 2 of the genes listed in Table 1, 2 and/or 3 at a level greater than the expression level of the respective genes in a normal reference sample, wherein detection of said cell is indicative of presence of an autoimmune disease state in the subject.

5. A method for assessing predisposition of a subject to develop an autoimmune disorder, said method comprising determining whether the subject comprises a cell that expresses at least 2 of the genes listed in Table 1, 2 and/or 3 at a level greater than the expression level of the respective genes in a normal reference sample, wherein detection of said cell is indicative of a predisposition for the subject to develop the autoimmune disorder.

6. A method for diagnosing an autoimmune disorder in a subject, said method comprising determining whether the subject comprises a cell that expresses at least 2 of the genes listed in Table 1, 2 and/or 3 at a level greater than the expression level of the respective genes in a normal reference sample, wherein detection of said cell indicates that the subject has said autoimmune disorder.

7. The method of claim 1, wherein said at least 2 genes comprise (i) OAS3 and HERC5; or (ii) ESPTI1 and HERC5; or (iii) ESPTI1 and TYKI; or HERC5 and TYKI.

8. The method of claim 1, wherein said at least 2 genes comprises a 3-gene combination as listed in Table 4B.

9. The method of claim 8, wherein the 3-gene combination comprises (1) IFIT4, OAS1, and MX1; or (2) OASL, CHMP5, and ZBP1; or (3) IFI44L, OASL, and CIG5; or (4) IFI44L, CIG5, and ZBP1; or (5) EPSTI1, TYKI, and MX1; or (6) IFIT4, HERC5, and TYKI; or (7) IFIT4, TYKI, and XIAP; or (8) IFI44L, OASL, and ZBP1; or (9) IFI44L, IFIT4, and OASL; or (10) IFI4, OAS1, and IFIT1; or (11) EPSTI1, HERC5, and TYKI; or (12) IFI44L, EPSTI1, and OASL; or (13) IFI44L, EPSTI1, and OAS3; or (14) EPSTI1, TYKI, and IFIT1; or (15) G1P2, SAMD9L, and SP110.

10. The method of claim 1, further comprising the use of a housekeeping gene.

11. The method of claim 1, wherein the normal reference sample comprises a healthy cell or tissue.

12. A composition comprising polynucleotides capable of specifically hybridizing to at least 2 of the genes listed in Table 1, 2, 3 and/or 4A or complements of said genes.

13. The composition of claim 12, wherein the polynucleotides are provided as an array, a gene chip, or gene set.

14. The composition of claim 12 comprising polynucleotides capable of specifically hybridizing to at least 3 genes listed in Table 1, 2, 3 and/or 4A or complements of said genes.

15. The composition of claim 14, wherein said at least 3 genes comprises a 3-gene combination listed in Table 4B.

16. The composition of claim 15, wherein the 3-gene combination comprises (1) IFIT4, OAS1, and MX1; or (2) OASL, CHMP5, and ZBP1; or (3) IFI44L, OASL, and CIG5; or (4) IFI44L, CIG5, and ZBP1; or (5) EPSTI1, TYKI, and MX1; or (6) IFIT4, HERC5, and TYKI; or (7) IFIT4, TYKI, and XIAP; or (8) IFI44L, OASL, and ZBP1; or (9) IFI44L, IFIT4, and OASL; or (10) IFI4, OAS1, and IFIT1; or (11) EPSTI1, HERC5, and TYKI; or (12) IFI44L, EPSTI1, and OASL; or (13) IFI44L, EPSTI1, and OAS3; or (14) EPSTI1, TYKI, and IFIT1; or (15) G1P2, SAMD9L, and SP110.

17. The composition of claim 12, further comprising a housekeeping gene.

18. A kit comprising the composition of claim 12, and instructions for using the composition to detect an autoimmune disorder by determining whether expression of the genes provided is at a level greater than the expression level of the respective genes in a normal reference sample.

19. The kit of any of claim 18, wherein the normal reference sample comprises a healthy cell or tissue.

20. 20-25. (canceled)

Description:

RELATED APPLICATION

This application is a non-provisional application filed under 37 CFR 1.53(b)(1), claiming priority under 35 USC 119(e) to provisional application No. 60/794,393 filed Apr. 24, 2006, the contents of which are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates generally to the fields of molecular determination of autoimmune diseases. More specifically, the invention concerns methods and compositions based on unique molecular signatures associated with various aspects of autoimmune disorders.

BACKGROUND

A number of autoimmune disorders are now believed to be characterized by the production of autoantibodies against a variety of self antigens. For example, systemic lupus erythematous (SLE) is an autoimmune disease in which autoantibodies cause organ damage by binding to host cells and tissues and by forming immune complexes that deposit in vascular tissues and activate immune cells. Sjogren's syndrome is an autoimmune disease characterized by inflammation in the glands of the body. Other autoimmune disorders are also commonly found, including but not limited to IgA nephropathy, psoriasis, rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, etc.

Interferon alpha (IFN-α) is a Type I interferon strongly implicated in the etiology of a number of immune disorders, such as SLE. It is believed that treatment approaches involving disruption of IFN-α signaling may be an effective treatment for such disorders. IFN-α levels are known to be elevated in SLE, and treatment of patients with IFN-α has been observed to reversibly cause symptoms similar to SLE in recipients. Numerous other lines of evidence have linked IFN-α and SLE.

The mechanisms by which IFN-α exerts its effects on the transcription of genes in target cells has been extensively investigated. The second messenger cascade has been determined, cis-regulatory binding sites for activated transcription factors have been defined, and several studies have explored what genes' expression is modulated. The most comprehensive of these studies have been performed with oligonucleotide microarrays, but definitions of interferon response gene expression profiles are still not complete, at least in part because until recently microarrays have not contained a very complete set of reporters for the genes of the human genome, and also because a variety of technical difficulties prevented identification of broadly applicable yet simple sets of marker genes that reliably correlate with pathological conditions of interest.

One of the most difficult challenges in clinical management of autoimmune diseases is the accurate and early identification of the diseases in a patient. To this end, it would be highly advantageous to have molecular-based diagnostic methods that can be used to objectively identify presence and/or extent of disease in a patient. The invention described herein provides these methods and other benefits.

All references cited herein, including patent applications and publications, are incorporated by reference in their entirety.

DISCLOSURE OF THE INVENTION

The invention provides methods and compositions for identifying autoimmune disorders based at least in part on identification of the gene(s) whose expression is associated with presence and/or extent of systemic lupus erythematosus (SLE), wherein SLE is in turn a prototypical autoimmune disease whose disease-associated gene signatures are also applicable in other autoimmune diseases. For example, as described herein, in one embodiment, genes modulated in response to signaling by IFN-α were identified. Information generated by this approach was then tested and modified to develop a concise and quantitative measure of the degree to which cell or tissue samples exhibit responses characteristic of autoimmune disorders. As shown herein, detection of one or more of specific genes disclosed herein can be a useful and informative indicator of presence and/or extent of autoimmune disorders in a patient. Moreover, metrics or equivalent quotients that are indicative of interferon-associated disease presentation and/or severity can be generated by appropriate transformation of biomarker gene expression information. Exemplary transformations and resultant metrics are disclosed herein, generated based on gene expression data that are also disclosed herein.

In one aspect, the invention provides a method comprising determining whether a subject comprises a cell that expresses at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or any number up to all of the genes listed in Table 1, 2 and/or 3 at a level greater than the expression level of the respective genes in a normal reference sample, wherein presence of said cell indicates that the subject has an autoimmune disorder.

In one aspect, the invention provides a method of predicting responsiveness of a subject to autoimmune disease therapy, said method comprising determining whether the subject comprises a cell that expresses at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or any number up to all of the genes listed in Table 1, 2 and/or 3 at a level greater than the expression level of the respective genes in a normal reference sample, wherein presence of said cell indicates that the subject would be responsive to the autoimmune disease therapy.

In one aspect, the invention provides a method for monitoring minimal residual disease in a subject treated for an autoimmune disease, said method comprising determining whether the subject comprises a cell that expresses at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or any number up to all of the genes listed in Table 1, 2 and/or 3 at a level greater than the expression level of the respective genes in a normal reference sample, wherein detection of said cell is indicative of presence of minimal residual autoimmune disease.

In one aspect, the invention provides a method for detecting an autoimmune disease state in a subject, said method comprising determining whether the subject comprises a cell that expresses at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or any number up to all of the genes listed in Table 1, 2 and/or 3 at a level greater than the expression level of the respective genes in a normal reference sample, wherein detection of said cell is indicative of presence of an autoimmune disease state in the subject.

In one aspect, the invention provides a method for assessing predisposition of a subject to develop an autoimmune disorder, said method comprising determining whether the subject comprises a cell that expresses at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or any number up to all of the genes listed in Table 1, 2 and/or 3 at a level greater than the expression level of the respective genes in a normal reference sample, wherein detection of said cell is indicative of a predisposition for the subject to develop the autoimmune disorder.

In one aspect, the invention provides a method for diagnosing an autoimmune disorder in a subject, said method comprising determining whether the subject comprises a cell that expresses at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or any number up to all of the genes listed in Table 1, 2 and/or 3 at a level greater than the expression level of the respective genes in a normal reference sample, wherein detection of said cell indicates that the subject has said autoimmune disorder.

In one aspect, the invention provides a method for distinguishing between active and inactive disease states (e.g., active and inactive SLE) in a subject, said method comprising determining whether the subject comprises a cell that expresses at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or any number up to all of the genes listed in Table 1, 2 and/or 3 at a level greater than the expression level of the respective genes in a normal reference sample, wherein detection of said cell indicates that the subject has the autoimmune disorder in an active state.

In one aspect, the invention provides a method for determining presence and/or elevation of anti-dsDNA antibodies in a subject, said method comprising determining whether the subject comprises a cell that expresses at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or any number up to all of the genes listed in Table 1, 2 and/or 3 at a level greater than the expression level of the respective genes in a normal reference sample, wherein detection of said cell indicates presence and/or elevation of anti-dsDNA antibodies in the subject.

Methods of the invention provide information useful for determining appropriate clinical intervention steps, if and as appropriate. Therefore, in one embodiment of a method of the invention, the method further comprises a clinical intervention step based on results of the assessment of the expression of one or more of the genes listed in Table 1, 2 and/or 3 (including, e.g., any combination of genes (e.g., those listed in Table 4)). For example, appropriate intervention may involve prophylactic and treatment steps, or adjustment(s) of any then-current prophylactic or treatment steps based on gene expression information obtained by a method of the invention.

As would be evident to one skilled in the art, in any method of the invention, while detection of increased expression of a gene would positively indicate a characteristic of a disease (e.g., presence, stage or extent of a disease), non-detection of increased expression of a gene would also be informative by providing the reciprocal characterization of the disease.

In one aspect, the invention provides a composition comprising polynucleotides capable of specifically hybridizing to at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or any number up to all of the genes listed in Table 1, 2 and/or 3, or complements of such genes. In one embodiment, the polynucleotides are provided as an array, gene chip, or gene set (e.g., a set of genes or fragments thereof, provided separately or as a mixture).

In one aspect, the invention provides a kit comprising a composition the invention, and instructions for using the composition to detect an autoimmune disorder by determining whether expression of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or any number up to all of the genes listed in Table 1, 2 and/or 3 are at a level greater than the expression level of the respective genes in a normal reference sample. In one embodiment, the composition of the invention comprises an array/gene chip/gene set capable of specifically hybridizing to at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or any number up to all of the genes listed in Table 1, 2 and/or 3. In one embodiment, the composition of the invention comprises nucleic acid molecules encoding at least a portion of a polypeptide encoded by a gene listed in Table 1, 2 and/or 3. In one embodiment, the composition of the invention comprises nucleic acid primers capable of binding to and effecting polymerization (e.g., amplification) of at least a portion of a gene listed in Table 1, 2 and/or 3. In one embodiment, the composition of the invention comprises a binding agent (e.g., primer, probe) that specifically detects a gene (or complement thereof) (or corresponding gene product) listed in Table 1, 2 and/or 3. In one embodiment, the composition of the invention comprises a binding agent that specifically binds to at least a portion of a polypeptide encoded by a gene listed in Table 1, 2 and/or 3.

Methods and compositions of the invention may comprise one or more of the genes listed in Table 1, 2 and/or 3. If more than one gene is utilized or included in a method or composition of the invention, the more than one gene can be any combination of any number of the genes as listed (in no particular order) in Table 1, 2 and/or 3. For example, in one embodiment, a combination of genes comprises only two genes that are listed, namely OAS3 and HERC5. In one embodiment, a combination of genes comprises only three, only four, only five, or only six genes that are listed. In one embodiment, a combination of genes comprises at least two, at least three, at least four, at least five, or at least six genes that are listed. In another embodiment, a combination of genes comprises OAS3, HERC5, and one or more of the other genes listed in Table 1, 2 and/or 3. In one embodiment, a gene combination of the invention comprises, consists, or consists essentially of a 3-gene combination (Genes 1, 2 and 3) as indicated in Table 4B. In one embodiment, such 3-gene combination is indicated as having a Pearson correlation value of at least about 0.7, or at least about 0.75, or at least about 0.8, or at least about 0.85, or at least about 0.9, or at least about 0.95, or at least about 0.97, or at least about 0.98, or at least about 0.99. In one embodiment, such 3-gene combination comprises (1) IFIT4, OAS1, and MX1; or (2) OASL, CHMP5, and ZBP1; or (3) IFI44L, OASL, and CIG5; or (4) IFI44L, CIG5, and ZBP1; or (5) EPSTI1, TYKI, and MX1; or (6) IFIT4, HERC5, and TYKI; or (7) IFIT4, TYKI, and XIAP; or (8) IFI44L, OASL, and ZBP1; or (9) IFI44L, IFIT4, and OASL; or (10) IFI4, OAS1, and IFIT1; or (11) EPSTI1, HERC5, and TYKI; or (12) IFI44L, EPSTI1, and OASL; or (13) IFI44L, EPSTI1, and OAS3; or (14) EPSTI1, TYKI, and IFIT1; or (15) G1P2, SAMD9L, and SP110. In yet another embodiment, a combination of genes comprises one or more of the genes listed in Table 1, 2 and/or 3, further combined with one or more other genes that are not listed in Table 1, 2 and/or 3 (e.g., a gene known to be associated with an autoimmune disease but not associated with induction by interferons specifically).

In any of the embodiments of the invention described herein, one or more reference genes (i.e., genes that, when assessed by themselves, are not known to be indicative of the disease and/or condition of interest) may be included. Such reference genes may include housekeeping genes. For example, suitable reference genes may be housekeeping genes that can serve as reference/control genes indicative of baseline gene expression levels in a sample. Thus, for example, in one embodiment, one or more genes listed in Tables 1, 2, 3 and/or 4 are used in combination with one or more housekeeping genes such as ribosomal protein L19 (RPL19; NP000972), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), actins (e.g. β-actin), tubulins, hypoxantine phosphoribosyltransferase (HRPT), and other ribosomal proteins/genes (e.g., 28S, 18S).

In one aspect, the invention provides a method of identifying a metric value correlated with presence and/or extent of an autoimmune disorder in a subject or sample, said method comprising:

(a) estimating a group of probesets that is collectively associated with a pattern wherein expression of genes represented by the probesets is associated with a disease characteristic;

(b) generating a weighting factor that weight probesets in accordance with a scale reflecting extent of match of each individual probeset to trend of the group of probesets, and calculating the correlation coefficient of each probeset's profile to the mean profile calculated;

(c) determining a scaling factor, wherein the scaling factor is the value required to scale individual probesets to 1;

(d) multiplying the scaling factor by the weighting factor to generate a composite factor;

(e) multiplying a normal blood sample's signatures with the composite factor, and the averaging the resulting values across both probesets and samples to generate an average value, and inverting the average value to yield a global scaling factor;

(f) multiplying each weighting factor by the global scaling factor to obtain a vector of scalar values, and multiplying the scalar values by an expression signature from a sample of interest, and averaging the resulting values to yield a single metric that is indicative of degree of gene expression associated with Type I interferons in the sample.

In one embodiment of the method of the preceding paragraph, in step (a), the group of probesets comprises probesets that include, or cluster around, the core most-tightly-correlated pair of probesets in subcluster associated with a disease characteristic.

In one embodiment of the method of the preceding paragraphs, in step (b), the factor is generated by transforming expression data of the group of probesets into z-scores comprising mean scaling to 1, base-2 log transformation, then scaling to a standard deviation of the mean of 1.

In one embodiment of the method of the preceding paragraphs, in step (e), the global scaling factor is useful for transforming output of the average of probesets from a sample of interest into a metric, wherein the metric is 1 if the sample is from a normal, healthy subject.

In one embodiment of the method of any of the preceding paragraphs, the group of probesets comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or any number up to all of those listed in Table 1, 2 and/or 3. In one embodiment, the group of probesets comprises all those listed in Table 1, 2 and/or 3.

In one aspect, the invention provides a method comprising comparing a first metric obtained by a method described herein for a sample obtained from a subject of interest to a reference metric obtained from a reference (e.g., normal, healthy, non-diseased) sample, wherein a first metric that is higher than a reference metric indicates presence of an autoimmune disorder in the subject of interest.

In one aspect, the invention provides a method of predicting responsiveness of a subject to autoimmune disease therapy, said method comprising comparing a first metric obtained by a method described herein for a sample obtained from the subject to a reference metric obtained from a reference (e.g., normal, healthy, non-diseased) sample, wherein a first metric that is higher than a reference metric indicates the subject would be responsive to the autoimmune disease therapy.

In one aspect, the invention provides a method for monitoring minimal residual disease in a subject treated for an autoimmune disease, said method comprising comparing a first metric obtained by a method described herein for a sample obtained from the subject to a reference metric obtained from a reference (e.g., normal, healthy, non-diseased and/or untreated) sample, wherein a first metric that is higher than a reference metric is indicative of presence of minimal residual autoimmune disease.

In one aspect, the invention provides a method for detecting an autoimmune disease state, said method comprising comparing a first metric obtained by a method described herein for a sample from a subject suspected of having the autoimmune disease state to a reference metric obtained from a reference (e.g., normal, healthy, non-diseased) sample, wherein a first metric that is higher than a reference metric is indicative of presence of the autoimmune disease state in the subject.

In one aspect, the invention provides a method for assessing predisposition of a subject to develop an autoimmune disorder, said method comprising comparing a first metric obtained by a method described herein for a sample obtained from the subject to a reference metric obtained from a reference (e.g., normal, healthy, non-diseased) sample, wherein a first metric that is higher than a reference metric is indicative of a predisposition for the subject to develop the autoimmune disorder.

In one aspect, the invention provides a method for diagnosing an autoimmune disorder in a subject, said method comprising comparing a first metric obtained by a method described herein for a sample obtained from the subject to a reference metric obtained from a reference (e.g., normal, healthy, non-diseased) sample, wherein a first metric that is higher than a reference metric indicates that the subject has said autoimmune disorder.

In one aspect, the invention provides a method for distinguishing between active and inactive disease states (e.g., active and inactive SLE) in a subject, said method comprising comparing a first metric obtained by a method described herein for a sample obtained from the subject to a reference metric obtained from a reference (e.g., normal, healthy, non-diseased) sample, wherein a first metric that is higher than a reference metric indicates that the subject has the autoimmune disorder in an active state.

In one aspect, the invention provides a method for determining presence and/or elevation of anti-dsDNA antibodies in a subject, said method comprising comparing a first metric obtained by a method described herein for a sample obtained from the subject to a reference metric obtained from a reference (e.g., normal, healthy, non-diseased) sample, wherein a first metric that is higher than a reference metric indicates presence and/or elevation of anti-dsDNA antibodies in the subject.

In one embodiment, a reference metric is obtained using a method described herein for a sample from a control sample (e.g., as obtained from a healthy and/or non-diseased and/or untreated tissue, cell and/or subject).

The steps in the methods for examining expression of one or more biomarkers may be conducted in a variety of assay formats, including assays detecting mRNA expression (including but not limited to converting mRNA to cDNA, optionally followed by nucleic acid amplification), enzymatic assays detecting presence of enzymatic activity, and immunohistochemistry assays. Optionally, the tissue or cell sample comprises disease tissue or cells.

Still further methods of the invention include methods of treating a disorder in a mammal, such as an immune related disorder, comprising steps of obtaining tissue or a cell sample from the mammal, examining the tissue or cells for expression (e.g., amount of expression) of one or more biomarkers, and upon determining said tissue or cell sample expresses said one or more biomarkers (e.g., wherein the biomarkers are expressed in amounts greater than a reference (control) sample), administering an effective amount of a therapeutic agent to said mammal. The steps in the methods for examining expression of one or more biomarkers may be conducted in a variety of assay formats, including assays detecting mRNA expression, enzymatic assays detecting presence of enzymatic activity, and immunohistochemistry assays. Optionally, the methods comprise treating an autoimmune disorder in a mammal. Optionally, the methods comprise administering an effective amount of a targeted therapeutic agent (e.g., an antibody that binds and/or blocks activity of Type 1 interferons and/or their corresponding receptor(s)), and, optionally, a second therapeutic agent (e.g., steroids, etc.) to said mammal.

In some embodiments, biomarkers are selected from those listed in Tables 1, 2 and/or 3.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Alignment of a density plot of interferon-induced genes with a 2D hierarchical cluster heatmap of control and SLE patient samples shows a single region highly enriched in interferon-induced genes.

FIG. 2. IRGM scores from Active SLE patients are significantly higher than normal controls.

FIG. 3. Examples of SLE patients whose IRGM and anti-dsDNA levels are well correlated.

FIG. 4. Rho values of Spearman correlation of probes to the IRG signature reveal the extent of the region containing IRG signal.

FIG. 5. Three-gene combination versus 24-gene combination Pearson correlation illustrated as a histogram.

MODES FOR CARRYING OUT THE INVENTION

General Techniques

The practice of the present invention will employ, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry, and immunology, which are within the skill of the art. Such techniques are explained fully in the literature, such as, “Molecular Cloning: A Laboratory Manual”, second edition (Sambrook et al., 1989); “Oligonucleotide Synthesis” (M. J. Gait, ed., 1984); “Animal Cell Culture” (R. I. Freshney, ed., 1987); “Methods in Enzymology” (Academic Press, Inc.); “Current Protocols in Molecular Biology” (F. M. Ausubel et al., eds., 1987, and periodic updates); “PCR: The Polymerase Chain Reaction”, (Mullis et al., eds., 1994).

Primers, oligonucleotides and polynucleotides employed in the present invention can be generated using standard techniques known in the art.

Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Singleton et al., Dictionary of Microbiology and Molecular Biology 2nd ed., J. Wiley & Sons (New York, N.Y. 1994), and March, Advanced Organic Chemistry Reactions, Mechanisms and Structure 4th ed., John Wiley & Sons (New York, N.Y. 1992), provide one skilled in the art with a general guide to many of the terms used in the present application.

DEFINITIONS

The term “array” or “microarray”, as used herein refers to an ordered arrangement of hybridizable array elements, preferably polynucleotide probes (e.g., oligonucleotides), on a substrate. The substrate can be a solid substrate, such as a glass slide, or a semi-solid substrate, such as nitrocellulose membrane. The nucleotide sequences can be DNA, RNA, or any permutations thereof.

A “target sequence”, “target nucleic acid” or “target protein”, as used herein, is a polynucleotide sequence of interest, in which a mutation of the invention is suspected or known to reside, the detection of which is desired. Generally, a “template,” as used herein, is a polynucleotide that contains the target nucleotide sequence. In some instances, the terms “target sequence,” “template DNA,” “template polynucleotide,” “target nucleic acid,” “target polynucleotide,” and variations thereof, are used interchangeably.

“Amplification,” as used herein, generally refers to the process of producing multiple copies of a desired sequence. “Multiple copies” means at least 2 copies. A “copy” does not necessarily mean perfect sequence complementarity or identity to the template sequence. For example, copies can include nucleotide analogs such as deoxyinosine, intentional sequence alterations (such as sequence alterations introduced through a primer comprising a sequence that is hybridizable, but not complementary, to the template), and/or sequence errors that occur during amplification.

Expression/amount of a gene or biomarker in a first sample is at a level “greater than” the level in a second sample if the expression level/amount of the gene or biomarker in the first sample is at least about 1.5×, 1.75×, 2×, 3×, 4×, 5×, 6×, 7×, 8×, 9× or 10× the expression level/amount of the gene or biomarker in the second sample. Expression levels/amounts can be determined based on any suitable criterion known in the art, including but not limited to mRNA, cDNA, proteins, protein fragments and/or gene copy. Expression levels/amounts can be determined qualitatively and/or quantitatively.

“Polynucleotide,” or “nucleic acid,” as used interchangeably herein, refer to polymers of nucleotides of any length, and include DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and/or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and their analogs. If present, modification to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component. Other types of modifications include, for example, “caps”, substitution of one or more of the naturally occurring nucleotides with an analog, internucleotide modifications such as, for example, those with uncharged linkages (e.g., methyl phosphonates, phosphotriesters, phosphoamidates, cabamates, etc.) and with charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.), those containing pendant moieties, such as, for example, proteins (e.g., nucleases, toxins, antibodies, signal peptides, ply-L-lysine, etc.), those with intercalators (e.g., acridine, psoralen, etc.), those containing chelators (e.g., metals, radioactive metals, boron, oxidative metals, etc.), those containing alkylators, those with modified linkages (e.g., alpha anomeric nucleic acids, etc.), as well as unmodified forms of the polynucleotide(s). Further, any of the hydroxyl groups ordinarily present in the sugars may be replaced, for example, by phosphonate groups, phosphate groups, protected by standard protecting groups, or activated to prepare additional linkages to additional nucleotides, or may be conjugated to solid supports. The 5′ and 3′ terminal OH can be phosphorylated or substituted with amines or organic capping groups moieties of from 1 to 20 carbon atoms. Other hydroxyls may also be derivatized to standard protecting groups. Polynucleotides can also contain analogous forms of ribose or deoxyribose sugars that are generally known in the art, including, for example, 2′-O-methyl-2′-O— allyl, 2′-fluoro- or 2′-azido-ribose, carbocyclic sugar analogs, α-anomeric sugars, epimeric sugars such as arabinose, xyloses or lyxoses, pyranose sugars, furanose sugars, sedoheptuloses, acyclic analogs and abasic nucleoside analogs such as methyl riboside. One or more phosphodiester linkages may be replaced by alternative linking groups. These alternative linking groups include, but are not limited to, embodiments wherein phosphate is replaced by P(O)S(“thioate”), P(S)S (“dithioate”), “(O)NR 2 (“amidate”), P(O)R, P(O)OR′, CO or CH 2 (“formacetal”), in which each R or R′ is independently H or substituted or unsubstituted alkyl (1-20 C) optionally containing an ether (—O—) linkage, aryl, alkenyl, cycloalkyl, cycloalkenyl or araldyl. Not all linkages in a polynucleotide need be identical. The preceding description applies to all polynucleotides referred to herein, including RNA and DNA.

“Oligonucleotide,” as used herein, generally refers to short, generally single stranded, generally synthetic polynucleotides that are generally, but not necessarily, less than about 200 nucleotides in length. The terms “oligonucleotide” and “polynucleotide” are not mutually exclusive. The description above for polynucleotides is equally and fully applicable to oligonucleotides.

A “primer” is generally a short single stranded polynucleotide, generally with a free 3′-OH group, that binds to a target potentially present in a sample of interest by hybridizing with a target sequence, and thereafter promotes polymerization of a polynucleotide complementary to the target.

The phrase “gene amplification” refers to a process by which multiple copies of a gene or gene fragment are formed in a particular cell or cell line. The duplicated region (a stretch of amplified DNA) is often referred to as “amplicon.” Usually, the amount of the messenger RNA (mRNA) produced, i.e., the level of gene expression, also increases in the proportion of the number of copies made of the particular gene expressed.

The term “mutation”, as used herein, means a difference in the amino acid or nucleic acid sequence of a particular protein or nucleic acid (gene, RNA) relative to the wild-type protein or nucleic acid, respectively. A mutated protein or nucleic acid can be expressed from or found on one allele (heterozygous) or both alleles (homozygous) of a gene, and may be somatic or germ line.

To “inhibit” is to decrease or reduce an activity, function, and/or amount as compared to a reference.

The term “3′” generally refers to a region or position in a polynucleotide or oligonucleotide 3′ (downstream) from another region or position in the same polynucleotide or oligonucleotide. The term “5′” . . . generally refers to a region or position in a polynucleotide or oligonucleotide 5′ (upstream) from another region or position in the same polynucleotide or oligonucleotide.

“Detection” includes any means of detecting, including direct and indirect detection.

The term “diagnosis” is used herein to refer to the identification of a molecular or pathological state, disease or condition, such as the identification of an autoimmune disorder. The term “prognosis” is used herein to refer to the prediction of the likelihood of autoimmune disorder-attributable disease symptoms, including, for example, recurrence, flaring, and drug resistance, of an autoimmune disease. The term “prediction” is used herein to refer to the likelihood that a patient will respond either favorably or unfavorably to a drug or set of drugs. In one embodiment, the prediction relates to the extent of those responses. In one embodiment, the prediction relates to whether and/or the probability that a patient will survive or improve following treatment, for example treatment with a particular therapeutic agent, and for a certain period of time without disease recurrence. The predictive methods of the invention can be used clinically to make treatment decisions by choosing the most appropriate treatment modalities for any particular patient. The predictive methods of the present invention are valuable tools in predicting if a patient is likely to respond favorably to a treatment regimen, such as a given therapeutic regimen, including for example, administration of a given therapeutic agent or combination, surgical intervention, steroid treatment, etc., or whether long-term survival of the patient, following a therapeutic regimen is likely.

The term “long-term” survival is used herein to refer to survival for at least 1 year, 5 years, 8 years, or 10 years following therapeutic treatment.

The term “increased resistance” to a particular therapeutic agent or treatment option, when used in accordance with the invention, means decreased response to a standard dose of the drug or to a standard treatment protocol.

The term “decreased sensitivity” to a particular therapeutic agent or treatment option, when used in accordance with the invention, means decreased response to a standard dose of the agent or to a standard treatment protocol, where decreased response can be compensated for (at least partially) by increasing the dose of agent, or the intensity of treatment.

“Patient response” can be assessed using any endpoint indicating a benefit to the patient, including, without limitation, (1) inhibition, to some extent, of disease progression, including slowing down and complete arrest; (2) reduction in the number of disease episodes and/or symptoms; (3) reduction in lesional size; (4) inhibition (i.e., reduction, slowing down or complete stopping) of disease cell infiltration into adjacent peripheral organs and/or tissues; (5) inhibition (i.e. reduction, slowing down or complete stopping) of disease spread; (6) decrease of auto-immune response, which may, but does not have to, result in the regression or ablation of the disease lesion; (7) relief, to some extent, of one or more symptoms associated with the disorder; (8) increase in the length of disease-free presentation following treatment; and/or (9) decreased mortality at a given point of time following treatment.

The term “interferon inhibitor” as used herein refers to a molecule having the ability to inhibit a biological function of wild type or mutated Type 1 interferon. Accordingly, the term “inhibitor” is defined in the context of the biological role of Type 1 interferon. In one embodiment, an interferon inhibitor referred to herein specifically inhibits cell signaling via the Type 1 interferon/interferon receptor pathway. For example, an interferon inhibitor may interact with (e.g. bind to) interferon alpha receptor, or with a Type 1 interferon which normally binds to interferon receptor. In one embodiment, an interferon inhibitor binds to the extracellular domain of interferon alpha receptor. In one embodiment, an interferon inhibitor binds to the intracellular domain of interferon alpha receptor. In one embodiment, an interferon inhibitor binds to Type 1 interferon. In one embodiment, the Type 1 interferon is an interferon alpha subtype. In one embodiment, the Type 1 interferon is not interferon beta. In one embodiment, the Type 1 interferon is not interferon omega. In one embodiment, interferon biological activity inhibited by an interferon inhibitor is associated with an immune disorder, such as an autoimmune disorder. An interferon inhibitor can be in any form, so long as it is capable of inhibiting interferon/receptor activity; inhibitors include antibodies (e.g., monoclonal antibodies as defined hereinbelow), small organic/inorganic molecules, antisense oligonucleotides, aptamers, inhibitory peptides/polypeptides, inhibitory RNAs (e.g., small interfering RNAs), combinations thereof, etc.

“Antibodies” (Abs) and “immunoglobulins” (Igs) are glycoproteins having the same structural characteristics. While antibodies exhibit binding specificity to a specific antigen, immunoglobulins include both antibodies and other antibody-like molecules which generally lack antigen specificity. Polypeptides of the latter kind are, for example, produced at low levels by the lymph system and at increased levels by myelomas.

The terms “antibody” and “immunoglobulin” are used interchangeably in the broadest sense and include monoclonal antibodies (e.g., full length or intact monoclonal antibodies), polyclonal antibodies, monovalent, multivalent antibodies, multispecific antibodies (e.g., bispecific antibodies so long as they exhibit the desired biological activity) and may also include certain antibody fragments (as described in greater detail herein). An antibody can be chimeric, human, humanized and/or affinity matured.

“Antibody fragments” comprise only a portion of an intact antibody, wherein the portion preferably retains at least one, preferably most or all, of the functions normally associated with that portion when present in an intact antibody. In one embodiment, an antibody fragment comprises an antigen binding site of the intact antibody and thus retains the ability to bind antigen. In another embodiment, an antibody fragment, for example one that comprises the Fc region, retains at least one of the biological functions normally associated with the Fc region when present in an intact antibody, such as FcRn binding, antibody half life modulation, ADCC function and complement binding. In one embodiment, an antibody fragment is a monovalent antibody that has an in vivo half life substantially similar to an intact antibody. For example, such an antibody fragment may comprise on antigen binding arm linked to an Fc sequence capable of conferring in vivo stability to the fragment.

The term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigen. Furthermore, in contrast to polyclonal antibody preparations that typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen.

The monoclonal antibodies herein specifically include “chimeric” antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Pat. No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA 81:6851-6855 (1984)).

“Humanized” forms of non-human (e.g., murine) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or nonhuman primate having the desired specificity, affinity, and capacity. In some instances, framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin sequence. The humanized antibody optionally will also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992). See also the following review articles and references cited therein: Vaswani and Hamilton, Ann. Allergy, Asthma &Immunol. 1:105-115 (1998); Harris, Biochem. Soc. Transactions 23:1035-1038 (1995); Hurle and Gross, Curr. Op. Biotech. 5:428-433 (1994).

A “human antibody” is one which possesses an amino acid sequence which corresponds to that of an antibody produced by a human and/or has been made using any of the techniques for making human antibodies as disclosed herein. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues.

An “affinity matured” antibody is one with one or more alterations in one or more CDRs/HVRs thereof which result in an improvement in the affinity of the antibody for antigen, compared to a parent antibody which does not possess those alteration(s). Preferred affinity matured antibodies will have nanomolar or even picomolar affinities for the target antigen. Affinity matured antibodies are produced by procedures known in the art. Marks et al. Bio/Technology 10:779-783 (1992) describes affinity maturation by VH and VL domain shuffling. Random mutagenesis of CDR/HVR and/or framework residues is described by: Barbas et al. Proc Nat. Acad. Sci, USA 91:3809-3813 (1994); Schier et al. Gene 169:147-155 (1995); Yelton et al. J. Immunol. 155:1994-2004 (1995); Jackson et al., J. Immunol. 154(7):3310-9 (1995); and Hawkins et al, J. Mol. Biol. 226:889-896 (1992).

The term “Fc region” is used to define the C-terminal region of an immunoglobulin heavy chain which may be generated by papain digestion of an intact antibody. The Fc region may be a native sequence Fc region or a variant Fc region. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is usually defined to stretch from an amino acid residue at about position Cys226, or from about position Pro230, to the carboxyl-terminus of the Fc region. The Fc region of an immunoglobulin generally comprises two constant domains, a CH2 domain and a CH3 domain, and optionally comprises a CH4 domain. By “Fc region chain” herein is meant one of the two polypeptide chains of an Fc region.

The term “cytotoxic agent” as used herein refers to a substance that inhibits or prevents the function of cells and/or causes destruction of cells. The term is intended to include radioactive isotopes (e.g. At211, I131, I125, Y90, Re186, Re188, Sm153, Bi212, P32 and radioactive isotopes of Lu), chemotherapeutic agents, and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof.

A “blocking” antibody or an “antagonist” antibody is one which inhibits or reduces biological activity of the antigen it binds. Such blocking can occur by any means, e.g. by interfering with protein-protein interaction such as ligand binding to a receptor. In on embodiment, blocking antibodies or antagonist antibodies substantially or completely inhibit the biological activity of the antigen.

An “autoimmune disease” herein is a non-malignant disease or disorder arising from and directed against an individual's own tissues. The autoimmune diseases herein specifically exclude malignant or cancerous diseases or conditions, especially excluding B cell lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hairy cell leukemia and chronic myeloblastic leukemia. Examples of autoimmune diseases or disorders include, but are not limited to, inflammatory responses such as inflammatory skin diseases including psoriasis and dermatitis (e.g. atopic dermatitis); systemic scleroderma and sclerosis; responses associated with inflammatory bowel disease (such as Crohn's disease and ulcerative colitis); respiratory distress syndrome (including adult respiratory distress syndrome; ARDS); dermatitis; meningitis; encephalitis; uveitis; colitis; glomerulonephritis; allergic conditions such as eczema and asthma and other conditions involving infiltration of T cells and chronic inflammatory responses; atherosclerosis; leukocyte adhesion deficiency; rheumatoid arthritis; systemic lupus erythematosus (SLE) (including but not limited to lupus nephritis, cutaneous lupus); diabetes mellitus (e.g. Type I diabetes mellitus or insulin dependent diabetes mellitis); multiple sclerosis; Reynaud's syndrome; autoimmune thyroiditis; Hashimoto's thyroiditis; allergic encephalomyelitis; Sjogren's syndrome; juvenile onset diabetes; and immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T-lymphocytes typically found in tuberculosis, sarcoidosis, polymyositis, granulomatosis and vasculitis; pernicious anemia (Addison's disease); diseases involving leukocyte diapedesis; central nervous system (CNS) inflammatory disorder; multiple organ injury syndrome; hemolytic anemia (including, but not limited to cryoglobinemia or Coombs positive anemia); myasthenia gravis; antigen-antibody complex mediated diseases; anti-glomerular basement membrane disease; antiphospholipid syndrome; allergic neuritis; Graves' disease; Lambert-Eaton myasthenic syndrome; pemphigoid bullous; pemphigus; autoimmune polyendocrinopathies; Reiter's disease; stiff-man syndrome; Behcet disease; giant cell arteritis; immune complex nephritis; IgA nephropathy; IgM polyneuropathies; immune thrombocytopenic purpura (YIP) or autoimmune thrombocytopenia etc.

As used herein, “treatment” refers to clinical intervention in an attempt to alter the natural course of the individual or cell being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. In some embodiments, methods and compositions of the invention are useful in attempts to delay development of a disease or disorder.

An “effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result. A “therapeutically effective amount” of a therapeutic agent may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the antibody to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the therapeutic agent are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically but not necessarily, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.

As used herein, the terms “type I interferon” and “human type I interferon” are defined as all species of native human and synthetic interferon which fall within the human and synthetic interferon-α, interferon-ω and interferon-β classes and which bind to a common cellular receptor. Natural human interferon-α comprises 23 or more closely related proteins encoded by distinct genes with a high degree of structural homology (Weissmann and Weber, Prog. Nucl. Acid. Res. Mol. Biol., 33: 251 (1986); J. Interferon Res., 13: 443-444 (1993)). The human IFN-α locus comprises two subfamilies. The first subfamily consists of at least 14 functional, non-allelic genes, including genes encoding IFN-αA (IFN-α2), IFN-αB (IFN-α8), IFN-α (IFN-α10), IFN-αD (IFN-α1), IFN-αE (IFN-α22), IFN-αF (IFN-α21), IFN-αG (IFN-α5), IFN-α16, IFN-α17, IFN-α4, IFN-α6, IFN-α7, and IFN-αH (IFN-α14), and pseudogenes having at least 80% homology. The second subfamily, αII or ω, contains at least 5 pseudogenes and 1 functional gene (denoted herein as “IFN-αII1” or “IFN-ω”) which exhibits 70% homology with the IFN-α genes (Weissmann and Weber (1986)). The human IFN-β is generally thought to be encoded by a single copy gene.

As used herein, the terms “first human interferon-α (hIFN-α) receptor”, “IFN-αR”, “hIFNAR1”, “IFNAR1”, and “Uze chain” are defined as the 557 amino acid receptor protein cloned by Uze et al., Cell, 60: 225-234 (1990), including an extracellular domain of 409 residues, a transmembrane domain of 21 residues, and an intracellular domain of 100 residues, as shown in FIG. 5 on page 229 of Uze et al. In one embodiment, the foregoing terms include fragments of IFNAR1 that contain the extracellular domain (ECD) (or fragments of the ECD) of IFNAR1.

As used herein, the terms “second human interferon-α (hIFN-α) receptor”, “IFN-αβR”, “hIFNAR2”, “IFNAR2”, and “Novick chain” are defined as the 515 amino acid receptor protein cloned by Domanski et al., J. Biol. Chem., 37: 21606-21611 (1995), including an extracellular domain of 217 residues, a transmembrane domain of 21 residues, and an intracellular domain of 250 residues, as shown in FIG. 1 on page 21608 of Domanski et al. In one embodiment, the foregoing terms include fragments of IFNAR2 that contain the extracellular domain (ECD) (or fragments of the ECD) of IFNAR2, and soluble forms of IFNAR2, such as IFNAR2 ECD fused to at least a portion of an immunoglobulin sequence.

The term “housekeeping gene” refers to a group of genes that codes for proteins whose activities are essential for the maintenance of cell function. These genes are typically similarly expressed in all cell types. Housekeeping genes include, without limitation, ribosomal protein L19 (NP000972), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), Cypl, albumin, actins (e.g. β-actin), tubulins, cyclophilin, hypoxantine phosphoribosyltransferase (HRPT), ribosomal protein L32 (NP001007075), and ribosomal protein/genes 28S (e.g., Q9Y399) and 18S.

The term “biomarker” as used herein refers generally to a molecule, including a gene, protein, carbohydrate structure, or glycolipid, the expression of which in or on a mammalian tissue or cell can be detected by standard methods (or methods disclosed herein) and is predictive, diagnostic and/or prognostic for a mammalian cell's or tissue's sensitivity to treatment regimes based on inhibition of interferons, e.g. Type 1 interferons. Optionally, the expression of such a biomarker is determined to be higher than that observed for a control/reference tissue or cell sample. Optionally, for example, the expression of such a biomarker will be determined in a PCR or FACS assay to be at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, or preferably at least about 100-fold higher in the test tissue or cell sample than that observed for a control tissue or cell sample. Optionally, the expression of such a biomarker will be determined in an IHC assay to score at least 2 or higher for staining intensity. Optionally, the expression of such a biomarker will be determined using a gene chip-based assay.

An “IRG” or “interferon response gene” or “interferon responsive gene”, as used herein, refers to one or more of the genes, and corresponding gene products, listed in Table 1, 2, 3 and/or 4. As shown herein, aberrant expression levels/amounts of one or more of these genes are correlated with a variety of autoimmune disorders. As would be evident to one skilled in the art, depending on context, the term IRG can refer to nucleic acid (e.g., genes) or polypeptides (e.g., proteins) having the designation or unique identifier listed in Table 1, 2, 3 and/or 4.

The term “sample”, as used herein, refers to a composition that is obtained or derived from a subject of interest that contains a cellular and/or other molecular entity that is to be characterized and/or identified, for example based on physical, biochemical, chemical and/or physiological characteristics. For example, the phrase “disease sample” and variations thereof refers to any sample obtained from a subject of interest that would be expected or is known to contain the cellular and/or molecular entity that is to be characterized.

By “tissue or cell sample” is meant a collection of similar cells obtained from a tissue of a subject or patient. The source of the tissue or cell sample may be solid tissue as from a fresh, frozen and/or preserved organ or tissue sample or biopsy or aspirate; blood or any blood constituents; bodily fluids such as cerebral spinal fluid, amniotic fluid, peritoneal fluid, or interstitial fluid; cells from any time in gestation or development of the subject. The tissue sample may also be primary or cultured cells or cell lines. Optionally, the tissue or cell sample is obtained from a disease tissue/organ. The tissue sample may contain compounds which are not naturally intermixed with the tissue in nature such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics, or the like. A “reference sample”, “reference cell”, or “reference tissue”, as used herein, refers to a sample, cell or tissue obtained from a source known, or believed, not to be afflicted with the disease or condition for which a method or composition of the invention is being used to identify. In one embodiment, a reference sample, reference cell or reference tissue is obtained from a healthy part of the body of the same subject or patient in whom a disease or condition is being identified using a composition or method of the invention. In one embodiment, a reference sample, reference cell or reference tissue is obtained from a healthy part of the body of an individual who is not the subject or patient in whom a disease or condition is being identified using a composition or method of the invention.

For the purposes herein a “section” of a tissue sample is meant a single part or piece of a tissue sample, e.g. a thin slice of tissue or cells cut from a tissue sample. It is understood that multiple sections of tissue samples may be taken and subjected to analysis according to the present invention, provided that it is understood that the present invention comprises a method whereby the same section of tissue sample is analyzed at both morphological and molecular levels, or is analyzed with respect to both protein and nucleic acid.

By “correlate” or “correlating” is meant comparing, in any way, the performance and/or results of a first analysis or protocol with the performance and/or results of a second analysis or protocol. For example, one may use the results of a first analysis or protocol in carrying out a second protocols and/or one may use the results of a first analysis or protocol to determine whether a second analysis or protocol should be performed. With respect to the embodiment of gene expression analysis or protocol, one may use the results of the gene expression analysis or protocol to determine whether a specific therapeutic regimen should be performed.

The word “label” when used herein refers to a compound or composition which is conjugated or fused directly or indirectly to a reagent such as a nucleic acid probe or an antibody and facilitates detection of the reagent to which it is conjugated or fused. The label may itself be detectable (e.g., radioisotope labels or fluorescent labels) or, in the case of an enzymatic label, may catalyze chemical alteration of a substrate compound or composition which is detectable.

General Illustrative Techniques

A sample comprising a target molecule can be obtained by methods well known in the art, and that are appropriate for the particular type and location of the disease of interest. Tissue biopsy is often used to obtain a representative piece of disease tissue. Alternatively, cells can be obtained indirectly in the form of tissues/fluids that are known or thought to contain the disease cells of interest. For instance, samples of disease lesions may be obtained by resection, bronchoscopy, fine needle aspiration, bronchial brushings, or from sputum, pleural fluid or blood. Genes or gene products can be detected from disease tissue or from other body samples such as urine, sputum or serum. The same techniques discussed above for detection of target genes or gene products in disease samples can be applied to other body samples. Disease cells are sloughed off from disease lesions and appear in such body samples. By screening such body samples, a simple early diagnosis can be achieved for these diseases. In addition, the progress of therapy can be monitored more easily by testing such body samples for target genes or gene products.

In one embodiment, methods of the invention are useful for detecting any autoimmune disorder with which abnormal activation (e.g., overexpression) of interferons, in particular Type 1 interferons and/or their associated signaling pathway, is associated. The diagnostic methods of the present invention are useful for clinicians so that they can decide upon an appropriate course of treatment. For example, a sample from a subject displaying a high level of expression of the genes or gene products disclosed herein might suggest a more aggressive therapeutic regimen than a sample exhibiting a comparatively lower level of expression. Methods of the invention can be utilized in a variety of settings, including for example in aiding in patient selection during the course of drug development, prediction of likelihood of success when treating an individual patient with a particular treatment regimen, in assessing disease progression, in monitoring treatment efficacy, in determining prognosis for individual patients, in assessing predisposition of an individual to develop a particular autoimmune disorder (e.g., systemic lupus erythematosus, Sjogren's syndrome), in differentiating disease staging, etc.

Means for enriching a tissue preparation for disease cells are known in the art. For example, the tissue may be isolated from paraffin or cryostat sections. Disease cells may also be separated from normal cells by flow cytometry or laser capture microdissection. These, as well as other techniques for separating disease from normal cells, are well known in the art. If the disease tissue is highly contaminated with normal cells, detection of signature gene expression profile may be more difficult, although techniques for minimizing contamination and/or false positive/negative results are known, some of which are described hereinbelow. For example, a sample may also be assessed for the presence of a biomarker (including a mutation) known to be associated with a disease cell of interest but not a corresponding normal cell, or vice versa.

The invention also provides a variety of compositions suitable for use in performing methods of the invention. For example, the invention provides arrays that can be used in such methods. In one embodiment, an array of the invention comprises individual or collections of nucleic acid molecules useful for detecting mutations of the invention. For instance, an array of the invention may comprises a series of discretely placed individual nucleic acid oligonucleotides or sets of nucleic acid oligonucleotide combinations that are hybridizable to a sample comprising target nucleic acids, whereby such hybridization is indicative of presence or absence of a mutation of the invention.

Several techniques are well-known in the art for attaching nucleic acids to a solid substrate such as a glass slide. One method is to incorporate modified bases or analogs that contain a moiety that is capable of attachment to a solid substrate, such as an amine group, a derivative of an amine group or another group with a positive charge, into nucleic acid molecules that are synthesized. The synthesized product is then contacted with a solid substrate, such as a glass slide, which is coated with an aldehyde or another reactive group which will form a covalent link with the reactive group that is on the amplified product and become covalently attached to the glass slide. Other methods, such as those using amino propryl silican surface chemistry are also known in the art, as disclosed at http://www.cmt.corning.com and http://cmgm.stanford.edu/pbrown1.

Attachment of groups to oligonucleotides which could be later converted to reactive groups is also possible using methods known in the art. Any attachment to nucleotides of oligonucleotides will become part of oligonucleotide, which could then be attached to the solid surface of the microarray.

Amplified nucleic acids can be further modified, such as through cleavage into fragments or by attachment of detectable labels, prior to or following attachment to the solid substrate, as required and/or permitted by the techniques used.

Typical Methods and Materials of the Invention

The methods and assays disclosed herein are directed to the examination of expression of one or more biomarkers in a mammalian tissue or cell sample, wherein the determination of that expression of one or more such biomarkers is predictive or indicative of whether the tissue or cell sample will be sensitive to treatment based on the use of interferon inhibitors. The methods and assays include those which examine expression of biomarkers such as one or more of those listed in Table 1, 2 and/or 3.

As discussed above, there are some populations of diseased human cell types that are associated with abnormal expression of interferons such as the Type 1 interferons which is associated with various autoimmune disorders. It is therefore believed that the disclosed methods and assays can provide for convenient, efficient, and potentially cost-effective means to obtain data and information useful in assessing appropriate or effective therapies for treating patients. For example, a patient having been diagnosed with an immune related condition could have a biopsy performed to obtain a tissue or cell sample, and the sample could be examined by way of various in vitro assays to determine whether the patient's cells would be sensitive to a therapeutic agent such as an interferon inhibitor (e.g., an anti-interferon alpha antibody or an antibody to interferon alpha receptor).

The invention provides methods for predicting the sensitivity of a mammalian tissue or cells sample (such as a cell associated with an autoimmune disorder) to an interferon inhibitor. In the methods, a mammalian tissue or cell sample is obtained and examined for expression of one or more biomarkers. The methods may be conducted in a variety of assay formats, including assays detecting mRNA expression, enzymatic assays detecting presence of enzymatic activity, and immunohistochemistry assays. Determination of expression of such biomarkers in said tissues or cells will be predictive that such tissues or cells will be sensitive to the interferon inhibitor therapy. Applicants surprisingly found that the expression of such particular biomarkers correlates closely with presence and/or extent of various autoimmune disorders.

As discussed below, expression of various biomarkers in a sample can be analyzed by a number of methodologies, many of which are known in the art and understood by the skilled artisan, including but not limited to, immunohistochemical and/or Western analysis, quantitative blood based assays (as for example Serum ELISA) (to examine, for example, levels of protein expression), biochemical enzymatic activity assays, in situ hybridization, Northern analysis and/or PCR analysis of mRNAs, as well as any one of the wide variety of assays that can be performed by gene and/or tissue array analysis. Typical protocols for evaluating the status of genes and gene products are found, for example in Ausubel et al. eds., 1995, Current Protocols In Molecular Biology, Units 2 (Northern Blotting), 4 (Southern Blotting), 15 (Immunoblotting) and 18 (PCR Analysis).

The protocols below relating to detection of particular biomarkers, such as those listed in Table 1, 2 and/or 3, in a sample are provided for illustrative purposes.

Optional methods of the invention include protocols which examine or test for presence of IRG in a mammalian tissue or cell sample. A variety of methods for detecting IRG can be employed and include, for example, immunohistochemical analysis, immunoprecipitation, Western blot analysis, molecular binding assays, ELISA, ELIFA, fluorescence activated cell sorting (FACS) and the like. For example, an optional method of detecting the expression of IRG in a tissue or sample comprises contacting the sample with a IRG antibody, a IRG-reactive fragment thereof, or a recombinant protein containing an antigen binding region of a IRG antibody; and then detecting the binding of IRG protein in the sample.

In particular embodiments of the invention, the expression of IRG proteins in a sample is examined using immunohistochemistry and staining protocols. Immunohistochemical staining of tissue sections has been shown to be a reliable method of assessing or detecting presence of proteins in a sample. Immunohistochemistry (“IHC”) techniques utilize an antibody to probe and visualize cellular antigens in situ, generally by chromogenic or fluorescent methods.

For sample preparation, a tissue or cell sample from a mammal (typically a human patient) may be used. Examples of samples include, but are not limited to, tissue biopsy, blood, lung aspirate, sputum, lymph fluid, etc. The sample can be obtained by a variety of procedures known in the art including, but not limited to surgical excision, aspiration or biopsy. The tissue may be fresh or frozen. In one embodiment, the sample is fixed and embedded in paraffin or the like.

The tissue sample may be fixed (i.e. preserved) by conventional methodology (See e.g., “Manual of Histological Staining Method of the Armed Forces Institute of Pathology,” 3rd edition (1960) Lee G. Luna, HT (ASCP) Editor, The Blakston Division McGraw-Hill Book Company, New York; The Armed Forces Institute of Pathology Advanced Laboratory Methods in Histology and Pathology (1994) Ulreka V. Mikel, Editor, Armed Forces Institute of Pathology, American Registry of Pathology, Washington, D.C.). One of skill in the art will appreciate that the choice of a fixative is determined by the purpose for which the sample is to be histologically stained or otherwise analyzed. One of skill in the art will also appreciate that the length of fixation depends upon the size of the tissue sample and the fixative used. By way of example, neutral buffered formalin, Bouin's or paraformaldehyde, may be used to fix a sample.

Generally, the sample is first fixed and is then dehydrated through an ascending series of alcohols, infiltrated and embedded with paraffin or other sectioning media so that the tissue sample may be sectioned. Alternatively, one may section the tissue and fix the sections obtained. By way of example, the tissue sample may be embedded and processed in paraffin by conventional methodology (See e.g., “Manual of Histological Staining Method of the Armed Forces Institute of Pathology”, supra). Examples of paraffin that may be used include, but are not limited to, Paraplast, Broloid, and Tissuemay. Once the tissue sample is embedded, the sample may be sectioned by a microtome or the like (See e.g., “Manual of Histological Staining Method of the Armed Forces Institute of Pathology”, supra). By way of example for this procedure, sections may range from about three microns to about five microns in thickness. Once sectioned, the sections may be attached to slides by several standard methods. Examples of slide adhesives include, but are not limited to, silane, gelatin, poly-L-lysine and the like. By way of example, the paraffin embedded sections may be attached to positively charged slides and/or slides coated with poly-L-lysine.

If paraffin has been used as the embedding material, the tissue sections are generally deparaffinized and rehydrated to water. The tissue sections may be deparaffinized by several conventional standard methodologies. For example, xylenes and a gradually descending series of alcohols may be used (See e.g., “Manual of Histological Staining Method of the Armed Forces Institute of Pathology”, supra). Alternatively, commercially available deparaffinizing non-organic agents such as Hemo-De7 (CMS, Houston, Tex.) may be used.

Optionally, subsequent to the sample preparation, a tissue section may be analyzed using IHC. IHC may be performed in combination with additional techniques such as morphological staining and/or fluorescence in-situ hybridization. Two general methods of IHC are available; direct and indirect assays. According to the first assay, binding of antibody to the target antigen (e.g., an IRG) is determined directly. This direct assay uses a labeled reagent, such as a fluorescent tag or an enzyme-labeled primary antibody, which can be visualized without further antibody interaction. In a typical indirect assay, unconjugated primary antibody binds to the antigen and then a labeled secondary antibody binds to the primary antibody. Where the secondary antibody is conjugated to an enzymatic label, a chromogenic or fluorogenic substrate is added to provide visualization of the antigen. Signal amplification occurs because several secondary antibodies may react with different epitopes on the primary antibody.

The primary and/or secondary antibody used for immunohistochemistry typically will be labeled with a detectable moiety. Numerous labels are available which can be generally grouped into the following categories:

(a) Radioisotopes, such as 35S, 14C, 125I, 3H, and 131I. The antibody can be labeled with the radioisotope using the techniques described in Current Protocols in Immunology, Volumes 1 and 2, Coligen et al., Ed. Wiley-Interscience, New York, N.Y., Pubs. (1991) for example and radioactivity can be measured using scintillation counting.

(b) Colloidal gold particles.

(c) Fluorescent labels including, but are not limited to, rare earth chelates (europium chelates), Texas Red, rhodamine, fluorescein, dansyl, Lissamine, umbelliferone, phycocrytherin, phycocyanin, or commercially available fluorophores such SPECTRUM ORANGE7 and SPECTRUM GREEN7 and/or derivatives of any one or more of the above. The fluorescent labels can be conjugated to the antibody using the techniques disclosed in Current Protocols in Immunology, supra, for example. Fluorescence can be quantified using a fluorimeter.

(d) Various enzyme-substrate labels are available and U.S. Pat. No. 4,275,149 provides a review of some of these. The enzyme generally catalyzes a chemical alteration of the chromogenic substrate that can be measured using various techniques. For example, the enzyme may catalyze a color change in a substrate, which can be measured spectrophotometrically. Alternatively, the enzyme may alter the fluorescence or chemiluminescence of the substrate. Techniques for quantifying a change in fluorescence are described above. The chemiluminescent substrate becomes electronically excited by a chemical reaction and may then emit light which can be measured (using a chemiluminometer, for example) or donates energy to a fluorescent acceptor. Examples of enzymatic labels include luciferases (e.g., firefly luciferase and bacterial luciferase; U.S. Pat. No. 4,737,456), luciferin, 2,3-dihydrophthalazinediones, malate dehydrogenase, urease, peroxidase such as horseradish peroxidase (HRPO), alkaline phosphatase, β-galactosidase, glucoamylase, lysozyme, saccharide oxidases (e.g., glucose oxidase, galactose oxidase, and glucose-6-phosphate dehydrogenase), heterocyclic oxidases (such as uricase and xanthine oxidase), lactoperoxidase, microperoxidase, and the like. Techniques for conjugating enzymes to antibodies are described in O'Sullivan et al., Methods for the Preparation of Enzyme-Antibody Conjugates for use in Enzyme Immunoassay, in Methods in Enzym. (ed. J. Langone & H. Van Vunakis), Academic press, New York, 73:147-166 (1981).

Examples of enzyme-substrate combinations include, for example:

(i) Horseradish peroxidase (HRPO) with hydrogen peroxidase as a substrate, wherein the hydrogen peroxidase oxidizes a dye precursor (e.g., orthophenylene diamine (OPD) or 3,3′,5,5′-tetramethyl benzidine hydrochloride (TMB));

(ii) alkaline phosphatase (AP) with para-Nitrophenyl phosphate as chromogenic substrate; and

(iii) β-D-galactosidase (β-D-Gal) with a chromogenic substrate (e.g., p-nitrophenyl-β-D-galactosidase) or fluorogenic substrate (e.g., 4-methylumbelliferyl-β-D-galactosidase).

Numerous other enzyme-substrate combinations are available to those skilled in the art. For a general review of these, see U.S. Pat. Nos. 4,275,149 and 4,318,980. Sometimes, the label is indirectly conjugated with the antibody. The skilled artisan will be aware of various techniques for achieving this. For example, the antibody can be conjugated with biotin and any of the four broad categories of labels mentioned above can be conjugated with avidin, or vice versa. Biotin binds selectively to avidin and thus, the label can be conjugated with the antibody in this indirect manner. Alternatively, to achieve indirect conjugation of the label with the antibody, the antibody is conjugated with a small hapten and one of the different types of labels mentioned above is conjugated with an anti-hapten antibody. Thus, indirect conjugation of the label with the antibody can be achieved.

Aside from the sample preparation procedures discussed above, further treatment of the tissue section prior to, during or following IHC may be desired. For example, epitope retrieval methods, such as heating the tissue sample in citrate buffer may be carried out (see, e.g., Leong et al. Appl. Immunohistochem. 4(3):201 (1996)).

Following an optional blocking step, the tissue section is exposed to primary antibody for a sufficient period of time and under suitable conditions such that the primary antibody binds to the target protein antigen in the tissue sample. Appropriate conditions for achieving this can be determined by routine experimentation. The extent of binding of antibody to the sample is determined by using any one of the detectable labels discussed above. Preferably, the label is an enzymatic label (e.g. HRPO) which catalyzes a chemical alteration of the chromogenic substrate such as 3,3′-diaminobenzidine chromogen. Preferably the enzymatic label is conjugated to antibody which binds specifically to the primary antibody (e.g. the primary antibody is rabbit polyclonal antibody and secondary antibody is goat anti-rabbit antibody).

Optionally, the antibodies employed in the IHC analysis to detect expression of an IRG are antibodies generated to bind primarily to the IRG of interest. Optionally, the anti-IRG antibody is a monoclonal antibody. Anti-IRG antibodies are readily available in the art, including from various commercial sources, and can also be generated using routine skills known in the art.

Specimens thus prepared may be mounted and coverslipped. Slide evaluation is then determined, e.g. using a microscope, and staining intensity criteria, routinely used in the art, may be employed. As one example, staining intensity criteria may be evaluated as follows:

TABLE A
Staining PatternScore
No staining is observed in cells.0  
Faint/barely perceptible staining is detected in more than 10% of1+
the cells.
Weak to moderate staining is observed in more than 10% of the2+
cells.
Moderate to strong staining is observed in more than 10% of the3+
cells.

In alternative methods, the sample may be contacted with an antibody specific for said biomarker under conditions sufficient for an antibody-biomarker complex to form, and then detecting said complex. The presence of the biomarker may be detected in a number of ways, such as by Western blotting and ELISA procedures for assaying a wide variety of tissues and samples, including plasma or serum. A wide range of immunoassay techniques using such an assay format are available, see, e.g., U.S. Pat. Nos. 4,016,043, 4,424,279 and 4,018,653. These include both single-site and two-site or “sandwich” assays of the non-competitive types, as well as in the traditional competitive binding assays. These assays also include direct binding of a labelled antibody to a target biomarker.

Sandwich assays are among the most useful and commonly used assays. A number of variations of the sandwich assay technique exist, and all are intended to be encompassed by the present invention. Briefly, in a typical forward assay, an unlabelled antibody is immobilized on a solid substrate, and the sample to be tested brought into contact with the bound molecule. After a suitable period of incubation, for a period of time sufficient to allow formation of an antibody-antigen complex, a second antibody specific to the antigen, labelled with a reporter molecule capable of producing a detectable signal is then added and incubated, allowing time sufficient for the formation of another complex of antibody-antigen-labelled antibody. Any unreacted material is washed away, and the presence of the antigen is determined by observation of a signal produced by the reporter molecule. The results may either be qualitative, by simple observation of the visible signal, or may be quantitated by comparing with a control sample containing known amounts of biomarker.

Variations on the forward assay include a simultaneous assay, in which both sample and labelled antibody are added simultaneously to the bound antibody. These techniques are well known to those skilled in the art, including any minor variations as will be readily apparent. In a typical forward sandwich assay, a first antibody having specificity for the biomarker is either covalently or passively bound to a solid surface. The solid surface is typically glass or a polymer, the most commonly used polymers being cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride or polypropylene. The solid supports may be in the form of tubes, beads, discs of microplates, or any other surface suitable for conducting an immunoassay. The binding processes are well-known in the art and generally consist of cross-linking covalently binding or physically adsorbing, the polymer-antibody complex is washed in preparation for the test sample. An aliquot of the sample to be tested is then added to the solid phase complex and incubated for a period of time sufficient (e.g. 2-40 minutes or overnight if more convenient) and under suitable conditions (e.g. from room temperature to 40° C. such as between 25° C. and 32° C. inclusive) to allow binding of any subunit present in the antibody. Following the incubation period, the antibody subunit solid phase is washed and dried and incubated with a second antibody specific for a portion of the biomarker. The second antibody is linked to a reporter molecule which is used to indicate the binding of the second antibody to the molecular marker.

An alternative method involves immobilizing the target biomarkers in the sample and then exposing the immobilized target to specific antibody which may or may not be labelled with a reporter molecule. Depending on the amount of target and the strength of the reporter molecule signal, a bound target may be detectable by direct labelling with the antibody. Alternatively, a second labelled antibody, specific to the first antibody is exposed to the target-first antibody complex to form a target-first antibody-second antibody tertiary complex. The complex is detected by the signal emitted by the reporter molecule. By “reporter molecule”, as used in the present specification, is meant a molecule which, by its chemical nature, provides an analytically identifiable signal which allows the detection of antigen-bound antibody. The most commonly used reporter molecules in this type of assay are either enzymes, fluorophores or radionuclide containing molecules (i.e. radioisotopes) and chemiluminescent molecules.

In the case of an enzyme immunoassay, an enzyme is conjugated to the second antibody, generally by means of glutaraldehyde or periodate. As will be readily recognized, however, a wide variety of different conjugation techniques exist, which are readily available to the skilled artisan. Commonly used enzymes include horseradish peroxidase, glucose oxidase, -galactosidase and alkaline phosphatase, amongst others. The substrates to be used with the specific enzymes are generally chosen for the production, upon hydrolysis by the corresponding enzyme, of a detectable color change. Examples of suitable enzymes include alkaline phosphatase and peroxidase. It is also possible to employ fluorogenic substrates, which yield a fluorescent product rather than the chromogenic substrates noted above. In all cases, the enzyme-labelled antibody is added to the first antibody-molecular marker complex, allowed to bind, and then the excess reagent is washed away. A solution containing the appropriate substrate is then added to the complex of antibody-antigen-antibody. The substrate will react with the enzyme linked to the second antibody, giving a qualitative visual signal, which may be further quantitated, usually spectrophotometrically, to give an indication of the amount of biomarker which was present in the sample. Alternately, fluorescent compounds, such as fluorescein and rhodamine, may be chemically coupled to antibodies without altering their binding capacity. When activated by illumination with light of a particular wavelength, the fluorochrome-labelled antibody adsorbs the light energy, inducing a state to excitability in the molecule, followed by emission of the light at a characteristic color visually detectable with a light microscope. As in the EIA, the fluorescent labelled antibody is allowed to bind to the first antibody-molecular marker complex. After washing off the unbound reagent, the remaining tertiary complex is then exposed to the light of the appropriate wavelength, the fluorescence observed indicates the presence of the molecular marker of interest. Immunofluorescence and EIA techniques are both very well established in the art. However, other reporter molecules, such as radioisotope, chemiluminescent or bioluminescent molecules, may also be employed.

It is contemplated that the above described techniques may also be employed to detect expression of IRG.

Methods of the invention further include protocols which examine the presence and/or expression of mRNAs, such as IRG mRNAs, in a tissue or cell sample. Methods for the evaluation of mRNAs in cells are well known and include, for example, hybridization assays using complementary DNA probes (such as in situ hybridization using labeled IRG riboprobes, Northern blot and related techniques) and various nucleic acid amplification assays (such as RT-PCR using complementary primers specific for IRG, and other amplification type detection methods, such as, for example, branched DNA, SISBA, TMA and the like).

Tissue or cell samples from mammals can be conveniently assayed for, e.g., IRG mRNAs using Northern, dot blot or PCR analysis. For example, RT-PCR assays such as quantitative PCR assays are well known in the art. In an illustrative embodiment of the invention, a method for detecting an IRG mRNA in a biological sample comprises producing cDNA from the sample by reverse transcription using at least one primer; amplifying the cDNA so produced using an IRG polynucleotide as sense and antisense primers to amplify IRG cDNAs therein; and detecting the presence of the amplified IRG cDNA. In addition, such methods can include one or more steps that allow one to determine the levels of IRG mRNA in a biological sample (e.g. by simultaneously examining the levels a comparative control mRNA sequence of a “housekeeping” gene such as an actin family member). Optionally, the sequence of the amplified IRG cDNA can be determined.

Material embodiments of this aspect of the invention include IRG primers and primer pairs, which allow the specific amplification of the polynucleotides of the invention or of any specific parts thereof, and probes that selectively or specifically hybridize to nucleic acid molecules of the invention or to any part thereof. Probes may be labeled with a detectable marker, such as, for example, a radioisotope, fluorescent compound, bioluminescent compound, a chemiluminescent compound, metal chelator or enzyme. Such probes and primers can be used to detect the presence of IRG polynucleotides in a sample and as a means for detecting a cell expressing IRG proteins. As will be understood by the skilled artisan, a great many different primers and probes may be prepared based on the sequences provided in herein and used effectively to amplify, clone and/or determine the presence and/or levels of IRG mRNAs.

Optional methods of the invention include protocols which examine or detect mRNAs, such as IRG mRNAs, in a tissue or cell sample by microarray technologies. Using nucleic acid microarrays, test and control mRNA samples from test and control tissue samples are reverse transcribed and labeled to generate cDNA probes. The probes are then hybridized to an array of nucleic acids immobilized on a solid support. The array is configured such that the sequence and position of each member of the array is known. For example, a selection of genes that have potential to be expressed in certain disease states may be arrayed on a solid support. Hybridization of a labeled probe with a particular array member indicates that the sample from which the probe was derived expresses that gene. Differential gene expression analysis of disease tissue can provide valuable information. Microarray technology utilizes nucleic acid hybridization techniques and computing technology to evaluate the mRNA expression profile of thousands of genes within a single experiment. (see, e.g., WO 01/75166 published Oct. 11, 2001; (See, for example, U.S. Pat. No. 5,700,637, U.S. Pat. No. 5,445,934, and U.S. Pat. No. 5,807,522, Lockart, Nature Biotechnology, 14:1675-1680 (1996); Cheung, V. G. et al., Nature Genetics 21(Suppl):15-19 (1999) for a discussion of array fabrication). DNA microarrays are miniature arrays containing gene fragments that are either synthesized directly onto or spotted onto glass or other substrates. Thousands of genes are usually represented in a single array. A typical microarray experiment involves the following steps: 1) preparation of fluorescently labeled target from RNA isolated from the sample, 2) hybridization of the labeled target to the microarray, 3) washing, staining, and scanning of the array, 4) analysis of the scanned image and 5) generation of gene expression profiles. Currently two main types of DNA microarrays are being used: oligonucleotide (usually 25 to 70 mers) arrays and gene expression arrays containing PCR products prepared from cDNAs. In forming an array, oligonucleotides can be either prefabricated and spotted to the surface or directly synthesized on to the surface (in situ).

The Affymetrix GeneChip® system is a commercially available microarray system which comprises arrays fabricated by direct synthesis of oligonucleotides on a glass surface. Probe/Gene Arrays: Oligonucleotides, usually 25 mers, are directly synthesized onto a glass wafer by a combination of semiconductor-based photolithography and solid phase chemical synthesis technologies. Each array contains up to 400,000 different oligos and each oligo is present in millions of copies. Since oligonucleotide probes are synthesized in known locations on the array, the hybridization patterns and signal intensities can be interpreted in terms of gene identity and relative expression levels by the Affymetrix Microarray Suite software. Each gene is represented on the array by a series of different oligonucleotide probes. Each probe pair consists of a perfect match oligonucleotide and a mismatch oligonucleotide. The perfect match probe has a sequence exactly complimentary to the particular gene and thus measures the expression of the gene. The mismatch probe differs from the perfect match probe by a single base substitution at the center base position, disturbing the binding of the target gene transcript. This helps to determine the background and nonspecific hybridization that contributes to the signal measured for the perfect match oligo. The Microarray Suite software subtracts the hybridization intensities of the mismatch probes from those of the perfect match probes to determine the absolute or specific intensity value for each probe set. Probes are chosen based on current information from Genbank and other nucleotide repositories. The sequences are believed to recognize unique regions of the 3′ end of the gene. A GeneChip Hybridization Oven (“rotisserie” oven) is used to carry out the hybridization of up to 64 arrays at one time. The fluidics station performs washing and staining of the probe arrays. It is completely automated and contains four modules, with each module holding one probe array. Each module is controlled independently through Microarray Suite software using preprogrammed fluidics protocols. The scanner is a confocal laser fluorescence scanner which measures fluorescence intensity emitted by the labeled cRNA bound to the probe arrays. The computer workstation with Microarray Suite software controls the fluidics station and the scanner. Microarray Suite software can control up to eight fluidics stations using preprogrammed hybridization, wash, and stain protocols for the probe array. The software also acquires and converts hybridization intensity data into a presence/absence call for each gene using appropriate algorithms. Finally, the software detects changes in gene expression between experiments by comparison analysis and formats the output into .txt files, which can be used with other software programs for further data analysis.

The expression of a selected biomarker may also be assessed by examining gene deletion or gene amplification. Gene deletion or amplification may be measured by any one of a wide variety of protocols known in the art, for example, by conventional Southern blotting, Northern blotting to quantitate the transcription of mRNA (Thomas, Proc. Natl. Acad. Sci. USA, 77:5201-5205 (1980)), dot blotting (DNA analysis), or in situ hybridization (e.g., FISH), using an appropriately labeled probe, cytogenetic methods or comparative genomic hybridization (CGH) using an appropriately labeled probe. By way of example, these methods may be employed to detect deletion or amplification of IRG genes.

Expression of a selected biomarker in a tissue or cell sample may also be examined by way of functional or activity-based assays. For instance, if the biomarker is an enzyme, one may conduct assays known in the art to determine or detect the presence of the given enzymatic activity in the tissue or cell sample.

In the methods of the present invention, it is contemplated that the tissue or cell sample may also be examined for the expression of interferons such as Type 1 interferons, and/or activation of the Type 1 interferon signaling pathway, in the sample. Examining the tissue or cell sample for expression of Type 1 interferons and/or the corresponding receptor(s), and/or activation of the Type interferon signaling pathway, may give further information as to whether the tissue or cell sample will be sensitive to an interferon inhibitor. By way of example, the IHC techniques described above may be employed to detect the presence of one of more such molecules in the sample. It is contemplated that in methods in which a tissue or sample is being examined not only for the presence of IRG, but also for the presence of, e.g., Type 1 interferon, interferon receptor(s), separate slides may be prepared from the same tissue or sample, and each slide tested with a reagent specific for each specific biomarker or receptor. Alternatively, a single slide may be prepared from the tissue or cell sample, and antibodies directed to each biomarker or receptor may be used in connection with a multi-color staining protocol to allow visualization and detection of the respective biomarkers or receptors.

Subsequent to the determination that the tissue or cell sample expresses one or more of the biomarkers indicating the tissue or cell sample will be sensitive to treatment with interferon inhibitors, it is contemplated that an effective amount of the interferon inhibitor may be administered to the mammal to treat a disorder, such as autoimmune disorder which is afflicting the mammal. Diagnosis in mammals of the various pathological conditions described herein can be made by the skilled practitioner. Diagnostic techniques are available in the art which allow, e.g., for the diagnosis or detection of autoimmune related disease in a mammal.

An interferon inhibitor can be administered in accord with known methods, such as intravenous administration as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intracerobrospinal, subcutaneous, intra-articular, intrasynovial, intrathecal, oral, topical, or inhalation routes. Optionally, administration may be performed through mini-pump infusion using various commercially available devices.

Effective dosages and schedules for administering interferon inhibitors may be determined empirically, and making such determinations is within the skill in the art. Single or multiple dosages may be employed. For example, an effective dosage or amount of interferon inhibitor used alone may range from about 1 μg/kg to about 100 mg/kg of body weight or more per day. Interspecies scaling of dosages can be performed in a manner known in the art, e.g., as disclosed in Mordenti et al., Pharmaceut. Res., 8:1351 (1991).

When in vivo administration of interferon inhibitor is employed, normal dosage amounts may vary from about 10 μg/kg to up to 100 mg/kg of mammal body weight or more per day, preferably about 1 μg/kg/day to 10 mg/kg/day, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature; see, for example, U.S. Pat. Nos. 4,657,760; 5,206,344; or 5,225,212. It is anticipated that different formulations will be effective for different treatment compounds and different disorders, that administration targeting one organ or tissue, for example, may necessitate delivery in a manner different from that to another organ or tissue.

It is contemplated that yet additional therapies may be employed in the methods. The one or more other therapies may include but are not limited to, administration of steroids and other standard of care regimens for the particular autoimmune disorder in question. It is contemplated that such other therapies may be employed as an agent separate from the interferon inhibitor.

For use in the applications described or suggested above, kits or articles of manufacture are also provided by the invention. Such kits may comprise a carrier means being compartmentalized to receive in close confinement one or more container means such as vials, tubes, and the like, each of the container means comprising one of the separate elements to be used in the method. For example, one of the container means may comprise a probe that is or can be detectably labeled. Such probe may be an antibody or polynucleotide specific for IRG gene or message, respectively. Where the kit utilizes nucleic acid hybridization to detect the target nucleic acid, the kit may also have containers containing nucleotide(s) for amplification of the target nucleic acid sequence and/or a container comprising a reporter-means, such as a biotin-binding protein, such as avidin or streptavidin, bound to a reporter molecule, such as an enzymatic, florescent, or radioisotope label.

The kit of the invention will typically comprise the container described above and one or more other containers comprising materials desirable from a commercial and user standpoint, including buffers, diluents, filters, needles, syringes, and package inserts with instructions for use. A label may be present on the container to indicate that the composition is used for a specific therapy or non-therapeutic application, and may also indicate directions for either in vivo or in vitro use, such as those described above.

The kits of the invention have a number of embodiments. A typical embodiment is a kit comprising a container, a label on said container, and a composition contained within said container; wherein the composition includes a primary antibody that binds to a IRG polypeptide sequence, the label on said container indicates that the composition can be used to evaluate the presence of IRG proteins in at least one type of mammalian cell, and instructions for using the IRG antibody for evaluating the presence of IRG proteins in at least one type of mammalian cell. The kit can further comprise a set of instructions and materials for preparing a tissue sample and applying antibody and probe to the same section of a tissue sample. The kit may include both a primary and secondary antibody, wherein the secondary antibody is conjugated to a label, e.g., an enzymatic label.

Another embodiment is a kit comprising a container, a label on said container, and a composition contained within said container; wherein the composition includes a polynucleotide that hybridizes to a complement of the IRG polynucleotide under stringent conditions, the label on said container indicates that the composition can be used to evaluate the presence of IRG in at least one type of mammalian cell, and instructions for using the IRG polynucleotide for evaluating the presence of IRG RNA or DNA in at least one type of mammalian cell.

Other optional components in the kit include one or more buffers (e.g., block buffer, wash buffer, substrate buffer, etc), other reagents such as substrate (e.g., chromogen) which is chemically altered by an enzymatic label, epitope retrieval solution, control samples (positive and/or negative controls), control slide(s) etc.

The following are examples of the methods and compositions of the invention. It is understood that various other embodiments may be practiced, given the general description provided above.

EXAMPLES

Example 1

Materials and Methods

Expression of IFN-alpha responsive genes (IRG's) was analyzed in data from blood—peripheral blood mononuclear cells (PBMC) from SLE patients (with active or inactive disease) and normal donors from the University Of Minnesota (Minneapolis, Minn.).

Data was produced as follows: 92 blood samples were collected on different dates from 18 patients with active SLE, 19 blood samples were collected on different dates from 5 patients with inactive SLE, and 4 blood samples were collected from 4 healthy donors. PBMC was isolated from whole blood by standard Ficoll gradient centrifugation. RNA was prepared from PBMC samples using RNA Isolation Kit from Qiagen (Valencia, Calif.) and hybridized to WHG oligonucleotide microarray chips from Agilent (Palo Alto, Calif.). Raw data was processed by standard Agilent Feature Extraction to yield Agilent log ratio data. Normal expression of genes in response to IFN-alpha was examined by isolating PBMC from healthy donors and incubating it in culture for four hours with 100 U/ml recombinant IFN-alpha, then taking samples of the cell culture at 4, 12, 28, and 52 hours following addition of IFN-alpha.

Microarray data was clustered hierarchically in two dimensions (samples and probes) using the xcluster software program (pearson on log 2 signal) on probes with both mean signal in the top 70% ile and coefficient of variability in the top 70% ile. Cluster data was viewed with the Java Treeview software program. Numerical analysis was performed with R (http://www [insert period] r-project [insert period]org/), JMP (SAS Institute, Cary, N.C.) and Excel (Microsoft, Redmond, Wash.).

Results and Analysis

Microarray clustering of all samples showed significant grouping of both samples and genes. Sample clustering showed grouping of a large fraction of SLE patients with active disease. Gene clustering showed several different tightly grouped gene subclusters with obvious biological patterns. For instance, one subcluster was highly enriched for genes known to be specific to B cells, another to neutrophils, another for antibodies, and another for IRG's. The IRG subcluster showed an interesting pattern with respect to samples: normal samples all showed low expression of IRG's, while SLE samples showed a wide range of expression that varied from normal-like to extremely high.

The expression profiles of probes within a tight subcluster are very similar but not identical, and the variation between very similar profiles may be due in significant part to noise either from biological or technological sources. For instance, some genes are represented on the microarray by more than one probe, and there are several pairs of probes in the IRG subcluster area that represent the same gene's expression. In these cases, the probes clustered near to each other, sometimes immediately adjacent. Thus it appeared that a clear pattern was present and reflected in many probes, and that utilizing the data from several probes in order to mitigate the interference of noise in the data might most clearly identify the pattern. Nonetheless, the genes that were identified could be used individually as genetic identifiers that correlate with presence of disease.

Identification of Genes Highly Induced by Interferon Alpha

In order to identify genes whose expression is highly induced by the presence of interferon alpha, PBMC samples from healthy donors were treated with recombinant interferon alpha and samples of the cell cultures were subjected to Agilent WHG expression analysis as described above. Log ratio data from these hybridizations were analyzed by two-way ANOVA (time and treatment), and 142 probes were identified by filtering of treatment p-value <5×10−7. This set of genes is a subset of genes whose expression is induced by interferon alpha, and it constitutes an effective tool for identifying clusters of genes in other experiments whose common basis for co-clustering is induction by interferon alpha.

Development of a Metric that Correlates with Disease, and Identification of Individual Genes that May Constitute Such Metric

The pattern of transcriptional activation in IRG's was measured by calculating a single metric proportional to the Agilent ratio levels of the specific subgroup of probes. For example, we describe this approach below with the IRG probes. The pattern (the aggregate profile of IRG's) was first defined by aligning a density plot of probes induced by interferon alpha in PBMC samples with the cluster heatmap of SLE and control samples (FIG. 1). Probes were defined as IRG's by starting from the two most highly correlated probes and expanding the set by adding the next most highly correlated probe or branch of probes until the set of probes appeared to contain most of the expression signature evident in its center but not so far that it contains a significant contribution from a different signature. The set is comprised of the thirty-five probes listed in Table 1.

The expression data of this group was then transformed into z-scores (mean scaled to 1, base-2 log transformed, then scaled to a standard deviation of the mean of 1), and the correlation coefficient of each probe's profile to the mean profile was calculated. These correlation coefficients were used as weighting factors to weight relatively heavily the probes that showed the strongest match to the trend of the group, and to weight relatively lightly those that apparently were more affected by other inputs or noise.

The factors required to scale probes to 1 were multiplied by the weighting factor, to produce a composite factor that could yield a normalized, weighted metric for a single hybridization. The normal blood samples' signatures were multiplied by that factor, averaged across both probes and samples, and this number was inverted to yield a global scaling factor that would transform the output of the average of probes from a sample into a metric that would be expected to be 1 for samples from healthy donors. Each normalization/weighting factor was multiplied by this factor. The result was a vector of scalar values that were multiplied by a sample expression signature and averaged to yield the Type I Interferon Response Gene Metric (IRGM), a single metric measuring the level of IFN-alpha transcriptional response in a sample.

IRGM scores were calculated and evaluated for the set of clinical samples used for selection of the IRGM genes. IRGM scores were significantly higher for patients suffering from active SLE than healthy patients (FIG. 2).

Clinical measures of SLE disease activity and severity such as SLEDAI quantitate patient disease symptoms and may correlate with expression of genes that underlie the etiology of the disease. In order to investigate this hypothesis, IRGM data on individual patients were compared to those patients' clinical scores and lab test results. No significant correlation was observed between IRGM and SLEDAI, but the titer of anti-dsDNA antibodies in serum correlated well with IRGM in many patients with active SLE (FIG. 3). This correlation could be the basis of either assay being a surrogate for the other. It also illustrates a biological relationship that could serve as a basis for a rational design of therapy for SLE.

The IRGM test, and expression of the genes that make up such a test (as set forth in Table 1), could be useful for selecting patients that would benefit from IFN-α-based treatment for autoimmune disorders (e.g., SLE) by identifying patients that have a relatively high IRGM score and thus have IFN-α signaling that could be blocked. Equivalently, it could be used to predict that certain patients would not benefit from IFN-α-based treatment because they do not exhibit a high IRGM score and thus are not currently experiencing active IFN-α signaling that could be disrupted.

The IRGM test, and expression of the genes that make up such a test (as set forth in Table 1), are useful indicators in a variety of drug development, diagnostic, prognostic and therapeutic settings as described above. For example, this information could be used to check whether patients that have responded well to anti-IFN-α treatment had high levels of expression of the signaling targets of IFN-α before treatment and afterwards whether the treatment abrogated that expression. It would be a useful gauge of the extent to which a particular treatment affects the IFN-α signaling pathway. It might be a useful bio- or pharmacodynamic marker, measuring the profile of the effects of treatment over time.

Other Interferons

The metric-based approach described above could be utilized in a variety of ways in characterizing disease pathways, mechanisms of action and drug pharmacodynamics. For example, different interferon molecules probably have different properties that the IRGM and/or a test made the same way based on different microarray data and/or analyses could help measure and elucidate. For instance:

1) Type I interferons all signal through the same heterodimeric receptor but may differ in their half-life, receptor affinity, or power to initiate signaling in a target cell. These differences in magnitudes might be measured easily and accurately by IRGM. This sort of measurement could be carried out either in a cell culture experiment or in a clinical setting. Likewise, the effect of candidate drugs or drugs used in clinical settings can be gauged using this approach.

2) Different IRGM-like tests could be constructed by microarray assays of cultured blood samples treated with different interferons. To the extent to which the tests differ from each other, they could be applied to clinical samples to determine the relative activities of different interferons and/or drugs.

Other Signatures

The method used to generate the IRGM test could also be applied to any sort of expression signature, either of a state or activity of cells or of a type of cell or cells. For instance, some SLE patients show marked upmodulation of immunoglobulin gene expression, an indicator of the production of antibodies by plasma cells. Microarray probes reporting expression of these genes could collectively support the calculation of a measurement of the overall level of plasma cell activity and antibody production. In another example, there are particular transcriptional changes associated with active mitotic cell replication. These transcriptional changes could be consolidated into a test that would be applied to a variety of biological samples to measure how actively they are dividing. Or in yet another example, the genes whose expression is specific to particular types of immune cells could be categorized by which cell type expresses them and then for each cell type a test could be made. This collection of tests could then be applied to any of a variety of clinical samples (blood from SLE patients, intestinal biopsies from Crohn's Disease patients, etc.) to determine the balance of immune cell types.

TABLE 1
Agilent WHG probes constituting a set of IRG's for WHG analysis. Thirty five
probes are listed, representing twenty nine unique genes. Refseq or Genbank accession
numbers, symbols and names of genes are also indicated.
probeidaccessiongene symbolgene description
A_24_P343929NM_001032731OAS22′-5′-oligoadenylate synthetase 2
A_24_P395966NM_030776ZBP1Z-D binding protein 1
A_23_P259141NM_030776ZBP1Z-D binding protein 1
A_23_P139786NM_003733OASL2′-5′-oligoadenylate synthetase-like
A_24_P316965NM_080657RSAD2 (CIG5)radical S-adenosyl methionine domain
containing 2
A_23_P17663NM_002462MX1myxovirus resistance 1
A_24_P378019NM_001572IRF7interferon regulatory factor 7
A_23_P64828NM_001032409OAS12′,5′-oligoadenylate synthetase 1
A_24_P943205NM_001002264EPSTI1epithelial stromal interaction 1
A_23_P23074NM_006417IFI44interferon-induced protein 44
A_23_P45871NM_006820IFI44Linterferon-induced protein 44-like
A_23_P819NM_005101G1P2interferon, alpha-inducible protein IFI-15K
A_24_P28722NM_080657RSAD2 (CIG5)radical S-adenosyl methionine domain
containing 2
A_24_P917810NM_000059BRCA2breast cancer 2, early onset
A_23_P52266NM_001001887IFIT1interferon-induced protein with
tetratricopeptide repeats 1
A_23_P110196NM_016323HERC5hect domain and RLD 5
A_23_P47955NM_006187OAS32′-5′-oligoadenylate synthetase 3
A_23_P35412NM_001031683IFIT3interferon-induced protein with
tetratricopeptide repeats 3
A_24_P557479NM_017523HSXIAPAF1XIAP associated factor-1
A_23_P4283NM_017523HSXIAPAF1XIAP associated factor-1
A_32_P132206NM_017414USP18ubiquitin specific peptidase 18
A_24_P317762NM_002346RIG-Elymphocyte antigen 6 complex, locus E
A_24_P316257NM_145270FLJ36208hypothetical protein FLJ36208
A_23_P105794NM_001002264EPSTI1epithelial stromal interaction 1
A_23_P166797NM_022147TMEM728 kD interferon responsive protein
A_23_P111804NM_022750PARP12poly (ADP-ribose) polymerase family,
member 12
A_23_P250353NM_001013000HERC6hect domain and RLD 6, transcript variant 3
A_24_P334361NM_017631SGRA12061hypothetical protein FLJ20035
A_23_P384355NM_207315TYKIthymidylate kinase family LPS-inducible
A_24_P30194NM_012420IFIT5interferon-induced protein with
tetratricopeptide repeats 5
A_23_P4286NM_017523HSXIAPAF1XIAP associated factor-1, transcript variant 1
A_32_P227059AA977193(no symbol)(no known gene)
A_23_P142750NM_002759EIF2AK2eukaryotic translation initiation factor 2-
alpha kinase 2
A_24_P161018NM_017554PARP14poly (ADP-ribose) polymerase family,
member 14
A_24_P335305NM_006187OAS32′-5′-oligoadenylate synthetase 3

Example 2

Materials and Methods

Expression of IFN-alpha responsive genes (IRG's) was analyzed in data from white blood cells (WBC) from SLE patients and healthy donors obtained by Gene Logic Inc. (Gaithersburg, Md.).

Data was produced as follows: 72 blood samples were collected from patients with active SLE, 46 blood samples were collected from healthy donors. RNA was prepared from WBC samples using RNA Isolation Kit from Qiagen (Valencia, Calif.) and hybridized to HGU133 oligonucleotide microarray chips from Affymetrix, Inc. (Santa Clara, Calif.). Raw data was processed by Affymetrix MAS5.0 feature extraction to yield Signal data.

Microarray data was clustered hierarchically in two dimensions (samples and probes) using the xcluster software program (pearson on log 2 signal) on probes with both mean signal in the top 70% ile and coefficient of variability in the top 70% ile. Cluster data was viewed with the Java Treeview software program. Numerical analysis was performed with R (http://www [insert period] r-project [insert period] org/), JMP (SAS Institute, Cary, N.C.).

Results and Analysis

Microarray clustering of all samples showed significant grouping of both samples and genes. Sample clustering showed grouping of a large fraction of SLE patients with active disease. Gene clustering showed several different tightly grouped gene subclusters with obvious biological patterns. For instance, one subcluster was highly enriched for genes known to be specific to B cells, another to neutrophils, another for antibodies, and another for IRG's. The IRG subcluster showed an interesting pattern with respect to samples: normal samples all showed low expression of IRG's, while SLE samples showed a wide range of expression that varied from normal-like to extremely high.

The expression profiles of probes within a tight subcluster were very similar but not identical, and the variation between very similar profiles may be due in significant part to noise either from biological or technological sources. For instance, some genes were represented on the microarray by more than one probe, and there were several pairs of probes in the IRG subcluster area that represent the same gene's expression. In these cases, the probes clustered near to each other, sometimes immediately adjacent. Thus it appeared that a clear pattern was present and reflected in many probes, and that utilizing the data from several probes in order to mitigate the interference of noise in the data might most clearly identify the pattern. Nonetheless, the genes that were identified could be used individually as genetic identifiers that correlate with presence of disease.

A relatively complete set of genes whose expression is indicative of a response to type 1 interferons (IRG) was identified. The IRG region, identified as a tightly clustered region of the clustered data containing 80 microarray probes highly enriched in known IRG's, was used as the definition of an interferon response profile by averaging the clustered data in this slice of 80 probes. The averaging was performed by taking the arithmetic mean across the 80 probes to yield a vector of length 118 that described the average relative interferon response in the 118 samples analyzed. The similarity of each probe in the cluster data was then compared to this signature vector by computing the Spearman correlation rho value of each pairwise comparison. Visual inspection of these rho values for probes in their clustered order showed an obvious maximum at the center of the IRG cluster (FIG. 4), and it also revealed clear boundaries between the region of locally elevated correlation and the adjacent regions that were less correlated and were influenced much more heavily by other signals and noise. The probes in this complete IRG region are listed in Table 2. Table 3 shows probes (in some cases, multiple probes) corresponding to a subset of novel genes from Table 2.

All probes in this set and their corresponding genes are useful markers for the level of response of blood cells to type I interferons. They are informative of the response individually or when combined in any number and combination as previously described to create an interferon signature metric (ISM). The measurement of their expression level for this purpose could be accomplished effectively using any of a variety of standard techniques, e.g., expression microarrays (e.g. commercially available arrays such as Affymetrix HGU133), or real-time PCR (e.g. Taqman).

TABLE 2
201 microarray probes constituting a set of type-I interferon responsive genes,
their Spearman (rho) correlation to the interferon signature, Refseq or
Genbank accession number, symbol, and name.
ProbeRhoAccessionSymbolName
226603_at0.9760NM_152703SAMD9Lsterile alpha motif domain containing 9-
like
230036_at0.9754NM_152703SAMD9Lsterile alpha motif domain containing 9-
like
226702_at0.9747NM_207315TYKIThymidylate kinase family LPS-inducible
242625_at0.9733NM_080657RSAD2 (CIG5)radical S-adenosyl methionine domain
containing 2
223220_s_at0.9725NM_031458PARP9poly ADP-ribose polymerase family,
member 9
213797_at0.9679NM_080657RSAD2 (CIG5)radical S-adenosyl methionine domain
containing 2
204747_at0.9664NM_001031683IFIT3interferon-induced protein with
tetratricopeptide repeats 3
203153_at0.9586NM_001001887IFIT1interferon-induced protein with
tetratricopeptide repeats 1
226757_at0.9582NM_001547IFIT2interferon-induced protein with
tetratricopeptide repeats 2
229450_at0.9572NM_001031683IFIT3interferon-induced protein with
tetratricopeptide repeats 3
208436_s_at0.9568NM_001572IRF7interferon regulatory factor 7
219062_s_at0.9544NM_017742ZCCHC2zinc finger, CCHC domain containing 2
224701_at0.9531NM_017554PARP14poly ADP-ribose polymerase family,
member 14
205483_s_at0.9511NM_005101G1P2interferon, alpha-inducible protein clone
IFI-15K
218943_s_at0.9495NM_014314DDX58 (RIG1)DEAD Asp-Glu-Ala-Asp box polypeptide
58
219863_at0.9462NM_016323HERC5hect domain and RLD 5
227609_at0.9458NM_001002264EPSTI1epithelial stromal interaction 1 breast
219356_s_at0.9456NM_016410CHMP5chromatin modifying protein 5
203596_s_at0.9456NM_012420IFIT5interferon-induced protein with
tetratricopeptide repeats 5
228152_s_at0.9422XM_037817LCGE22799FLJ31033
228531_at0.9417NM_017654SAMD9sterile alpha motif domain containing 9
203595_s_at0.9406NM_012420IFIT5interferon-induced protein with
tetratricopeptide repeats 5
202446_s_at0.9383NM_021105PLSCR2phospholipid scramblase 2
228617_at0.9379NM_017523HSXIAPAF1XIAP associated factor-1
232222_at0.9374NM_017742ZCCHC2zinc finger, CCHC domain containing 2
204439_at0.9356NM_006820IFI44Linterferon-induced protein 44-like
212657_s_at0.9346NM_000577IL1RNinterleukin 1 receptor antagonist
210797_s_at0.9341NM_003733OASL2′-5′-oligoadenylate synthetase-like
213294_at0.9334P_ADB12769PRKRdsRNA-dependent protein kinase
211012_s_at0.9311NM_002675PMLpromyelocytic leukemia
202086_at0.9302NM_002462MX1myxovirus influenza virus resistance 1
223502_s_at0.9300NM_006573TNFSF13Btumor necrosis factor ligand superfamily,
member 13b
227807_at0.9295NM_031458PARP9poly ADP-ribose polymerase family,
member 9
214453_s_at0.9278NM_006417IFI44interferon-induced protein 44
205660_at0.9275NM_003733OASL2′-5′-oligoadenylate synthetase-like
228230_at0.9273NM_033405PRIC285peroxisomal proliferator-activated
receptor A
218400_at0.9253NM_006187OAS32′-5′-oligoadenylate synthetase 3
223501_at0.9227NM_006573TNFSF13Btumor necrosis factor ligand superfamily,
member 13b
214059_at0.9186NM_006417IFI44interferon-induced protein 44
202687_s_at0.9178NM_003810Apo-2LApo-2 Ligand
202863_at0.9176NM_003113SP140SP140 nuclear body protein
217502_at0.9158NM_001547IFIT2interferon-induced protein with
tetratricopeptide repeats 2
218085_at0.9130NM_016410CHMP5chromatin modifying protein 5
228439_at0.9123NM_138456BATF2basic leucine zipper transcription factor,
ATF-like 2
209593_s_at0.9089NM_014506TOR1Btorsin family 1, member B torsin B
222793_at0.9079NM_014314DDX58 (RIG1)DEAD Asp-Glu-Ala-Asp box polypeptide
58
204994_at0.9061NM_002463MX2myxovirus influenza virus resistance 2
mouse
219691_at0.9029NM_017654SAMD9sterile alpha motif domain containing 9
208087_s_at0.9027NM_030776ZBP1Z-D binding protein 1
202270_at0.9008NM_002053GBP1guanylate binding protein 1, interferon-
inducible, 67 kDa
231577_s_at0.9007NM_002053GBP1guanylate binding protein 1, interferon-
inducible, 67 kDa
219209_at0.9004NM_022168IFIH1interferon induced with helicase C
domain 1
200986_at0.8978NM_000062SERPING1Serine/cysteine proteinase inhibitor, clade
G C1 inhibitor, 1
204972_at0.8964NM_001032731OAS22′-5′-oligoadenylate synthetase 2,
69/71 kDa
242020_s_at0.8948NM_030776ZBP1Z-D binding protein 1
209498_at0.8933NM_001024912CEACAM1carcinoembryonic antigen-related cell
adhesion molecule 1
235276_at0.8931NM_001002264EPSTI1epithelial stromal interaction 1 breast
219211_at0.8925NM_017414USP18ubiquitin specific protease 41
239277_at0.8897NM_001033583ACOT9acyl-CoA thioesterase 9
243271_at0.8892NM_152703SAMD9Lsterile alpha motif domain containing 9-
like
205098_at0.8887NM_001295CCR1chemokine C—C motif receptor 1
202430_s_at0.8859NM_021105PLSCR2phospholipid scramblase 2
209417_s_at0.8837NM_005533IFI35interferon-induced protein 35
205552_s_at0.8789NM_001032409OAS12′,5′-oligoadenylate synthetase 1,
40/46 kDa
231769_at0.8783NM_018438FBXO6F-box protein 6
241916_at0.8782NM_021105PLSCR2phospholipid scramblase 2
233425_at0.8778NM_017742ZCCHC2zinc finger, CCHC domain containing 2
218543_s_at0.8762NM_022750PARP12poly ADP-ribose polymerase family,
member 12
202307_s_at0.8742NM_000593TAP1transporter 1, ATP-binding cassette, sub-
family B
204698_at0.8735NM_002201ISG20interferon stimulated gene 20 kDa
202269_x_at0.8730NM_002053GBP1guanylate binding protein 1, interferon-
inducible, 67 kDa
232666_at0.8711NM_006187OAS32′-5′-oligoadenylate synthetase 3, 100 kDa
218986_s_at0.8703NM_017631SGRA12061Hypothetical protein FLJ20035 FLJ20035
205569_at0.8675NM_014398LAMP3lysosomal-associated membrane protein 3
202145_at0.8672NM_002346LY6E (RIGE)lymphocyte antigen 6 complex, locus E
219352_at0.8671NM_001013000HERC6hect domain and RLD 6
239979_at0.8665NM_001002264EPSTI1epithelial stromal interaction 1 breast
223599_at0.8664NM_001003818TRIMP1tripartite motif-containing pseudogene 1
230866_at0.8656NM_006639CYSLTR1cysteinyl leukotriene receptor 1
216565_x_at0.8650XM_497663LOC391020similar to Interferon-induced
transmembrane protein 3
212659_s_at0.8635NM_000577IL1RNinterleukin 1 receptor antagonist
202869_at0.8634NM_001032409OAS12′,5′-oligoadenylate synthetase 1,
40/46 kDa
223952_x_at0.8623NM_005771DHRS9dehydrogenase/reductase SDR family
member 9
205241_at0.8614NM_001953SCO2SCO cytochrome oxidase deficient
homolog 2 yeast
227458_at0.8601NM_014143PDL1/B7-H1programmed cell death 1 ligand 1
231747_at0.8600NM_006639CYSLTR1cysteinyl leukotriene receptor 1
209969_s_at0.8576NM_007315STAT1signal transducer and activator of
transcription 1, 91 kDa
218999_at0.8561NM_018295AGPR4538hypothetical protein MGC5242
224009_x_at0.8535NM_005771DHRS9dehydrogenase/reductase SDR family
member 9
228607_at0.8529NM_001032731OAS22′-5′-oligoadenylate synthetase 2,
69/71 kDa
205099_s_at0.8516NM_001295CCR1chemokine C—C motif receptor 1
219799_s_at0.8479NM_005771DHRS9dehydrogenase/reductase SDR family
member 9
206133_at0.8420NM_017523HSXIAPAF1XIAP associated factor-1
211889_x_at0.8386NM_001024912CEACAM1carcinoembryonic antigen-related cell
adhesion molecule 1
222154_s_at0.8365NM_015535DNAPTP6DNA polymerase-transactivated protein 6
225291_at0.8350NM_033109PNPT1polyribonucleotide nucleotidyltransferase 1
202864_s_at0.8347NM_003113SP140SP140 nuclear body protein
210705_s_at0.8341NM_033034TRIM5tripartite motif-containing 5
223167_s_at0.8334NM_013396USP25ubiquitin specific protease 25
229625_at0.8324NM_004120GBP5guanylate binding protein 5
202837_at0.8278NM_006700TRAFD1TRAF-type zinc finger domain containing 1
216243_s_at0.8185NM_000577IL1RNinterleukin 1 receptor antagonist
223849_s_at0.8180NM_020963MOV10Mov10, Moloney leukemia virus 10,
homolog mouse
222498_at0.8175NM_022461AZI25-azacytidine induced 2
238581_at0.8173NM_004120GBP5guanylate binding protein 5
217933_s_at0.8138NM_015907LAP3leucine aminopeptidase 3
219519_s_at0.8108NM_023068SIGLEC1sialoadhesin
208392_x_at0.8084NM_004509SP110SP110 nuclear body protein
239988_at0.8079NM_017912SKKS30637Hect domain and RLD 6
230314_at0.8074P_ADH28842CMLM110chronic myclogenous leukaemia (CML)
gene marker #110
206576_s_at0.8072NM_001024912CEACAM1carcinoembryonic antigen-related cell
adhesion molecule 1
227347_x_at0.8047NM_021170HES4hairy and enhancer of split 4 Drosophila
202411_at0.8038NM_005532IFI27interferon, alpha-inducible protein 27
219684_at0.7998NM_022147TMEM7transmembrane protein 7
205003_at0.7974NM_014705DOCK4dedicator of cytokinesis 4
212185_x_at0.7969NM_005953MT2Ametallothionein 2A
235256_s_at0.7957NM_138801GALMgalactose mutarotase aldose 1-epimerase
242234_at0.7948NM_017523HSXIAPAF1XIAP associated factor-1
211883_x_at0.7916NM_001024912CEACAM1carcinoembryonic antigen-related cell
adhesion molecule 1
206513_at0.7891NM_004833AIM2absent in melanoma 2
44673_at0.7884NM_023068SIGLEC1sialoadhesin
209546_s_at0.7869NM_003661APOL1apolipoprotein L, 1
204415_at0.7838NM_002038G1P3interferon, alpha-inducible protein clone
IFI-6-16
206553_at0.7821NM_001032731OAS22′-5′-oligoadenylate synthetase 2,
69/71 kDa
206461_x_at0.7758NM_005946MT2Ametallothionein 2A
226169_at0.7746NM_030962SBF2SET binding factor 2
244398_x_at0.7742NM_152373ZNF684zinc finger protein 684
238439_at0.7659NM_144590ANKRD22ankyrin repeat domain 22
227649_s_at0.7646NM_015326SRGAP2SLIT-ROBO Rho GTPase activating
protein 2
220998_s_at0.7644NM_030930UNC93B1unc-93 homolog B1 C. elegans
204211_x_at0.7628NM_002759EIF2AK2eukaryotic translation initiation factor 2-
alpha kinase 2
224973_at0.7612NM_017633FAM46Afamily with sequence similarity 46,
member A
234974_at0.7601NM_138801GALMgalactose mutarotase aldose 1-epimerase
242898_at0.7588NM_002759EIF2AK2eukaryotic translation initiation factor 2-
alpha kinase 2
232034_at0.7581BC080605LOC203274hypothetical protein LOC203274
231455_at0.7560NM_001001695FLJ42418FLJ42418
208581_x_at0.7546NM_005952MT1Xmetallothionein 1X
224225_s_at0.7545NM_016135ETV7ets variant gene 7 (TEL2 oncogene)
205875_s_at0.7543NM_016381TREX1three prime repair exonuclease 1
209286_at0.7522NM_006449CDC42EP3CDC42 effector protein Rho GTPase
binding 3
205715_at0.7472NM_004334BST1bone marrow stromal cell antigen 1
223834_at0.7465NM_014143PDL1/B7-H1programmed cell death 1 ligand 1
212285_s_at0.7414NM_198576AGRNagrin
230695_s_at0.7381NM_152732C6orf206chromosome 6 open reading frame 206
219364_at0.7381NM_024119LGP2likely ortholog of mouse D11lgp2
238455_at0.7371NM_032812PLXDC2Plexin domain containing 2
201641_at0.7343NM_004335BST2Bone marrow stromal antigen 2
219439_at0.7273NM_020156C1GALT1core 1 synthase, glyc-N-acetylgal 3-beta-
galtransferase, 1
224503_s_at0.7231NM_017742ZCCHC2zinc finger, CCHC domain containing 2
234942_s_at0.7226NM_052951DNTTIP1deoxynucleotidyltransferase, terminal,
interacting protein 1
214933_at0.7212NM_000068CAC1Acalcium channel, voltage-dependent, P/Q
type, alpha 1A
219055_at0.7189NM_018079SRBD1S1 RNA binding domain 1
225447_at0.7179NM_000408GPD2glycerol-3-phosphate dehydrogenase 2
mitochondrial
236285_at0.7173P_AAF17573SYN22A2Breast cancer associated SYN22A2
coding sequence
217165_x_at0.7168NM_005946MT2Ametallothionein 2A
200923_at0.7164NM_005567LGALS3BPlectin, galactoside-binding, soluble, 3
binding protein
220104_at0.7159NM_020119ZC3HAV1zinc finger CCCH-type, antiviral 1
216950_s_at0.7133NM_000566FCGR1AFc fragment of IgG, high affinity Ia,
receptor CD64
227905_s_at0.7115NM_022461AZI25-azacytidine induced 2
230997_at0.7109NM_145755TTC21Atetratricopeptide repeat domain 21A
210889_s_at0.7099NM_001002273FCGR2BLow affinity immunoglobulin gamma fc
receptor ii-b
214511_x_at0.7050NM_000566FCGR1AFc fragment of IgG, high affinity Ia,
receptor (CD64)
211456_x_at0.7045NM_001039954MT1P2metallothionein 1 pseudogene 2
232563_at0.7017NM_152373ZNF684zinc finger protein 684
235456_at0.6926NM_021063HIST1H2BDhistone 1, H2bd
229194_at0.6917NM_032373PCGF5polycomb group ring finger 5
235157_at0.6859NM_017554PARP14poly ADP-ribose polymerase family,
member 14
230333_at0.6851NM_002970SATSpermidine/spermine N1-
acetyltransferase
231956_at0.6813NM_020954KIAA1618KIAA1618
235175_at0.6803NM_052941GBP4guanylate binding protein 4
232149_s_at0.6777NM_003580NSMAFneutral sphingomyelinase N-SMase
activation assoc factor
235331_x_at0.6769NM_032373PCGF5polycomb group ring finger 5
221653_x_at0.6762NM_030882APOL2apolipoprotein L, 2
219716_at0.6689NM_030641APOL6apolipoprotein L, 6
214909_s_at0.6669NM_013974DDAH2dimethylarginine
dimethylaminohydrolase 2
207500_at0.6654NM_004347CASP5caspase 5, apoptosis-related cysteine
protease
232081_at0.6648NM_004915ABCG1ATP-binding cassette, sub-family G
WHITE, member 1
241812_at0.6584NM_015535DNAPTP6DNA polymerase-transactivated protein 6
230166_at0.6571NM_133465KIAA1958KIAA1958
239143_x_at0.6554NM_016271RNF138ring finger protein 138
217823_s_at0.6543NM_016021UBE2J1ubiquitin-conjugating enzyme E2, J1
UBC6 homolog, yeast
242109_at0.6501NM_006519TCTEL1t-complex-associated-testis-expressed 1-
like 1
206175_x_at0.6420NM_013360ZNF230zinc finger protein 230
215537_x_at0.6366NM_013974DDAH2dimethylarginine
dimethylaminohydrolase 2
220252_x_at0.6318NM_025159CXorf21chromosome X open reading frame 21
227268_at0.6213NM_016125PLFL4625PTD016 protein
216336_x_at0.6153NM_153341IBRDC3IBR domain containing 3
229804_x_at0.6077NM_018491CBWD1COBW domain containing 1
236013_at0.6011NM_000721CAC1Ecalcium channel, voltage-dependent,
alpha 1E subunit
227004_at0.5968NM_003159CDKL5cyclin-dependent kinase-like 5
226099_at0.5788NM_012081ELL2elongation factor, R polymerase II, 2
227947_at0.5761NM_014721PHACTR2phosphatase and actin regulator 2
210985_s_at0.5722NM_003113SP140SP140 nuclear body protein
204326_x_at0.5699NM_005952MT1Xmetallothionein 1X
233264_at0.5515AK022088FLJ12026HEMBB1001816
212859_x_at0.5285NM_005953MT1Xmetallothionein 1X
235348_at0.5251NM_032859C13orf6chromosome 13 open reading frame 6
225872_at0.5053NM_025181SLC35F5solute carrier family 35, member F5
235681_at0.4913NM_021063HIST1H2BDhistone 1, H2bd
207291_at0.4851NM_024081PRRG4proline rich Gla G-carboxyglutamic acid
4 transmembrane
234997_x_at0.4617CD684982EST1502human spermidine/spermine N1 acetyl
transferase

TABLE 3
Selected subset of novel probesets/genes from Table 2. Where appropriate, multiple
probesets (with their respective rho values) are listed with their respective corresponding
gene.
ProbeRhoAccessionSymbolName
228152_s_at0.9422XM_037817LCGE22799FLJ31033
202446_s_at;0.9383;NM_021105PLSCR2phospholipid scramblase 2
202430_s_at;0.8859;
241916_at0.8782
213294_at0.9334P_ADB12769PRKRdsRNA-dependent protein
kinase
211012_s_at0.9311NM_002675PMLpromyelocytic leukemia
228230_at0.9273NM_033405PRIC285peroxisomal proliferator-
activated receptor A
202687_s_at0.9178NM_003810Apo-2LApo-2 Ligand
202863_at;0.9176;NM_003113SP140SP140 nuclear body protein
202864_s_at;0.8347;
210985_s_at0.5722
209498_at;0.8933;NM_001024912CEACAM1carcinoembryonic antigen-
211889_x_at;0.8386;related cell adhesion molecule 1
206576_s_at;0.8072;
211883_x_at0.7916
239277_at0.8897NM_001033583ACOT9acyl-CoA thioesterase 9
231769_at0.8783NM_018438FBXO6F-box protein 6
202307_s_at0.8742NM_000593TAP1transporter 1, ATP-binding
cassette, sub-family B
204698_at0.8735NM_002201ISG20interferon stimulated gene
20 kDa
218986_s_at0.8703NM_017631SGRA12061Hypothetical protein FLJ20035
FLJ20035
205569_at0.8675NM_014398LAMP3lysosomal-associated membrane
protein 3
223599_at0.8664NM_001003818TRIMP1tripartite motif-containing
pseudogene 1
230866_at;0.8656;NM_006639CYSLTR1cysteinyl leukotriene receptor 1
231747_at0.8600similar to Interferon-induced
216565_x_at0.8650XM_497663LOC391020transmembrane protein 3
223952_x_at;0.8623;NM_005771DHRS9dehydrogenase/reductase SDR
224009_x_at;0.8535;family member 9
219799_s_at0.8479
205241_at0.8614NM_001953SCO2SCO cytochrome oxidase
deficient homolog 2 yeast
227458_at;0.8601;NM_014143PDL1/B7-H1programmed cell death 1 ligand 1
223834_at0.7465
209969_s_at0.8576NM_007315STAT1signal transducer and activator
of transcription 1, 91 kDa
218999_at0.8561NM_018295AGPR4538hypothetical protein MGC5242
210705_s_at0.8341NM_033034TRIM5tripartite motif-containing 5
223167_s_at0.8334NM_013396USP25ubiquitin specific protease 25
229625_at;0.8324;NM_004120GBP5guanylate binding protein 5
238581_at0.8173
202837_at0.8278NM_006700TRAFD1TRAF-type zinc finger domain
containing 1
223849_s_at0.8180NM_020963MOV10Mov10, Moloney leukemia virus
10, homolog mouse
222498_at;0.8175;NM_022461AZI25-azacytidine induced 2
227905_s_at0.7115
217933_s_at0.8138NM_015907LAP3leucine aminopeptidase 3
219519_s_at;0.8108;NM_023068SIGLEC1sialoadhesin
44673_at0.7884
208392_x_at0.8084NM_004509SP110SP110 nuclear body protein
239988_at0.8079NM_017912SKKS30637Hect domain and RLD 6
230314_at0.8074P_ADH28842CMLM110chronic myclogenous leukaemia
(CML) gene marker #110
227347_x_at0.8047NM_021170HES4hairy and enhancer of split 4
Drosophila
202411_at0.8038NM_005532IFI27interferon, alpha-inducible
protein 27
205003_at0.7974NM_014705DOCK4dedicator of cytokinesis 4
212185_x_at;0.7969;NM_005953MT2Ametallothionein 2A
206461_x_at;0.7758;
217165_x_at0.7168
235256_s_at;0.7957;NM_138801GALMgalactose mutarotase aldose 1-
234974_at0.7601epimerase
206513_at0.7891NM_004833AIM2absent in melanoma 2
209546_s_at0.7869NM_003661APOL1apolipoprotein L, 1
204415_at0.7838NM_002038G1P3interferon, alpha-inducible
protein clone IFI-6-16
206553_at0.7821NM_001032731OAS22′-5′-oligoadenylate synthetase
2, 69/71 kDa
226169_at0.7746NM_030962SBF2SET binding factor 2
244398_x_at;0.7742;NM_152373ZNF684zinc finger protein 684
232563_at0.7017
238439_at0.7659NM_144590ANKRD22ankyrin repeat domain 22
227649_s_at0.7646NM_015326SRGAP2SLIT-ROBO Rho GTPase
activating protein 2
220998_s_at0.7644NM_030930UNC93B1unc-93 homolog B1 C. elegans
224973_at0.7612NM_017633FAM46Afamily with sequence similarity
46, member A
232034_at0.7581LOC203274
231455_at0.7560NM_001001695FLJ42418FLJ42418
208581_x_at;0.7546;NM_005952MT1Xmetallothionein 1X
204326_x_at;0.5699;
212859_x_at0.5285
224225_s_at0.7545NM_016135ETV7ets variant gene 7 (TEL2
oncogene)
205875_s_at0.7543NM_016381TREX1three prime repair exonuclease 1
209286_at0.7522NM_006449CDC42EP3CDC42 effector protein Rho
GTPase binding 3
205715_at0.7472NM_004334BST1bone marrow stromal cell
antigen 1
212285_s_at0.7414NM_198576AGRNagrin
230695_s_at0.7381NM_152732C6orf206chromosome 6 open reading
frame 206
219364_at0.7381NM_024119LGP2likely ortholog of mouse
D11lgp2
238455_at0.7371NM_032812PLXDC2Plexin domain containing 2
201641_at0.7343NM_004335BST2Bone marrow stromal antigen 2
219439_at0.7273NM_020156C1GALT1core 1 synthase, glyc-N-
acetylgal 3-beta-galtransferase, 1
234942_s_at0.7226NM_052951DNTTIP1deoxynucleotidyltransferase,
terminal, interacting protein 1
214933_at0.7212NM_000068CAC1Acalcium channel, voltage-
dependent, P/Q type, alpha 1A
219055_at0.7189NM_018079SRBD1S1 RNA binding domain 1
225447_at0.7179NM_000408GPD2glycerol-3-phosphate
dehydrogenase 2 mitochondrial
Breast cancer associated
236285_at0.7173P_AAF17573SYN22A2SYN22A2 coding sequence
200923_at0.7164NM_005567LGALS3BPlectin, galactoside-binding,
soluble, 3 binding protein
220104_at0.7159NM_020119ZC3HAV1zinc finger CCCH-type, antiviral 1
216950_s_at;0.7133;NM_000566FCGR1AFc fragment of IgG, high affinity
214511_x_at0.7050Ia, receptor CD64
230997_at0.7109NM_145755TTC21Atetratricopeptide repeat domain
21A
210889_s_at0.7099NM_001002273FCGR2BLow affinity immunoglobulin
gamma fc receptor ii-b
211456_x_at0.7045NM_001039954MT1P2metallothionein 1 pseudogene 2
235456_at;0.6926;NM_021063HIST1H2BDhistone 1, H2bd
235681_at0.4913
229194_at;0.6917;NM_032373PCGF5polycomb group ring finger 5
235331_x_at0.6769
230333_at0.6851NM_002970SATSpermidine/spermine N1-
acetyltransferase
231956_at0.6813NM_020954KIAA1618KIAA1618
235175_at0.6803NM_052941GBP4guanylate binding protein 4
232149_s_at0.6777NM_003580NSMAFneutral sphingomyelinase N-
SMase activation assoc factor
221653_x_at0.6762NM_030882APOL2apolipoprotein L, 2
219716_at0.6689NM_030641APOL6apolipoprotein L, 6
214909_s_at;0.6669;NM_013974DDAH2dimethylarginine
215537_x_at0.6366dimethylaminohydrolase 2
207500_at0.6654NM_004347CASP5caspase 5, apoptosis-related
cysteine protease
232081_at0.6648NM_004915ABCG1ATP-binding cassette, sub-
family G WHITE, member 1
230166_at0.6571NM_133465KIAA1958KIAA1958
239143_x_at0.6554NM_016271RNF138ring finger protein 138
217823_s_at0.6543NM_016021UBE2J1ubiquitin-conjugating enzyme
E2, J1 UBC6 homolog, yeast
242109_at0.6501NM_006519TCTEL1t-complex-associated-testis-
expressed 1-like 1
206175_x_at0.6420NM_013360ZNF230zinc finger protein 230
220252_x_at0.6318NM_025159CXorf21chromosome X open reading
frame 21
227268_at0.6213NM_016125PLFL4625PTD016 protein
216336_x_at0.6153NM_153341IBRDC3IBR domain containing 3
229804_x_at0.6077NM_018491CBWD1COBW domain containing 1
236013_at0.6011NM_000721CAC1Ecalcium channel, voltage-
dependent, alpha 1E subunit
227004_at0.5968NM_003159CDKL5cyclin-dependent kinase-like 5
226099_at0.5788NM_012081ELL2elongation factor, R polymerase
II, 2
227947_at0.5761NM_014721PHACTR2phosphatase and actin regulator 2
233264_at0.5515AK022088FLJ12026HEMBB1001816
235348_at0.5251NM_032859C13orf6chromosome 13 open reading
frame 6
225872_at0.5053NM_025181SLC35F5solute carrier family 35, member
F5
207291_at0.4851NM_024081PRRG4proline rich Gla G-
carboxyglutamic acid 4
transmembrane
234997_x_at0.4617CD684982EST1502human spermidine/spermine N1
acetyl transferase

Example 3

To further assess the extent to which gene combinations comprising one or more of the genes that have been identified herein correlate with an interferon response gene signature, the Pearson correlation of all possible three-gene combinations of 24 selected genes (Table 4A) were assessed. Data are shown in Table 4B.

Materials and Methods

PAXgene tubes from Qiagen/PreAnalytix (Valencia, Calif.) were used to collect whole blood from 35 SLE samples and 10 healthy donors. RNA was prepared by using a blood RNA isolation kit from Qiagen/PreAnalytix (Valencia, Calif.) and the expression of twenty-four interferon-alpha (IFN α) responsive genes was assayed using routine methods, e.g., by using primers/probes with TaqMan reagents from ABI (Foster City, Calif.). Relative abundance was determined by normalizing expression to RPL19. One “healthy” donor sample was removed from the analysis due to abnormally high expression of IFN responsive genes probably due to a recent viral infection. An Interferon Signature Metric (ISM) score was defined in the following manner:

    • 1. The average expression for each gene was calculated in the normal samples (“average normal expression”).
    • 2. Ratio of expression relative to the average normal expression (step #1) was tabulated.
    • 3. The ISM score is defined for each sample using a set of genes. The ISM score was the average of the expression ratios (step #2) for the set of genes in the given sample.

From the 24 IFNα responsive genes, it was possible to generate 2024 unique three-gene subsets. For each of the possible 2024 three-gene combination, Pearson correlations between three-gene ISM score and the twenty four-gene ISM score were calculated. All numerical analysis was performed using R (http://www [insert period] r-project [insert period] org/).

Result and Analysis

While most healthy donor samples had an ISM score near one, a significant fraction of SLE patients had considerably higher ISM scores. Further, all three-gene combination ISM scores served as high quality surrogates for the twenty four-gene ISM score. The histogram for the three-gene ISM score correlation with the twenty four-gene ISM score is shown in FIG. 5. The lowest Pearson correlation was 0.73 and 70% of the correlations were greater than 0.95.

As evident from Table 4B, all combinations showed significant correlation values, with the lowest value being about 0.73. This demonstrated the usefulness and flexibility of the genes disclosed hereinabove as markers of disease. Most, but not all, of the 24 selected genes are from Tables 1, 2 and/or 3. The high correlation observed, even for combinations comprising a gene(s) that is not listed in Tables 1, 2 and/or 3, further confirmed the usefulness and broad applicability of the genes disclosed hereinabove as disease markers.

TABLE 4A
List of selected 24 genes, with corresponding RefSeq ID.
EPSTI1NM_001002264
RIG1NM_014314
(DDX58)
OAS3NM_006187
HERC5NM_016323
PARP9NM_031458
SAMD9LNM_152703
TYKINM_207315
CHMP5NM_016410
ZBP1NM_030776
CIG5NM_080657
(RSAD2)
IFI44NM_006417
IFI44LNM_006820
IFIT1NM_001548
IFIT4 (IFIT3)NM_001549
IFIT5NM_012420
IRF7NM_004029
G1P2NM_005101
MX1NM_002462
OAS1NM_002534
OAS2NM_002535
OASLNM_003733
SP110NM_004509
RIGENM_002346
(LY6E)
XIAPNM_001167

TABLE 4B
All possible 3-gene combinations of a selected group of 24 genes,
indicated with their respective Pearson correlation values.
Pearson
Gene1Gene2Gene3Correlation
IFIT4OAS1MX10.996514
OASLCHMP5ZBP10.996478
IFI44LOASLCIG50.996391
IFI44LCIG5ZBP10.995869
EPSTI1TYKIMX10.995702
IFIT4HERC5TYKI0.995611
IFIT4TYKIXIAP0.995609
IFI44LOASLZBP10.995602
IFI44LIFIT4OASL0.995504
IFIT4OAS1IFIT10.995422
EPSTI1HERC5TYKI0.995392
IFI44LEPSTI1OASL0.995385
IFI44LEPSTI1OAS30.995345
EPSTI1TYKIIFIT10.99515
G1P2SAMD9LSP1100.99489
IRF7HERC5TYKI0.994867
IFIT5CIG5ZBP10.994863
IFI44LEPSTI1ZBP10.994776
IFI44LSP110ZBP10.994649
RIG1IRF7HERC50.994588
TYKIIFIT1XIAP0.994564
IFIT4TYKIMX10.994522
OASLIFI44ZBP10.994503
EPSTI1G1P2SAMD9L0.994402
IRF7SAMD9LMX10.99428
IFI44LOAS2OASL0.994232
IFI44LCIG5SP1100.994183
TYKIMX1XIAP0.994176
IFI44LOASLIRF70.994168
IFIT5IFIT4OAS30.994107
IRF7HERC5SAMD9L0.994056
OASLCIG5CHMP50.994043
IRF7TYKIIFIT10.993998
TYKIIFIT1SP1100.993932
IFIT4TYKIIFIT10.993875
CIG5HERC5TYKI0.993865
IFIT5IFIT4ZBP10.993786
OAS2OASLCHMP50.993676
IFI44LIFIT4RIGE0.993594
EPSTI1OAS3CHMP50.993546
IFI44LIFIT4OAS30.993513
EPSTI1G1P2TYKI0.993511
EPSTI1G1P2HERC50.99349
OAS1IRF7IFIT10.99348
IRF7TYKIMX10.993472
IFIT5OAS2ZBP10.993459
IRF7HERC5IFIT10.99345
IFI44LOASLXIAP0.993443
OAS1CIG5IFIT10.993431
IFIT4IRF7TYKI0.993429
HERC5TYKISP1100.993356
IFIT4RIG1TYKI0.993297
OAS1IRF7MX10.993259
IFIT5IRF7ZBP10.993164
IFIT4G1P2OAS10.993068
G1P2IRF7HERC50.992975
IFI44LOAS2CIG50.992931
CIG5SAMD9LTYKI0.992894
IRF7HERC5MX10.99289
OAS2OASLIFI440.992876
HERC5TYKIXIAP0.992863
OASLCIG5IFI440.992852
CIG5IFI44ZBP10.992827
IFIT5OAS2IRF70.992666
IFI44LIRF7CIG50.992636
TYKIMX1SP1100.992558
IFI44LOASLMX10.992556
OAS1CIG5MX10.992546
EPSTI1IFI44OAS30.992546
G1P2CIG5SAMD9L0.992522
EPSTI1RIG1TYKI0.99252
OASLSAMD9LIFIT10.992509
IFIT5EPSTI1ZBP10.992466
IFI44LHERC5RIGE0.992413
CIG5TYKIIFIT10.992392
IFI44LIRF7ZBP10.992374
G1P2IRF7SAMD9L0.992327
IFIT4SAMD9LTYKI0.992311
IFI44LOASLSP1100.992307
IFIT5OAS2CIG50.992229
IFI44LIFIT1RIGE0.992209
IFI44LIFIT4ZBP10.992195
IFI44LCIG5XIAP0.992193
IFIT5EPSTI1OAS30.99217
IFI44LOAS2EPSTI10.992154
IFI44LEPSTI1CIG50.992137
IFI44LOAS2SP1100.99207
EPSTI1SAMD9LTYKI0.99207
IFI44LMX1RIGE0.992058
OASLCHMP5XIAP0.992049
G1P2HERC5XIAP0.992014
IFI44LOASLIFIT10.992005
G1P2SAMD9LZBP10.991994
IFI44LEPSTI1RIGE0.991991
IFIT5OAS2MX10.991941
IRF7SAMD9LIFIT10.991891
IFI44LIRF7OAS30.991715
IFIT4EPSTI1TYKI0.991674
EPSTI1G1P2OAS10.991603
IFI44LOAS2ZBP10.991594
EPSTI1OAS1MX10.991562
CIG5HERC5SAMD9L0.99156
IFIT5OAS3IFIT10.991555
IFIT5OASLMX10.991528
OAS1IFIT1MX10.991486
IFIT4G1P2SAMD9L0.991439
IFIT5CIG5XIAP0.991397
OAS2IFI44ZBP10.991331
EPSTI1OASLCHMP50.991303
HERC5IFIT1XIAP0.991268
G1P2HERC5SP1100.99125
CIG5TYKIMX10.991247
OASLSAMD9LMX10.991199
IFIT5IFIT4OAS20.991186
IFIT5IRF7OAS30.991178
IFI44LOAS2IRF70.991172
IFIT5IFIT4OASL0.991098
IFIT5IRF7CIG50.991095
IFI44LOASLHERC50.991094
IFI44LRIGEXIAP0.99101
OASLIRF7CHMP50.990968
IFIT4SAMD9LMX10.990947
IFIT5OAS3MX10.990942
IFIT4G1P2HERC50.990937
G1P2OAS1CIG50.990933
G1P2IFIT1XIAP0.990886
SAMD9LMX1XIAP0.990878
OAS3CHMP5SP1100.990877
G1P2TYKISP1100.990867
EPSTI1OAS1IFIT10.990838
G1P2OASLSAMD9L0.990826
IFI44LCIG5RIGE0.990812
SAMD9LTYKISP1100.990776
IFIT5CIG5MX10.990775
CHMP5RIGEXIAP0.990758
OASLTYKIIFIT10.990748
HERC5MX1XIAP0.990729
EPSTI1G1P2IFIT10.9907
IRF7OAS3CHMP50.990687
EPSTI1OASLIFI440.990632
G1P2OAS1IFIT10.990614
IFIT5XIAPZBP10.990611
IFIT4OAS1HERC50.990512
IFIT4HERC5SAMD9L0.990506
EPSTI1IFI44ZBP10.990464
OASLCHMP5SP1100.990463
IFIT5OASLIFIT10.990412
EPSTI1TYKIXIAP0.990325
EPSTI1IRF7TYKI0.990315
G1P2SAMD9LXIAP0.990306
IFI44LCIG5OAS30.990281
IFIT5OAS2EPSTI10.990115
CIG5SAMD9LMX10.990079
SAMD9LTYKIZBP10.989993
OAS2TYKIIFIT10.989986
EPSTI1SAMD9LMX10.989945
IFI44RIGEZBP10.989942
IFIT5MX1RIGE0.989937
IFI44LOAS3SP1100.989929
IFIT5MX1ZBP10.98985
IFI44LSAMD9LRIGE0.989814
CIG5IFI44RIGE0.989794
OAS2CIG5IFI440.989763
OASLHERC5SAMD9L0.989717
IFIT4IRF7SAMD9L0.989667
IFIT5IFIT1RIGE0.989587
IFIT4IRF7HERC50.989574
IFIT5OASLZBP10.989563
TYKIIFIT1ZBP10.989561
G1P2CIG5HERC50.989534
HERC5TYKIMX10.9895
EPSTI1IFI44RIGE0.989498
G1P2OAS1MX10.989491
IRF7SAMD9LTYKI0.989455
CIG5IFI44OAS30.989384
IFIT5OASLCIG50.989345
IFIT4G1P2TYKI0.989323
IFI44LOAS3HERC50.989322
IFIT4TYKIZBP10.989292
IFIT5SP110ZBP10.98929
IFI44SP110ZBP10.989289
IFI44LXIAPZBP10.989258
HERC5TYKIIFIT10.989244
IFIT5OAS2IFIT10.989239
EPSTI1G1P2MX10.98921
G1P2IRF7IFIT10.989159
IFI44LIFIT4OAS20.989146
OAS3CHMP5XIAP0.989141
OASLOAS3CHMP50.989136
OASLIFI44XIAP0.989112
IFI44LEPSTI1SP1100.989091
IFI44LIRF7SP1100.989077
IFI44LIFIT4CIG50.989073
CIG5OAS3CHMP50.989057
IFI44RIGEXIAP0.989037
CIG5SAMD9LIFIT10.989029
IFI44LCIG5HERC50.989011
IFIT5OAS3HERC50.988963
IFIT4HERC5XIAP0.988945
IFIT4HERC5MX10.988925
IFIT5OAS3XIAP0.988891
IFI44LIFIT4SP1100.988869
IFI44LOAS3XIAP0.988845
CHMP5RIGEZBP10.988767
CIG5CHMP5RIGE0.988756
IFI44LOAS3IFIT10.988746
RIG1IRF7SAMD9L0.988717
IFI44MX1RIGE0.988705
SAMD9LIFIT1XIAP0.988634
EPSTI1CHMP5RIGE0.988543
IFI44LCIG5MX10.988509
IFIT5MX1SP1100.988438
HERC5TYKIZBP10.988437
OAS1IFIT1ZBP10.988433
IFIT4HERC5IFIT10.988422
IRF7TYKIXIAP0.988382
IFIT5IFIT1ZBP10.988359
IFIT5OAS2OASL0.988341
IFIT5IFIT4CIG50.988316
SAMD9LIFIT1ZBP10.988312
G1P2IFIT1SP1100.988303
OAS1IFIT1XIAP0.9883
OASLSAMD9LTYKI0.988278
HERC5CHMP5RIGE0.988269
IFIT4OAS1TYKI0.988268
OAS2OAS1IFIT10.988248
G1P2MX1XIAP0.988232
OAS1HERC5MX10.988215
OAS1CIG5HERC50.988211
HERC5SAMD9LZBP10.988167
OAS2HERC5TYKI0.988163
IFI44OAS3ZBP10.988139
CIG5CHMP5ZBP10.988136
IFI44LIRF7RIGE0.988106
IFIT4IFI44OAS30.988101
OAS2SAMD9LTYKI0.988081
IFIT5CIG5IFIT10.988073
IFIT5EPSTI1CIG50.988072
IFIT4OASLIFI440.98801
IFI44HERC5RIGE0.987984
IFIT4G1P2XIAP0.987951
IFI44LMX1SP1100.98795
OAS1MX1XIAP0.987945
RIG1IRF7IFIT10.987936
IFIT4RIG1HERC50.987933
IFIT4SAMD9LIFIT10.987928
IFI44LEPSTI1IRF70.987927
IFIT4OAS1IRF70.987914
IFIT5OASLXIAP0.987913
IFIT4IFI44RIGE0.987912
IFIT5CIG5OAS30.987904
IFIT4SAMD9LXIAP0.987896
OAS2G1P2SAMD9L0.987775
OASLHERC5IFIT10.987735
IRF7IFI44OAS30.987734
IFIT5CIG5HERC50.98773
EPSTI1HERC5MX10.987723
G1P2CIG5TYKI0.98772
IFIT5IFIT4RIGE0.987715
IFI44LRIGEZBP10.987715
IFIT5OASLIRF70.987699
OAS1HERC5IFIT10.987696
EPSTI1HERC5SAMD9L0.987685
OASLIRF7IFI440.98768
IFI44LRIG1OASL0.987635
EPSTI1RIG1G1P20.987607
IFIT4CIG5TYKI0.987605
OAS2EPSTI1IFI440.987589
IFIT5OAS2XIAP0.987588
OAS2TYKIMX10.987555
OASLIFI44MX10.987554
CHMP5MX1RIGE0.987534
IFI44LOAS3MX10.987521
IFI44OAS3SP1100.987441
EPSTI1HERC5IFIT10.987435
G1P2HERC5IFIT10.987431
IFIT4TYKISP1100.9874
OAS2IFI44RIGE0.987335
IRF7HERC5XIAP0.987327
OAS3CHMP5ZBP10.987314
HERC5SAMD9LXIAP0.987305
G1P2HERC5SAMD9L0.987303
OASLHERC5TYKI0.987292
RIG1IRF7TYKI0.987272
IFI44OAS3XIAP0.987263
OASLTYKIMX10.987226
SAMD9LMX1ZBP10.987216
G1P2TYKIXIAP0.987186
RIG1IFIT1XIAP0.987143
CIG5HERC5IFIT10.987143
OASLCHMP5MX10.987113
IFIT5CIG5SP1100.987103
HERC5SAMD9LMX10.987078
EPSTI1SAMD9LIFIT10.987021
IFI44LEPSTI1XIAP0.986996
IFIT4G1P2IFIT10.986962
IFIT5OAS2SP1100.986961
TYKIIFIT1MX10.986955
IFI44IFIT1RIGE0.98694
G1P2OAS1IRF70.986929
RIG1TYKIXIAP0.986927
IFI44LSP110XIAP0.986913
IFIT5EPSTI1OASL0.986895
OASLIFI44SP1100.986847
SAMD9LMX1SP1100.986839
IFIT4IFIT1XIAP0.986801
G1P2SAMD9LMX10.986792
SAMD9LTYKIMX10.986776
IFIT1MX1XIAP0.986772
RIG1HERC5XIAP0.986653
IFIT4SAMD9LZBP10.986638
CIG5IFI44SP1100.986615
RIG1TYKIMX10.986584
IFI44LCIG5IFIT10.986574
CIG5TYKIXIAP0.986567
SAMD9LTYKIXIAP0.986554
IFI44LRIG1RIGE0.986514
IFIT4OASLCHMP50.986483
IFI44LOAS2MX10.986478
CIG5IFI44XIAP0.98647
IFI44LG1P2RIGE0.986469
IRF7IFI44ZBP10.986437
EPSTI1CIG5IFI440.986418
RIG1CIG5TYKI0.986387
RIG1TYKIIFIT10.986336
IFIT5EPSTI1MX10.986313
IRF7IFIT1XIAP0.986307
IFIT4MX1XIAP0.98627
IFIT4OAS3CHMP50.986258
G1P2IRF7MX10.986258
OAS2IFI44SP1100.986255
IFIT5G1P2CIG50.986247
IFI44LHERC5SP1100.986229
G1P2OASLIFIT10.986183
G1P2SAMD9LIFIT10.986168
TYKIMX1ZBP10.986151
CHMP5IFIT1RIGE0.986136
OAS1IRF7HERC50.986057
IRF7IFIT1MX10.986039
IFIT5HERC5RIGE0.985983
IFIT5OAS2HERC50.985946
RIG1IRF7MX10.985944
IFI44XIAPZBP10.985944
IFI44LG1P2OASL0.985941
IFIT5OASLHERC50.98592
G1P2HERC5MX10.985913
OAS2OAS1MX10.98591
IFIT5G1P2ZBP10.985875
OAS1CIG5TYKI0.985852
RIG1G1P2HERC50.985831
OAS1OASLIFIT10.985827
G1P2CIG5IFIT10.985799
IFI44LOAS3ZBP10.985763
IFI44LOAS2XIAP0.985746
IFIT5HERC5ZBP10.985738
RIG1HERC5MX10.985734
IRF7CIG5TYKI0.985724
CIG5HERC5MX10.985709
IFIT4RIG1SAMD9L0.985702
OAS2SAMD9LMX10.985696
OAS3HERC5CHMP50.985677
OASLHERC5CHMP50.985675
EPSTI1G1P2XIAP0.985614
IFIT4G1P2MX10.985575
OAS2SAMD9LIFIT10.985558
IFI44OAS3HERC50.985493
IFIT4OASLTYKI0.985491
IFIT5OAS2G1P20.985467
CHMP5SP110ZBP10.985431
RIG1MX1XIAP0.985418
IFI44LHERC5ZBP10.985411
G1P2HERC5ZBP10.985399
IFI44LMX1ZBP10.985399
RIG1HERC5IFIT10.985388
OASLIFI44IFIT10.985349
RIG1OAS1MX10.985314
IFIT4IFI44ZBP10.985306
IFIT4OASLSAMD9L0.985271
OASLIFI44HERC50.985262
IFIT4OAS2TYKI0.985259
IRF7CHMP5RIGE0.985241
G1P2IRF7TYKI0.98524
RIG1SAMD9LMX10.985203
G1P2OASLHERC50.985184
IFI44LIFIT4EPSTI10.985167
SAMD9LIFIT1SP1100.985161
HERC5SAMD9LSP1100.985136
IFI44LEPSTI1MX10.985133
IFIT4CHMP5RIGE0.985089
IFI44LIFIT1SP1100.985074
OASLCHMP5IFIT10.985052
IFI44LOAS2RIGE0.985038
OAS1MX1ZBP10.985036
IFIT5G1P2SP1100.985035
RIG1HERC5TYKI0.98502
IFI44LOAS2HERC50.985013
OASLIFI44OAS30.984994
IFIT5OAS3ZBP10.984992
IRF7CIG5IFI440.984947
EPSTI1CHMP5ZBP10.984947
IFI44LG1P2SP1100.984929
IFIT5IFIT4SP1100.984889
IFI44OAS3MX10.984882
IFIT5IFIT4XIAP0.984858
G1P2OAS1ZBP10.984857
IFI44LOAS2IFIT10.984833
IFIT5EPSTI1IRF70.984785
IFI44LIFIT1ZBP10.984771
G1P2OAS1HERC50.984751
IFI44LOAS3SAMD9L0.984637
IFIT5EPSTI1XIAP0.984622
OAS2IRF7IFI440.984619
IFIT4IRF7IFIT10.984565
IFIT5IFIT1SP1100.984547
SAMD9LTYKIIFIT10.984535
HERC5SAMD9LIFIT10.984528
IFI44LCIG5TYKI0.984518
RIG1OAS1IFIT10.984505
IFI44LOASLSAMD9L0.984455
IRF7IFI44RIGE0.984421
IFI44LG1P2CIG50.98441
OAS2CHMP5RIGE0.98438
G1P2TYKIIFIT10.984362
IFIT5G1P2OASL0.98435
SAMD9LCHMP5RIGE0.98435
IFIT4OAS1CIG50.984347
OAS2HERC5SAMD9L0.98434
IFIT4G1P2IRF70.984323
G1P2HERC5TYKI0.984302
IRF7CIG5SAMD9L0.984261
EPSTI1G1P2IRF70.984258
OAS1TYKIMX10.984212
IFI44LRIG1CIG50.984189
IFI44OAS3IFIT10.984148
OAS1CIG5SAMD9L0.984088
IRF7SAMD9LXIAP0.984046
IFIT4OAS1XIAP0.983986
G1P2MX1SP1100.983965
OAS1TYKIIFIT10.983952
IFIT4OAS1SAMD9L0.983939
IRF7MX1XIAP0.983917
G1P2IFI44RIGE0.983911
EPSTI1OAS1TYKI0.983904
IFI44LOASLTYKI0.983891
IFIT5OAS2PARP90.983888
RIG1G1P2XIAP0.983881
IFIT5G1P2RIGE0.983874
OAS2CHMP5ZBP10.983861
IFIT4RIG1OAS10.983828
G1P2IFIT1ZBP10.983828
IFIT4IRF7MX10.983803
OASLHERC5MX10.983775
RIG1CIG5SAMD9L0.983728
IFIT5RIGEXIAP0.983696
HERC5IFIT1SP1100.983625
IFIT5CIG5PARP90.983607
OASLCHMP5RIGE0.983598
IFI44LIFIT4XIAP0.983588
IRF7SAMD9LZBP10.983584
IFIT5OAS3SAMD9L0.983578
G1P2TYKIZBP10.983567
EPSTI1OAS1HERC50.983564
HERC5IFIT1MX10.983432
IFIT4EPSTI1G1P20.98341
IFIT5MX1XIAP0.983401
SAMD9LIFIT1MX10.983359
OAS3CHMP5MX10.983261
OAS2IFI44OAS30.983253
IFIT4OAS1ZBP10.983249
G1P2IRF7XIAP0.983205
OAS3CHMP5IFIT10.983177
HERC5IFIT1ZBP10.983163
IFIT5IFIT4EPSTI10.983135
IFIT5OAS3SP1100.983121
OAS1IFIT1SP1100.983118
OAS2CIG5CHMP50.983111
IFI44LOASLOAS30.983103
G1P2OAS1SP1100.983094
G1P2OAS1XIAP0.983073
EPSTI1IRF7HERC50.983059
IFIT5EPSTI1G1P20.983057
IFIT5IFIT4IRF70.983047
IFI44LEPSTI1HERC50.982974
OAS2G1P2OAS10.982973
IFIT4RIG1G1P20.98284
EPSTI1IRF7SAMD9L0.982832
OAS3SAMD9LIFIT10.98283
G1P2TYKIMX10.982823
IFIT5IRF7MX10.982823
CIG5IFI44MX10.982815
IFIT5IRF7SP1100.982806
EPSTI1IFIT1MX10.982804
OAS2G1P2HERC50.982779
HERC5SAMD9LTYKI0.982773
OASLTYKICHMP50.98276
OAS1SAMD9LMX10.982709
IFI44LTYKIRIGE0.982691
IFI44LRIG1OAS30.982688
IFIT4IFIT1MX10.982616
EPSTI1CIG5TYKI0.982605
G1P2CIG5MX10.982585
TYKICHMP5RIGE0.982585
IFI44LIFIT4IRF70.982564
IFIT5CIG5TYKI0.982489
G1P2CHMP5RIGE0.98248
IFIT5OAS3PARP90.982456
IFIT4EPSTI1OAS10.98245
CIG5CHMP5XIAP0.982444
IRF7CHMP5ZBP10.982443
IFIT5SAMD9LRIGE0.982442
CIG5CHMP5SP1100.982432
IFIT5EPSTI1IFIT10.982364
IFIT5G1P2OAS30.982346
OAS2IFI44XIAP0.982312
CIG5IFI44HERC50.982284
OAS2G1P2TYKI0.982279
RIG1G1P2IFIT10.982209
IFI44LEPSTI1G1P20.982198
OASLIFIT1MX10.982165
OAS1OASLMX10.982158
IFIT4RIG1MX10.982123
IFI44LTYKISP1100.982105
IFIT5RIG1ZBP10.982033
IFI44LSP110RIGE0.982032
IFI44LEPSTI1IFIT10.982017
IFIT4CIG5SAMD9L0.981999
IFIT5IFIT4MX10.981994
IFIT5RIG1OAS30.981987
OAS2IFI44MX10.981967
OAS2G1P2IFIT10.981944
IFIT4OAS2IFI440.981942
IFIT5CIG5RIGE0.981929
RIG1G1P2SAMD9L0.981924
EPSTI1TYKIZBP10.981909
IFIT5RIG1CIG50.9819
IFI44LG1P2ZBP10.981887
OAS2HERC5IFIT10.981886
G1P2OASLIFI440.981878
IFI44SAMD9LRIGE0.981874
IFIT5SP110XIAP0.981729
CIG5PARP9SAMD9L0.981712
OAS3HERC5SAMD9L0.981703
EPSTI1RIG1HERC50.981663
IFIT5EPSTI1RIGE0.981653
RIG1SAMD9LZBP10.981639
HERC5MX1SP1100.981627
IFIT5IRF7XIAP0.981625
IFIT4RIG1IFIT10.981605
IFI44MX1ZBP10.9816
RIG1G1P2IRF70.98159
IFI44LCIG5PARP90.981588
IRF7TYKIZBP10.981572
IFI44LOAS1CIG50.981535
OAS1MX1SP1100.981522
IRF7CIG5HERC50.981504
OASLIFI44RIGE0.98145
IFIT5HERC5SP1100.981389
IFIT4CIG5IFI440.981344
EPSTI1PARP9TYKI0.981338
IFI44LIRF7XIAP0.981327
G1P2IFIT1MX10.981177
SAMD9LIFIT1RIGE0.981164
CHMP5XIAPZBP10.981034
IRF7CIG5CHMP50.98102
IFI44LCIG5SAMD9L0.980991
G1P2OASLTYKI0.980952
IFIT4EPSTI1SAMD9L0.980931
CIG5SAMD9LXIAP0.98087
IFI44LRIG1ZBP10.980847
G1P2OASLCHMP50.98084
RIG1CIG5HERC50.980836
IFI44LOAS2G1P20.980731
IFI44LOAS2TYKI0.980703
IFIT5OAS2RIG10.980656
IFI44LEPSTI1TYKI0.980647
RIG1TYKISP1100.980579
EPSTI1IFIT1XIAP0.980575
IFI44SP110RIGE0.980565
IFI44HERC5ZBP10.980564
EPSTI1CIG5CHMP50.980544
EPSTI1IFI44XIAP0.980516
IFIT5OAS2TYKI0.980487
EPSTI1IRF7IFIT10.980474
IFI44LTYKIZBP10.98047
IFI44LOAS2OAS30.980469
EPSTI1IFI44SP1100.980453
OAS1OAS3IFIT10.980399
G1P2OASLMX10.980398
OAS1CHMP5RIGE0.980281
IFIT5EPSTI1HERC50.98028
OAS1SAMD9LIFIT10.980165
OAS3TYKICHMP50.980145
IFIT4EPSTI1HERC50.980116
OAS2EPSTI1CHMP50.980093
IFI44LOAS3TYKI0.980031
EPSTI1HERC5XIAP0.980031
RIG1SAMD9LIFIT10.98002
IFI44LOAS1RIGE0.980003
G1P2SAMD9LRIGE0.979981
IFIT5IFIT1XIAP0.979977
IFI44LOASLPARP90.979964
CHMP5SP110RIGE0.979922
OAS2OAS3CHMP50.979909
IFIT5EPSTI1SP1100.97989
RIG1HERC5SAMD9L0.97989
OAS2CHMP5SP1100.979884
G1P2SAMD9LTYKI0.979881
IFIT5OAS2OAS30.979865
CIG5IFIT1MX10.97981
IFI44LG1P2OAS30.979733
IFIT5TYKIZBP10.97972
CIG5IFI44IFIT10.979594
OAS2IFI44HERC50.979577
IFIT4PARP9TYKI0.979539
OAS1OAS3CHMP50.979509
IFIT5IRF7RIGE0.979509
TYKIXIAPZBP10.979497
EPSTI1MX1XIAP0.979484
CIG5HERC5XIAP0.979467
IFIT5RIGEZBP10.979447
OAS3SAMD9LCHMP50.979429
IFIT5IRF7IFIT10.979416
EPSTI1IRF7IFI440.979334
G1P2CIG5IFI440.979329
IFIT4G1P2ZBP10.979297
IFIT4OASLIFIT10.979261
EPSTI1IRF7MX10.979237
IFI44IFIT1ZBP10.979214
IFI44LMX1XIAP0.979195
HERC5MX1ZBP10.979186
IFI44LIRF7MX10.979186
OAS1PARP9IFIT10.979168
OAS2IRF7TYKI0.979158
EPSTI1RIG1IFIT10.979136
EPSTI1RIG1MX10.979132
IFI44LOAS3PARP90.979131
IFI44MX1SP1100.979127
OAS1IRF7CIG50.979073
IFIT4PARP9SAMD9L0.979062
IFIT4HERC5ZBP10.979058
RIG1CHMP5RIGE0.979057
G1P2CIG5XIAP0.979049
OAS1HERC5ZBP10.979026
IFI44LOASLRIGE0.979004
OAS2IRF7CHMP50.978997
EPSTI1RIG1SAMD9L0.978996
OASLIRF7SAMD9L0.978946
OAS2HERC5MX10.978889
HERC5SAMD9LRIGE0.978849
IFIT4CIG5HERC50.978822
IFIT4OASLHERC50.978804
RIG1G1P2MX10.978789
IFIT5CIG5SAMD9L0.978769
IFI44LOAS1OAS30.978759
OAS3SAMD9LMX10.978718
RIG1TYKIZBP10.978668
G1P2IFI44ZBP10.978638
EPSTI1IFI44MX10.97863
OAS2IFI44IFIT10.978619
CIG5PARP9TYKI0.978512
EPSTI1PARP9SAMD9L0.978467
EPSTI1SAMD9LXIAP0.978424
IFIT5OAS3TYKI0.978409
IFIT5OASLSP1100.978403
IFI44SP110XIAP0.978398
IFI44LIFIT4MX10.978348
IFI44LOAS2RIG10.978343
CIG5IFIT1XIAP0.978337
RIG1OASLCHMP50.978325
IFI44LSAMD9LZBP10.978297
IFIT5IFIT4IFIT10.978296
OAS1IRF7TYKI0.97822
IFIT5OASLSAMD9L0.978202
IRF7TYKISP1100.978191
SAMD9LMX1RIGE0.978177
IFIT5OASLTYKI0.978163
PARP9SAMD9LXIAP0.978139
G1P2IFI44OAS30.978119
OAS1HERC5XIAP0.97802
IFIT4OAS2SAMD9L0.978019
IFI44LIRF7HERC50.978014
RIG1OASLSAMD9L0.97801
G1P2MX1ZBP10.977958
IFI44LOAS2PARP90.977945
OAS3SAMD9LTYKI0.977935
PARP9IFIT1XIAP0.977901
G1P2OAS1OASL0.977848
IFIT4OAS2OAS10.977813
IFI44OAS3SAMD9L0.977801
IFI44TYKIRIGE0.97779
IFIT5SAMD9LZBP10.977734
OAS2EPSTI1TYKI0.977724
PARP9SAMD9LIFIT10.977718
RIG1SAMD9LXIAP0.977704
OAS3TYKIIFIT10.977699
IFIT5RIG1OASL0.977613
TYKISP110XIAP0.977603
PARP9TYKIIFIT10.977602
G1P2OAS1SAMD9L0.977585
PARP9TYKIXIAP0.977542
OASLIFI44TYKI0.977504
IFIT5IRF7HERC50.977473
IRF7IFI44SP1100.977459
IFIT5EPSTI1TYKI0.977454
IRF7CIG5IFIT10.977446
OAS2OAS1HERC50.977433
CIG5TYKICHMP50.977361
IFIT5IFIT4HERC50.977353
IFIT4EPSTI1MX10.977281
IFI44LRIG1SP1100.977267
IFIT5OASLPARP90.977265
IFIT4EPSTI1IFIT10.977256
RIG1IFIT1MX10.977255
IFI44LIFIT4HERC50.977207
IFIT4G1P2CIG50.977176
CIG5IFI44TYKI0.9771
OAS1TYKIZBP10.977098
OAS2G1P2IFI440.977092
OASLSAMD9LCHMP50.977068
IFIT4IFI44SP1100.977067
G1P2PARP9SAMD9L0.977067
IFIT4CHMP5ZBP10.977042
CIG5HERC5CHMP50.976966
IFIT4G1P2OASL0.976916
OAS2G1P2MX10.976841
G1P2IRF7CIG50.97684
IFIT4OAS1PARP90.976808
OAS1SAMD9LZBP10.976794
IFIT4OAS3SAMD9L0.976791
IFI44LIFIT1XIAP0.97677
IFI44LIRF7IFIT10.976769
IFIT4IFIT1ZBP10.976725
G1P2IFI44SP1100.976722
OAS2OAS1TYKI0.976711
IFIT5OAS2RIGE0.976711
EPSTI1G1P2PARP90.97671
IFIT5TYKISP1100.976687
G1P2OAS3SAMD9L0.976675
RIG1IFI44RIGE0.976614
IFIT4EPSTI1IFI440.976597
RIG1OAS3CHMP50.976452
EPSTI1OAS1SAMD9L0.976439
RIG1G1P2CIG50.976418
CIG5CHMP5MX10.976409
OAS1IRF7SAMD9L0.976378
OAS3HERC5IFIT10.976367
OAS2IRF7SAMD9L0.976358
IFIT5IFIT4G1P20.976294
EPSTI1OAS1IRF70.976291
IFI44HERC5SP1100.976272
IFI44OAS3RIGE0.976262
IFIT4G1P2SP1100.976253
EPSTI1G1P2IFI440.976186
OASLIFIT1XIAP0.976181
IRF7PARP9SAMD9L0.976177
IRF7HERC5ZBP10.976154
OAS3CHMP5RIGE0.976111
OASLTYKIXIAP0.976092
IFI44LOAS2SAMD9L0.976088
IFI44LOAS1OASL0.976054
IFIT1MX1SP1100.976025
IFI44LHERC5XIAP0.975972
IFIT5G1P2XIAP0.975971
IFIT5OAS2SAMD9L0.975959
IFIT5HERC5XIAP0.975949
OASLIFI44SAMD9L0.975842
IFIT5EPSTI1PARP90.975824
EPSTI1IFI44HERC50.975738
SAMD9LTYKIRIGE0.975714
IFI44OAS3TYKI0.975702
IFIT5TYKIRIGE0.97567
RIG1CIG5IFIT10.975658
HERC5PARP9SAMD9L0.975637
G1P2OAS3CHMP50.975579
OAS1HERC5TYKI0.975575
IFIT5OASLOAS30.975559
IFI44LIFIT4IFIT10.975549
SAMD9LXIAPZBP10.975489
EPSTI1OASLTYKI0.975407
IFI44LEPSTI1PARP90.975398
OASLIRF7IFIT10.975396
RIG1OAS1CIG50.975346
RIG1OASLIFIT10.975344
IFIT4OAS1OASL0.975331
OAS3HERC5TYKI0.975303
OAS1IFI44RIGE0.975295
OAS2IFIT1MX10.97529
IFIT1MX1ZBP10.975252
CIG5MX1XIAP0.975204
OAS1CIG5PARP90.97518
IFIT5PARP9ZBP10.975163
IFI44LOAS1ZBP10.97516
IFI44LEPSTI1RIG10.975122
IFIT4OASLMX10.975118
OASLIRF7TYKI0.975116
OAS2RIG1TYKI0.97509
OAS2CHMP5XIAP0.975079
OASLSAMD9LXIAP0.975079
HERC5PARP9IFIT10.975059
RIG1G1P2OAS10.975034
RIG1OASLIFI440.974999
IFI44OAS3PARP90.974929
IFIT4IFI44XIAP0.974925
IRF7IFIT1ZBP10.974912
PARP9SAMD9LMX10.97489
OAS1IFIT1RIGE0.974859
EPSTI1SAMD9LZBP10.974825
HERC5PARP9XIAP0.974823
EPSTI1TYKISP1100.974822
IFIT4CIG5IFIT10.974778
G1P2OAS1TYKI0.974713
IFI44IFIT1SP1100.974708
HERC5PARP9TYKI0.9747
EPSTI1G1P2ZBP10.974674
IFI44LOAS2OAS10.974667
IFI44TYKIZBP10.974642
EPSTI1CHMP5XIAP0.974537
IFIT4SAMD9LSP1100.974501
TYKICHMP5ZBP10.974475
EPSTI1G1P2CIG50.974468
OAS1IFI44OAS30.974458
EPSTI1IFI44IFIT10.974387
OAS1OAS3MX10.974382
OAS2TYKIXIAP0.974363
OAS1OASLHERC50.974357
IFIT5G1P2IRF70.974308
OAS1OASLCHMP50.974297
TYKIIFIT1RIGE0.974282
OAS1PARP9MX10.974256
OAS2IFI44TYKI0.974177
OAS1CIG5IFI440.974175
RIG1IFI44OAS30.974125
IFI44LIFIT4TYKI0.974105
OAS1CIG5CHMP50.974105
OAS2PARP9SAMD9L0.974104
IRF7CIG5MX10.974084
CHMP5SP110XIAP0.974042
EPSTI1CHMP5SP1100.973988
OAS1TYKIXIAP0.973951
HERC5CHMP5ZBP10.973937
CIG5TYKIZBP10.973936
IFI44LSAMD9LSP1100.973933
IFIT4HERC5PARP90.973933
IFIT5OAS1CIG50.97391
G1P2PARP9XIAP0.973887
OAS1CIG5XIAP0.973886
CHMP5MX1ZBP10.973864
TYKICHMP5SP1100.973768
EPSTI1PARP9IFIT10.97373
IRF7CHMP5SP1100.973693
CIG5IFI44PARP90.973655
G1P2PARP9IFIT10.973599
EPSTI1CIG5SAMD9L0.973586
G1P2IRF7ZBP10.97357
EPSTI1IRF7CHMP50.973555
OASLIFI44PARP90.973554
OAS2TYKICHMP50.973542
RIG1G1P2TYKI0.973532
IRF7IFI44XIAP0.973462
IFIT5RIG1RIGE0.973451
IFIT5IFIT4TYKI0.973442
G1P2HERC5PARP90.97344
OAS2CHMP5MX10.973422
PARP9SAMD9LTYKI0.973386
IFI44MX1XIAP0.973355
RIG1SAMD9LTYKI0.973328
CIG5CHMP5IFIT10.973246
CIG5HERC5PARP90.973244
IFI44LIFIT4G1P20.973197
OASLIRF7HERC50.973112
IFIT4CIG5CHMP50.973104
OAS2OAS1SAMD9L0.973103
G1P2CIG5CHMP50.973073
RIG1G1P2SP1100.973048
IFIT4CIG5MX10.973006
IFI44LEPSTI1OAS10.973006
IFIT4OAS3TYKI0.973003
G1P2XIAPZBP10.97295
OASLPARP9SAMD9L0.972938
EPSTI1HERC5PARP90.972841
IFIT1XIAPZBP10.972814
IFIT4PARP9IFIT10.972796
CHMP5MX1SP1100.972719
PARP9TYKIMX10.972707
IFIT4MX1ZBP10.972638
IFI44LEPSTI1SAMD9L0.972539
IFIT5IFIT1MX10.972533
IFI44LG1P2XIAP0.972515
EPSTI1IFI44TYKI0.972495
IFIT4OAS2HERC50.97249
IFIT4RIG1XIAP0.97246
IFIT5HERC5MX10.972458
OAS1TYKISP1100.972445
EPSTI1OAS1CIG50.972368
CIG5PARP9IFIT10.972329
IFIT4OAS2G1P20.972297
IFIT4IRF7IFI440.972137
HERC5IFIT1RIGE0.97204
IFI44LPARP9RIGE0.971994
RIG1CIG5MX10.971955
CIG5IFI44SAMD9L0.971908
CHMP5IFIT1ZBP10.971907
CIG5SAMD9LZBP10.971889
G1P2OAS1PARP90.971807
IRF7PARP9IFIT10.97179
OAS3TYKIMX10.971782
OAS2HERC5CHMP50.97176
IRF7HERC5PARP90.971671
IFIT4G1P2PARP90.971625
EPSTI1TYKICHMP50.971602
IRF7IFI44MX10.971595
OAS1OASLSAMD9L0.971575
IFIT4OAS2CHMP50.971528
IFI44LG1P2IRF70.971506
OAS1HERC5SP1100.971466
RIG1OASLTYKI0.971392
IRF7PARP9TYKI0.971348
IFIT4OAS1OAS30.971335
G1P2CHMP5ZBP10.971335
IFIT4HERC5SP1100.971301
IFI44TYKISP1100.971298
OAS2IRF7HERC50.97127
IFIT4OAS2IFIT10.971233
IFI44LPARP9SP1100.971191
IFIT5OAS1OAS30.971185
OAS2IRF7IFIT10.971184
OAS2IFI44PARP90.971174
IFI44LPARP9ZBP10.971145
G1P2CHMP5SP1100.971088
OAS1HERC5SAMD9L0.971083
G1P2CIG5PARP90.971042
IFIT5PARP9XIAP0.971027
EPSTI1CHMP5MX10.970954
G1P2SP110XIAP0.970897
OASLHERC5XIAP0.970881
RIG1IFIT1ZBP10.97081
G1P2OASLXIAP0.970803
OAS2PARP9TYKI0.970766
IFI44LIFIT4OAS10.970742
IFIT5G1P2MX10.970738
EPSTI1CIG5HERC50.970734
EPSTI1OAS1PARP90.970723
HERC5TYKIRIGE0.970716
OAS1OAS3HERC50.970715
G1P2IFIT1RIGE0.970712
IFIT4IRF7XIAP0.970712
HERC5CHMP5SP1100.970697
IFI44LOAS3RIGE0.970693
RIG1CIG5IFI440.970657
EPSTI1OASLSAMD9L0.970657
RIG1G1P2ZBP10.970629
RIG1HERC5ZBP10.970593
IFI44SAMD9LZBP10.970587
OAS1IRF7XIAP0.970567
IFIT4IFI44MX10.970564
OAS1OASLTYKI0.970536
OAS1OASLIFI440.970435
OAS1OAS3SAMD9L0.970395
OAS1IRF7ZBP10.970393
IFI44LTYKIXIAP0.970382
HERC5XIAPZBP10.970322
OAS2CHMP5IFIT10.970286
EPSTI1OAS1XIAP0.970174
IFI44LIRF7TYKI0.970096
IFI44LHERC5MX10.970092
PARP9MX1XIAP0.970089
IFIT5EPSTI1RIG10.970015
IFIT5IFIT4PARP90.97001
G1P2OAS3IFIT10.96993
OAS3HERC5MX10.969845
OASLMX1XIAP0.969812
OAS1IFI44ZBP10.969803
G1P2HERC5RIGE0.969762
IFIT5PARP9SP1100.969753
G1P2OAS3HERC50.969712
OAS1MX1RIGE0.969615
HERC5PARP9MX10.969607
IFI44IFIT1XIAP0.969589
RIG1OASLHERC50.969589
CIG5TYKISP1100.969581
G1P2IRF7SP1100.969568
IFIT5IFI44LRIGE0.969542
IFI44HERC5XIAP0.96949
RIG1IFI44ZBP10.969468
IFIT5HERC5IFIT10.969441
IRF7IFI44HERC50.96943
RIG1OAS1HERC50.969339
IFIT5TYKIXIAP0.969273
EPSTI1G1P2OASL0.969257
IFIT5G1P2IFIT10.969226
TYKIMX1RIGE0.969116
OAS3PARP9CHMP50.969112
EPSTI1G1P2CHMP50.96899
IFIT4SAMD9LRIGE0.968926
IFIT4OAS1SP1100.968908
OAS2CIG5TYKI0.968886
EPSTI1CIG5IFIT10.968832
IFIT4RIG1IRF70.968749
OASLIRF7MX10.968693
IFIT4IFIT1SP1100.968688
OAS2OAS1IFI440.968687
OAS2RIG1SAMD9L0.968678
IFIT5EPSTI1SAMD9L0.968673
OAS1CHMP5ZBP10.968667
IFI44LOAS1SP1100.968637
EPSTI1RIG1OAS10.968633
G1P2OAS1OAS30.968589
IFIT4IFI44HERC50.968562
IFI44PARP9RIGE0.96854
IRF7SAMD9LSP1100.96853
OASLCIG5TYKI0.968523
EPSTI1HERC5CHMP50.96846
OAS2G1P2CHMP50.968446
IRF7OAS3SAMD9L0.968439
G1P2OASLIRF70.968413
EPSTI1OASLIFIT10.968391
IFIT4OAS3HERC50.968353
IFIT5IRF7TYKI0.968333
RIG1OAS1IRF70.968329
EPSTI1IFIT1ZBP10.968297
OASLCIG5SAMD9L0.968278
IRF7MX1ZBP10.968177
OAS1HERC5PARP90.968172
G1P2PARP9TYKI0.968154
CHMP5IFIT1SP1100.968058
IFIT4CHMP5SP1100.968014
IFI44LIFIT1MX10.967969
IFIT4OAS2MX10.967961
IRF7CHMP5XIAP0.967909
IFIT5OAS1ZBP10.967889
IRF7IFI44IFIT10.967883
IFI44LHERC5IFIT10.967852
OAS2IFI44SAMD9L0.967841
OAS2G1P2IRF70.967815
EPSTI1PARP9MX10.967795
EPSTI1HERC5ZBP10.967772
OASLPARP9CHMP50.967676
G1P2IFI44XIAP0.967671
PARP9SAMD9LZBP10.967633
IFIT5TYKIMX10.967584
OAS2EPSTI1G1P20.967581
IFIT4OAS3IFIT10.967551
IFIT5OAS2OAS10.967489
IFIT5IFI44LOAS30.967466
OAS3IFIT1MX10.967409
IFIT5SAMD9LSP1100.967392
IFIT4PARP9MX10.967359
EPSTI1OAS1ZBP10.967286
IFIT5PARP9RIGE0.967265
OAS1SAMD9LXIAP0.967252
PARP9IFIT1MX10.967202
OASLPARP9IFIT10.967188
IFIT4PARP9XIAP0.967184
G1P2OAS1RIGE0.967087
IFI44LPARP9XIAP0.967006
IRF7HERC5SP1100.966994
IFIT5G1P2HERC50.96692
IFI44LIFIT4SAMD9L0.966918
EPSTI1G1P2SP1100.966913
IFIT4EPSTI1CHMP50.966844
OAS2OAS1CHMP50.966812
EPSTI1IFI44PARP90.966774
IFIT4IFI44IFIT10.966763
CIG5SAMD9LCHMP50.966661
IFI44LIFIT4PARP90.966617
IFIT5RIG1SP1100.966575
EPSTI1CIG5MX10.966555
EPSTI1CHMP5IFIT10.966528
OAS2IFIT1XIAP0.966404
MX1XIAPZBP10.966334
HERC5MX1RIGE0.966315
IFIT5OAS1RIGE0.966293
G1P2PARP9MX10.966277
IFI44LTYKIMX10.96627
IFI44PARP9ZBP10.966234
OAS1CIG5ZBP10.966217
IFIT4G1P2IFI440.966203
IFIT4MX1SP1100.966196
OAS2OAS1IRF70.966139
IFIT4CHMP5XIAP0.966104
IFIT5IFIT4SAMD9L0.966044
RIG1OASLMX10.966034
IFIT5IRF7PARP90.96594
G1P2IRF7PARP90.965876
OAS2RIG1IFI440.965818
IFI44LG1P2MX10.96579
IRF7IFIT1SP1100.965745
OAS2EPSTI1SAMD9L0.965666
CHMP5MX1XIAP0.965604
OAS2PARP9IFIT10.965491
EPSTI1OAS1IFI440.96548
OAS2IRF7MX10.965404
OAS1SAMD9LRIGE0.965336
IFIT1SP110XIAP0.965321
RIG1G1P2OASL0.965315
IFI44LOAS1MX10.965307
G1P2IRF7IFI440.965102
IFIT5TYKIIFIT10.965094
IFI44LG1P2HERC50.965057
IFI44LG1P2IFIT10.965022
IFIT5SP110RIGE0.965009
EPSTI1OASLHERC50.964998
OAS2RIG1IFIT10.964968
IFI44LIRF7SAMD9L0.964937
OAS3PARP9SAMD9L0.964908
IFIT4IFI44TYKI0.964883
PARP9TYKISP1100.964876
IFIT5IFIT4RIG10.964868
EPSTI1OAS3TYKI0.964834
IFI44LIFIT4RIG10.964794
IFIT1MX1RIGE0.96478
OAS2SAMD9LXIAP0.964778
IFIT5IFIT4OAS10.964745
OASLPARP9TYKI0.96474
OAS1SAMD9LTYKI0.964718
EPSTI1OAS3SAMD9L0.964666
CIG5PARP9MX10.96462
OAS2G1P2XIAP0.964584
G1P2TYKIRIGE0.964575
OAS1OAS3TYKI0.964457
SAMD9LCHMP5ZBP10.964434
IFI44LTYKIIFIT10.964427
G1P2OAS3TYKI0.964415
IFIT4TYKIRIGE0.964415
IFIT5PARP9IFIT10.964404
IFI44HERC5MX10.964284
IFI44LOAS1IRF70.964253
OAS1IRF7PARP90.964194
IFIT5OASLRIGE0.964094
IFIT5PARP9MX10.963954
G1P2CIG5ZBP10.963938
IFIT5OAS1OASL0.963852
IRF7CHMP5MX10.963787
IFIT5EPSTI1OAS10.963774
OAS1PARP9XIAP0.963475
OAS1HERC5RIGE0.963465
EPSTI1MX1ZBP10.963452
EPSTI1OASLMX10.963447
IRF7PARP9MX10.963413
IFI44TYKIXIAP0.963301
G1P2MX1RIGE0.96322
EPSTI1IFI44SAMD9L0.963203
OAS1PARP9SAMD9L0.963196
IFI44LOAS1IFIT10.963135
IFI44LIRF7PARP90.963058
OAS1SAMD9LSP1100.963012
IFIT5IRF7SAMD9L0.963
EPSTI1OAS1CHMP50.962935
IFIT4IRF7CHMP50.962925
IFIT4EPSTI1XIAP0.96284
CIG5HERC5ZBP10.962817
PARP9TYKIZBP10.96278
OASLCIG5IFIT10.962747
OAS1PARP9TYKI0.962615
IFI44LHERC5TYKI0.962603
OAS2EPSTI1IFIT10.962552
CIG5PARP9CHMP50.962508
IFI44LRIG1IRF70.962495
IFI44LSAMD9LXIAP0.962462
IFI44LIFI44RIGE0.9624
IRF7HERC5CHMP50.962383
OASLSAMD9LZBP10.962363
OAS2CIG5SAMD9L0.962348
OAS2RIG1HERC50.962318
OAS2HERC5XIAP0.962291
IFIT5SAMD9LMX10.962201
CIG5IFIT1ZBP10.962115
HERC5SP110XIAP0.962086
RIG1IFIT1SP1100.962019
OAS2OAS1PARP90.962018
RIG1CIG5CHMP50.961991
IFI44IFIT1MX10.961953
IFIT5OAS1MX10.961952
HERC5CHMP5XIAP0.961934
RIG1HERC5SP1100.961903
OAS3SAMD9LXIAP0.961841
RIG1SAMD9LSP1100.961804
CHMP5IFIT1XIAP0.961773
G1P2OAS3MX10.961665
TYKICHMP5XIAP0.961658
TYKISP110ZBP10.961568
OAS2HERC5PARP90.961517
G1P2IFI44MX10.961483
IFIT4OAS1IFI440.961474
IRF7IFI44TYKI0.961401
IFI44LRIG1XIAP0.961392
SAMD9LSP110XIAP0.961343
PARP9SAMD9LSP1100.961334
IFIT5IFI44LOASL0.961265
OAS2G1P2PARP90.961245
OASLHERC5PARP90.961238
RIG1MX1ZBP10.96122
OAS2RIG1G1P20.961201
IRF7OAS3IFIT10.961186
OAS2EPSTI1OAS10.96115
IFI44SAMD9LSP1100.961138
OAS1XIAPZBP10.961114
IFIT4G1P2OAS30.961085
IFIT5RIG1XIAP0.961054
IFIT5SAMD9LXIAP0.961053
IFI44HERC5IFIT10.960963
IFIT5RIG1IRF70.96093
IFI44LCHMP5RIGE0.960881
IFIT4OAS3MX10.960838
IFIT5OAS3RIGE0.960806
OAS2EPSTI1HERC50.960756
OAS2MX1XIAP0.960748
IFIT4TYKICHMP50.960741
EPSTI1RIG1IFI440.960722
IFIT5HERC5TYKI0.960702
OASLCIG5HERC50.960689
IFI44LSAMD9LMX10.960664
IFIT5IFI44LCIG50.960571
IFIT4EPSTI1IRF70.960461
IRF7MX1SP1100.96046
IFI44LOAS1XIAP0.960455
IFIT5CHMP5RIGE0.960416
IFIT5IFI44RIGE0.960385
IFIT5RIG1MX10.960368
MX1SP110XIAP0.960338
IRF7OAS3HERC50.960332
IRF7OAS3TYKI0.960205
IFI44PARP9SP1100.960125
OASLTYKIZBP10.960125
IRF7CHMP5IFIT10.960021
OAS2SAMD9LCHMP50.959993
G1P2IFI44HERC50.959978
IFIT4CHMP5MX10.959927
IFI44TYKIMX10.959842
G1P2OASLCIG50.959832
IFIT4CIG5XIAP0.959816
IFIT4OAS1RIGE0.959814
OAS2TYKIZBP10.959811
IRF7TYKICHMP50.959787
OAS3IFIT1XIAP0.959775
OAS2OAS1CIG50.959672
G1P2CHMP5XIAP0.959471
G1P2IFI44IFIT10.959467
IFI44LPARP9IFIT10.959464
G1P2OASLPARP90.959415
IFIT5HERC5PARP90.959387
OAS1OASLIRF70.959375
OAS1IFI44SP1100.959304
IFI44PARP9XIAP0.959285
IFIT5OAS1IFIT10.959283
PARP9CHMP5RIGE0.959251
OAS3TYKIXIAP0.959059
IFIT5IFI44OAS30.959005
IFIT5OAS3CHMP50.959002
RIG1CHMP5ZBP10.958994
IFIT4IFIT1RIGE0.958926
EPSTI1PARP9XIAP0.958805
RIG1OAS1ZBP10.958689
OAS1IFI44MX10.958663
EPSTI1OAS3IFIT10.958634
IFIT5G1P2PARP90.95861
OAS2EPSTI1MX10.958508
PARP9IFIT1ZBP10.958503
IFIT4HERC5CHMP50.958451
G1P2CIG5SP1100.958403
IFI44LPARP9MX10.958264
OAS1CHMP5SP1100.95826
G1P2PARP9SP1100.958153
OAS1TYKIRIGE0.958151
IFIT4HERC5RIGE0.958132
RIG1OAS1TYKI0.958104
IFIT4IRF7PARP90.958024
IFIT4EPSTI1PARP90.957986
IFIT5SAMD9LIFIT10.957766
RIG1IRF7XIAP0.957764
CIG5SAMD9LSP1100.957721
IFI44LIFI44OAS30.957601
IFIT5G1P2TYKI0.9576
IFI44LHERC5PARP90.957553
RIG1OAS3SAMD9L0.957356
EPSTI1OAS1OASL0.957294
IFIT4XIAPZBP10.95721
IFI44LSAMD9LIFIT10.957107
IFI44LG1P2TYKI0.957049
OAS2RIG1MX10.957032
IFI44TYKIIFIT10.957022
CIG5PARP9XIAP0.957014
IFIT4IRF7ZBP10.956993
IFI44LG1P2OAS10.956925
OAS1OASLCIG50.956894
IFIT4IFI44PARP90.95679
EPSTI1OAS3HERC50.956754
IFIT4G1P2RIGE0.956716
IFIT4IRF7CIG50.956703
IFIT4OAS1CHMP50.956662
IFI44LOAS1HERC50.956626
G1P2IRF7CHMP50.956597
IFIT4IFI44SAMD9L0.956274
IFIT5IFI44LZBP10.956233
IFI44LRIG1MX10.956172
IFIT4CHMP5IFIT10.95615
IFIT5OAS1IRF70.956078
OASLCIG5MX10.956076
OASLIFIT1ZBP10.956072
OAS2G1P2CIG50.956019
OAS2PARP9CHMP50.956009
G1P2PARP9ZBP10.955951
OAS2OASLTYKI0.955901
OAS1IRF7IFI440.955882
IFI44HERC5TYKI0.955752
OAS3HERC5XIAP0.955729
RIG1PARP9IFIT10.955722
OAS2CIG5IFIT10.955705
IFIT4OASLXIAP0.955698
IFIT4CIG5PARP90.955687
OASLPARP9MX10.955668
PARP9IFIT1SP1100.955597
IFIT4EPSTI1RIG10.95557
EPSTI1OAS1OAS30.955534
OAS2TYKISP1100.955523
IFIT4G1P2CHMP50.955509
OAS1IFI44IFIT10.955489
IFIT5IFI44LOAS20.955474
RIG1IFI44SP1100.955462
IFIT5G1P2SAMD9L0.955415
RIG1MX1SP1100.955384
CIG5MX1ZBP10.955366
IFI44LHERC5SAMD9L0.955348
EPSTI1SAMD9LCHMP50.955332
RIG1OAS1XIAP0.955331
EPSTI1IRF7XIAP0.95532
IFIT5RIG1IFIT10.955282
EPSTI1SAMD9LSP1100.955279
EPSTI1G1P2OAS30.955231
OAS2CIG5HERC50.955226
TYKICHMP5MX10.955217
IFI44LOAS3CHMP50.955174
SAMD9LRIGEXIAP0.955126
OAS3PARP9IFIT10.955055
RIG1PARP9SAMD9L0.955049
HERC5PARP9ZBP10.954901
OAS2SAMD9LZBP10.954865
EPSTI1IFIT1SP1100.954814
IFIT5OAS1SP1100.954676
OAS1PARP9ZBP10.954667
SAMD9LCHMP5SP1100.954657
IFI44LG1P2SAMD9L0.954471
IRF7PARP9XIAP0.954463
CIG5OAS3SAMD9L0.95446
OAS1IRF7OAS30.954415
HERC5CHMP5MX10.954364
OAS1IFI44XIAP0.954344
IRF7IFI44SAMD9L0.954318
OAS1OASLXIAP0.954263
IFI44LOASLIFI440.954204
IFI44SAMD9LXIAP0.954127
OAS2PARP9MX10.9541
OAS1CHMP5MX10.95402
OAS2OASLSAMD9L0.953851
IRF7IFI44PARP90.953769
OAS2OAS1XIAP0.953577
IFI44LG1P2PARP90.953542
EPSTI1HERC5SP1100.953434
IRF7SAMD9LRIGE0.953308
EPSTI1PARP9CHMP50.953256
OAS1IRF7CHMP50.953118
IFIT5HERC5SAMD9L0.95311
IFIT5G1P2OAS10.953008
IFI44SAMD9LMX10.952969
IFIT5OAS1XIAP0.952878
IFIT4MX1RIGE0.952876
IFI44LRIG1IFIT10.952657
CIG5HERC5SP1100.95255
IFIT4OASLIRF70.952437
IFIT5PARP9TYKI0.952387
OAS1OASLPARP90.952351
IFIT5OASLIFI440.952334
TYKICHMP5IFIT10.952291
EPSTI1IRF7PARP90.95219
IRF7CIG5XIAP0.952171
IFIT1RIGEXIAP0.952097
CIG5IFIT1SP1100.952015
G1P2OASLZBP10.951985
EPSTI1RIG1IRF70.951946
IFI44LPARP9TYKI0.951921
IFI44PARP9MX10.951919
OAS3PARP9TYKI0.951916
CIG5OAS3TYKI0.951891
G1P2IFI44TYKI0.951838
OAS2RIG1CHMP50.951825
EPSTI1TYKIRIGE0.951667
RIG1PARP9TYKI0.951655
HERC5PARP9SP1100.951639
IFIT4RIG1ZBP10.951613
RIG1HERC5PARP90.951503
G1P2OAS1IFI440.951439
IRF7OAS3MX10.951423
IFI44PARP9IFIT10.95141
CHMP5IFIT1MX10.951388
EPSTI1MX1SP1100.951254
OAS2RIG1OAS10.951245
IFI44LRIG1HERC50.951245
IFIT5CIG5IFI440.951244
TYKIRIGEXIAP0.951171
EPSTI1SAMD9LRIGE0.951147
HERC5TYKICHMP50.951145
EPSTI1OAS3MX10.951138
HERC5CHMP5IFIT10.951107
IFI44LCIG5IFI440.951044
IFI44LOASLCHMP50.951043
G1P2SP110ZBP10.951027
SAMD9LSP110ZBP10.95089
G1P2CHMP5MX10.950868
OAS2OASLIFIT10.950862
PARP9CHMP5ZBP10.950852
OAS3HERC5PARP90.95078
EPSTI1RIG1XIAP0.950771
OASLTYKISP1100.950742
IFIT4RIG1CIG50.950667
OAS1IRF7SP1100.950651
OAS1CHMP5IFIT10.950645
IFIT5IFI44LEPSTI10.950585
IFIT5OASLCHMP50.950564
OAS1CHMP5XIAP0.950413
OAS3MX1XIAP0.950368
OASLHERC5ZBP10.950235
IFI44HERC5PARP90.950187
OAS1IFI44HERC50.95016
RIG1OAS1SAMD9L0.950071
G1P2HERC5CHMP50.949965
RIG1OAS3IFIT10.9499
IRF7CIG5PARP90.949776
IFI44LSAMD9LTYKI0.949773
IFI44CHMP5RIGE0.949687
G1P2OAS3XIAP0.949642
OAS1CIG5SP1100.949578
OAS2CIG5MX10.949555
IFIT5OAS1HERC50.949513
OAS1OAS3PARP90.94951
G1P2IRF7OAS30.949402
G1P2CHMP5IFIT10.949251
IFIT5RIG1HERC50.948959
IFIT4RIG1IFI440.948886
IFI44LOAS1TYKI0.948871
RIG1IFI44XIAP0.94863
IFIT5PARP9SAMD9L0.948596
IFI44SAMD9LIFIT10.948585
IFIT4OASLPARP90.948562
IFIT4EPSTI1ZBP10.948539
IFIT5RIG1G1P20.948086
OAS1CIG5OAS30.947983
G1P2IFI44PARP90.947968
IFIT5IFI44LSP1100.947938
EPSTI1CIG5PARP90.947921
EPSTI1RIG1CHMP50.947831
IFIT5IFI44ZBP10.947787
IFI44LPARP9SAMD9L0.947734
G1P2IFI44SAMD9L0.947721
IFI44LOAS1PARP90.947446
IFI44HERC5SAMD9L0.947347
OAS2IFIT1ZBP10.947303
IFIT4EPSTI1CIG50.947143
RIG1G1P2PARP90.947042
IFIT4RIG1OASL0.946997
OAS2G1P2ZBP10.946916
CIG5OAS3IFIT10.946822
G1P2RIGEXIAP0.946802
OAS1OAS3XIAP0.946769
IFIT5SAMD9LTYKI0.946742
RIG1CIG5XIAP0.946738
CIG5SAMD9LRIGE0.946558
IRF7IFIT1RIGE0.946462
IFI44LIFI44ZBP10.946452
PARP9MX1ZBP10.946362
IFIT5OAS2IFI440.946333
EPSTI1G1P2RIGE0.946322
HERC5RIGEXIAP0.946188
CIG5MX1SP1100.946153
RIG1SAMD9LRIGE0.946083
RIG1IRF7IFI440.946068
IRF7SAMD9LCHMP50.946026
G1P2TYKICHMP50.945962
RIG1OAS3HERC50.945918
RIG1IRF7CIG50.945803
OASLMX1ZBP10.945774
G1P2OAS1CHMP50.945734
IFIT4OAS2IRF70.945691
CIG5OAS3HERC50.945585
IFIT4SAMD9LCHMP50.945499
IFIT5CIG5CHMP50.945489
EPSTI1OAS1SP1100.945479
IRF7TYKIRIGE0.945447
RIG1IFI44MX10.945413
EPSTI1IFIT1RIGE0.945395
IFIT4OAS2PARP90.945338
IFI44LRIG1G1P20.945334
IFI44OAS3CHMP50.945317
OAS2OAS1ZBP10.945291
RIG1OAS3TYKI0.945221
SAMD9LCHMP5XIAP0.945205
PARP9SAMD9LRIGE0.945185
OAS2G1P2OASL0.944851
PARP9CHMP5XIAP0.944816
IFIT4EPSTI1OASL0.944671
IFI44LOAS2IFI440.944632
IFIT4PARP9ZBP10.944622
EPSTI1CIG5XIAP0.944456
RIG1OAS1OASL0.944438
OAS1HERC5CHMP50.94431
IFI44PARP9TYKI0.944208
PARP9CHMP5SP1100.944124
IFIT1SP110ZBP10.944046
IFI44LCIG5CHMP50.943778
IFIT5IFI44LIFIT40.943771
PARP9MX1SP1100.943665
RIG1CHMP5SP1100.943533
OAS2OASLHERC50.9435
OAS1OASLZBP10.9435
IFIT4OAS2XIAP0.943449
MX1RIGEXIAP0.943426
CIG5TYKIRIGE0.943328
EPSTI1IRF7CIG50.943287
IRF7HERC5RIGE0.943132
RIG1PARP9MX10.942814
OAS2HERC5ZBP10.942715
IFIT4RIG1PARP90.942684
SAMD9LCHMP5MX10.942597
OASLSAMD9LSP1100.942585
G1P2OAS3PARP90.942554
OAS1IFI44TYKI0.942437
OASLIFIT1SP1100.942318
IFI44LEPSTI1IFI440.942267
OAS3SAMD9LZBP10.942149
OAS1PARP9SP1100.942068
OAS1SP110XIAP0.942012
IFI44LRIG1TYKI0.94201
IFIT5OAS1PARP90.94199
G1P2OASLSP1100.941717
IFI44SAMD9LTYKI0.941631
IFIT4CIG5ZBP10.941466
EPSTI1HERC5RIGE0.941431
IFIT5OAS1TYKI0.941419
IFIT5EPSTI1IFI440.941395
IFI44LOAS1SAMD9L0.941117
OAS2OASLMX10.941065
IFIT5CHMP5ZBP10.940941
OAS2G1P2SP1100.940753
OAS3PARP9MX10.940695
OASLIFI44CHMP50.940462
RIG1IFI44IFIT10.940444
IRF7XIAPZBP10.940387
IFIT4OAS3XIAP0.940303
OAS1TYKICHMP50.940259
HERC5SP110ZBP10.940142
G1P2CIG5OAS30.939919
OAS1IFI44PARP90.939836
IFIT4PARP9CHMP50.9396
RIG1IFI44HERC50.939599
IFIT4IRF7OAS30.939488
G1P2IRF7RIGE0.939474
IFIT5IFI44LXIAP0.939166
EPSTI1OAS1RIGE0.938921
RIG1PARP9XIAP0.938797
EPSTI1IRF7ZBP10.938775
IFIT5OAS2CHMP50.938637
IFIT4OASLCIG50.938552
EPSTI1MX1RIGE0.938432
IFIT5IFI44LIRF70.938421
OASLPARP9XIAP0.938359
IFIT5IFI44LMX10.93825
CIG5IFIT1RIGE0.938229
EPSTI1RIG1PARP90.938162
IFIT5RIG1TYKI0.938067
IFI44PARP9SAMD9L0.937964
IRF7PARP9CHMP50.937956
SAMD9LCHMP5IFIT10.937945
IFI44LIFI44SP1100.937911
OAS3TYKIZBP10.937748
IFIT4OAS3PARP90.937712
CIG5OAS3MX10.937685
IFI44LCHMP5ZBP10.937606
RIG1OAS1PARP90.937438
OAS2SAMD9LSP1100.937426
IRF7MX1RIGE0.937279
OAS2OAS1OASL0.937248
RIG1IFIT1RIGE0.93718
OAS2MX1ZBP10.937132
G1P2SAMD9LCHMP50.936982
EPSTI1XIAPZBP10.936697
RIG1G1P2IFI440.936637
OAS1CIG5RIGE0.936614
OASLIRF7XIAP0.936603
PARP9IFIT1RIGE0.936593
HERC5SAMD9LCHMP50.93654
IFIT4SP110XIAP0.936501
IFIT4OAS2EPSTI10.936231
RIG1CIG5PARP90.936225
IFIT4EPSTI1OAS30.936192
IFIT5IFI44SP1100.936081
PARP9CHMP5IFIT10.935858
SAMD9LTYKICHMP50.935842
OAS2IFIT1SP1100.935741
OAS1IRF7RIGE0.935686
OASLOAS3SAMD9L0.935639
CIG5HERC5RIGE0.935444
OAS1RIGEXIAP0.935361
G1P2CIG5RIGE0.935304
IFIT5IFI44LIFIT10.935275
PARP9CHMP5MX10.935232
RIG1OAS3MX10.935175
IFI44LOAS2CHMP50.934781
RIG1OAS1OAS30.934681
OASLHERC5SP1100.934566
PARP9TYKICHMP50.934504
OAS3IFIT1ZBP10.934375
SAMD9LRIGEZBP10.934283
HERC5PARP9CHMP50.93411
IFIT5IFIT4IFI440.934012
EPSTI1OASLPARP90.933922
OAS3TYKISP1100.933864
CIG5IFI44CHMP50.933838
MX1SP110ZBP10.933692
RIG1CHMP5XIAP0.933629
OAS1IFI44SAMD9L0.933607
IFI44LIFIT4IFI440.933553
PARP9TYKIRIGE0.933515
IFIT4IRF7SP1100.933498
OAS2EPSTI1PARP90.933446
OAS1SP110ZBP10.933405
OAS2PARP9XIAP0.933338
IFIT5EPSTI1CHMP50.933165
EPSTI1OASLXIAP0.933115
IFIT4OASLZBP10.933099
EPSTI1PARP9ZBP10.932945
IFI44LEPSTI1CHMP50.932873
OASLOAS3IFIT10.932774
PARP9XIAPZBP10.932749
EPSTI1RIG1CIG50.93261
IFIT5OAS1SAMD9L0.932602
OASLMX1SP1100.932194
IFIT4OAS2RIG10.932084
RIG1TYKIRIGE0.932067
RIG1IRF7ZBP10.931911
EPSTI1OASLIRF70.931811
RIG1G1P2OAS30.931711
OAS2IRF7PARP90.931653
IFI44LRIG1OAS10.931497
G1P2PARP9CHMP50.931468
IFIT5RIG1PARP90.931134
IFIT5IFI44LHERC50.931073
RIG1IRF7CHMP50.930931
IFIT5IFI44XIAP0.930929
OAS3SAMD9LSP1100.930851
OASLOAS3TYKI0.930816
IFIT5IFI44MX10.930811
IRF7CIG5ZBP10.930782
RIG1IFI44TYKI0.930705
IFI44LIFI44XIAP0.930504
OASLIRF7PARP90.930323
CIG5XIAPZBP10.930024
IFIT5IFI44LG1P20.929939
OAS1OAS3ZBP10.92992
IFIT4RIG1CHMP50.929849
OAS2HERC5SP1100.929752
CIG5MX1RIGE0.929631
RIG1HERC5RIGE0.929627
HERC5PARP9RIGE0.929502
IFI44LRIG1SAMD9L0.929277
OAS3HERC5ZBP10.929262
IFIT4PARP9SP1100.929202
IFI44LIFI44MX10.929036
OAS1PARP9CHMP50.928969
IFI44LIRF7IFI440.928905
TYKIRIGEZBP10.928873
IFIT5IRF7IFI440.928864
IFIT4OAS2CIG50.928862
G1P2PARP9RIGE0.928789
IFI44LRIG1PARP90.928757
IFI44CHMP5ZBP10.928586
OAS2OAS3TYKI0.928574
OASLCIG5PARP90.928457
IFI44LCHMP5SP1100.928425
IFIT5CHMP5SP1100.92804
OAS2OAS3SAMD9L0.928004
RIG1OAS1SP1100.927916
IRF7PARP9ZBP10.927757
RIG1CHMP5MX10.927685
OASLCIG5XIAP0.927452
IFIT5IFI44IFIT10.927301
RIG1G1P2RIGE0.927147
OAS1PARP9RIGE0.926871
CIG5PARP9ZBP10.926818
OAS2EPSTI1IRF70.926537
OAS3IFIT1SP1100.926516
OAS2IRF7XIAP0.926247
OAS2MX1SP1100.926135
IFI44LIFI44IFIT10.926123
OAS1SAMD9LCHMP50.925906
OAS2CIG5PARP90.925828
EPSTI1OAS3PARP90.925671
G1P2OAS3ZBP10.925573
IFIT1RIGEZBP10.925539
IFIT4RIGEXIAP0.925317
OAS2IFI44CHMP50.925256
RIG1XIAPZBP10.925255
OASLIRF7CIG50.925231
OASLOAS3HERC50.92508
IFIT5IFI44LTYKI0.924932
EPSTI1RIG1ZBP10.924695
IFIT5RIG1SAMD9L0.924337
OAS2OAS3IFIT10.924255
IFI44LIFI44HERC50.924174
RIG1IRF7PARP90.923945
EPSTI1CIG5ZBP10.923914
OAS2OAS1SP1100.923858
IFIT5IFI44HERC50.923703
IFIT5G1P2IFI440.923603
RIG1MX1RIGE0.923568
IFIT4CIG5OAS30.92356
IFIT5IFIT4CHMP50.923303
EPSTI1IFI44CHMP50.923176
IFIT4RIG1OAS30.923081
RIG1OASLXIAP0.922837
RIG1CHMP5IFIT10.922695
PARP9MX1RIGE0.922687
OAS2SAMD9LRIGE0.922634
IFIT5IFI44LPARP90.92262
IFIT4EPSTI1SP1100.922466
IFI44LG1P2IFI440.922343
OAS3PARP9XIAP0.921953
OAS2EPSTI1XIAP0.921908
OAS2TYKIRIGE0.921747
IFIT4OAS2ZBP10.921651
RIG1HERC5CHMP50.92161
IFI44LIFIT4CHMP50.921594
EPSTI1IRF7OAS30.921499
RIG1OASLIRF70.921365
G1P2RIGEZBP10.921333
PARP9SAMD9LCHMP50.92129
IFIT5CHMP5XIAP0.921284
OAS3MX1ZBP10.921266
RIG1TYKICHMP50.92113
IFIT4OAS2OASL0.921102
RIG1OAS1IFI440.921011
OASLSAMD9LRIGE0.92072
OAS3HERC5SP1100.920417
EPSTI1OAS3XIAP0.920342
IFIT5CHMP5MX10.920248
OASLOAS3MX10.920206
G1P2OAS3SP1100.920122
G1P2OASLOAS30.920062
IFIT4CIG5SP1100.919544
IFI44LCHMP5XIAP0.919301
EPSTI1OASLCIG50.91928
OAS1OASLSP1100.919179
IFIT5IRF7CHMP50.919067
OAS2OAS1OAS30.918994
IFI44LIFI44TYKI0.918961
OAS1OASLOAS30.918852
HERC5RIGEZBP10.918551
OASLIFIT1RIGE0.91841
IFIT5RIG1OAS10.91814
OAS2IRF7CIG50.918041
IRF7OAS3XIAP0.918037
IFIT5IFI44TYKI0.917786
OAS1RIGEZBP10.917732
RIG1G1P2CHMP50.917667
IFI44LIRF7CHMP50.917628
OAS2IFIT1RIGE0.917465
OAS2OAS3HERC50.91737
IRF7OAS3PARP90.917026
IFI44LCHMP5MX10.916997
IFIT4IRF7RIGE0.916887
IFIT4RIG1SP1100.916864
IFIT5CHMP5IFIT10.916571
OASLTYKIRIGE0.916429
IFIT4EPSTI1RIGE0.916258
EPSTI1RIG1OASL0.916184
RIG1IFI44PARP90.916107
IFIT5IFI44LOAS10.915943
RIG1IFI44SAMD9L0.915918
IFI44CHMP5SP1100.915791
PARP9SP110XIAP0.915523
RIG1OAS1RIGE0.915317
OAS2CIG5XIAP0.915027
IFIT5IFI44LSAMD9L0.914239
IFI44LCHMP5IFIT10.914106
IFIT5IFI44PARP90.913922
OAS1OAS3SP1100.913805
IFI44LOAS1IFI440.913685
OAS2G1P2OAS30.913341
OAS3MX1SP1100.913024
MX1RIGEZBP10.91295
IFI44LIFI44PARP90.912714
RIG1CIG5ZBP10.912402
IFIT5HERC5CHMP50.912293
IFIT4SP110ZBP10.912203
CIG5OAS3PARP90.912168
IFIT5G1P2CHMP50.912138
IFIT4OAS3ZBP10.912117
IFIT4IFI44CHMP50.912012
OAS2RIG1IRF70.911984
IRF7SP110XIAP0.911965
TYKISP110RIGE0.9118
IFI44LHERC5CHMP50.911777
OAS2OAS3MX10.91137
OAS2G1P2RIGE0.911317
IFIT4PARP9RIGE0.911158
IFI44CHMP5XIAP0.910766
OAS2EPSTI1CIG50.910517
OASLIRF7ZBP10.910488
OASLXIAPZBP10.909994
IFI44LTYKICHMP50.909904
EPSTI1PARP9SP1100.909711
IFI44CHMP5MX10.909689
IFIT5TYKICHMP50.90968
G1P2OASLRIGE0.90961
IFI44LG1P2CHMP50.909576
IFIT5OAS1IFI440.909388
IFIT4CIG5RIGE0.908925
OAS2OAS1RIGE0.908806
OAS2HERC5RIGE0.908751
OASLHERC5RIGE0.908541
CIG5PARP9SP1100.908525
EPSTI1OASLZBP10.908429
RIG1OAS1CHMP50.90836
IFI44LIFI44SAMD9L0.907964
IRF7IFI44CHMP50.907863
CIG5OAS3XIAP0.907513
IRF7CIG5OAS30.907333
IFIT4OASLOAS30.906832
RIG1OASLCIG50.90659
SAMD9LSP110RIGE0.906569
EPSTI1SP110XIAP0.906534
IFIT5IFI44SAMD9L0.90643
EPSTI1CIG5OAS30.906354
IFI44CHMP5IFIT10.906304
OASLMX1RIGE0.906245
IRF7PARP9SP1100.906101
EPSTI1IRF7SP1100.906008
IFIT4OASLSP1100.905978
OAS2MX1RIGE0.90518
CIG5SP110XIAP0.90499
IFIT1SP110RIGE0.904324
IFI44HERC5CHMP50.904282
RIG1OASLPARP90.904259
OAS3SAMD9LRIGE0.904065
IFI44LOAS1CHMP50.903581
IRF7CIG5SP1100.903302
G1P2IFI44CHMP50.903298
G1P2SP110RIGE0.903287
OAS2EPSTI1RIG10.903249
OASLPARP9ZBP10.902995
OAS2OASLPARP90.902848
IFI44TYKICHMP50.902228
OAS1OASLRIGE0.901099
OAS2IRF7ZBP10.900596
OAS2RIG1PARP90.900166
OAS3IFIT1RIGE0.900065
OASLCIG5ZBP10.899594
EPSTI1RIGEXIAP0.899556
IFIT5OAS1CHMP50.89953
OAS2RIG1XIAP0.899013
IFIT5PARP9CHMP50.898064
OAS2OASLIRF70.898064
OAS3TYKIRIGE0.897749
OAS2EPSTI1ZBP10.897534
IFIT4RIG1RIGE0.897168
EPSTI1RIG1OAS30.896978
OAS2PARP9ZBP10.896335
IFIT4RIGEZBP10.896273
OAS1IFI44CHMP50.896108
IFIT5IFI44LRIG10.895894
IFI44LPARP9CHMP50.895497
IFIT4OAS2OAS30.895401
OAS2EPSTI1OASL0.895303
OAS2OASLXIAP0.895129
HERC5SP110RIGE0.894807
EPSTI1CIG5SP1100.894768
IFIT4OAS2SP1100.894337
IRF7RIGEXIAP0.8943
RIG1SAMD9LCHMP50.89381
IFI44LSAMD9LCHMP50.893745
PARP9RIGEXIAP0.89358
OAS2XIAPZBP10.893376
EPSTI1IRF7RIGE0.893012
EPSTI1PARP9RIGE0.892978
IFIT5SAMD9LCHMP50.892943
RIG1PARP9ZBP10.892935
CIG5RIGEXIAP0.892719
IFIT4OAS3SP1100.891861
MX1SP110RIGE0.891301
OAS3HERC5RIGE0.891101
RIG1IRF7OAS30.890525
OAS2RIG1CIG50.890495
EPSTI1OAS3ZBP10.890069
OAS1OAS3RIGE0.89006
IFI44LRIG1IFI440.88778
IFIT5IFI44LIFI440.88776
RIG1OAS3XIAP0.887549
IFI44PARP9CHMP50.887524
G1P2OAS3RIGE0.887416
EPSTI1CIG5RIGE0.887118
OAS2CIG5ZBP10.886902
OAS1SP110RIGE0.88684
CIG5PARP9RIGE0.886773
OAS2OASLCIG50.886112
IFI44SAMD9LCHMP50.885956
IFIT4OASLRIGE0.885918
IFIT5RIG1IFI440.885817
IRF7CIG5RIGE0.885643
IRF7OAS3ZBP10.885583
OAS3MX1RIGE0.885561
EPSTI1OASLOAS30.883489
IRF7SP110ZBP10.883248
OAS3XIAPZBP10.883087
RIG1PARP9CHMP50.882158
IFIT4OAS2RIGE0.881223
SP110XIAPZBP10.881076
OASLOAS3PARP90.880696
OAS3PARP9ZBP10.880421
RIG1IRF7SP1100.880086
EPSTI1SP110ZBP10.879636
RIG1OASLZBP10.879626
IRF7PARP9RIGE0.87949
OASLOAS3XIAP0.879447
RIG1SP110XIAP0.879006
OASLIRF7OAS30.878692
RIG1OAS3PARP90.878538
OASLSP110XIAP0.876723
OASLPARP9SP1100.875724
RIG1CIG5OAS30.875511
CIG5OAS3ZBP10.875241
OASLIRF7SP1100.874351
PARP9SP110ZBP10.873999
OAS2OAS3PARP90.873713
CIG5SP110ZBP10.873581
IFIT5IFI44LCHMP50.873435
EPSTI1OASLSP1100.872477
OAS2EPSTI1OAS30.872405
OAS2PARP9SP1100.87155
EPSTI1RIG1SP1100.871342
OASLCIG5OAS30.870785
RIG1CIG5SP1100.869263
EPSTI1RIGEZBP10.868804
IFIT4OAS3RIGE0.868713
OASLCIG5SP1100.867945
IFI44LIFI44CHMP50.867675
OAS2IRF7OAS30.867456
IFIT5IFI44CHMP50.867157
RIGEXIAPZBP10.866861
IFI44LRIG1CHMP50.864815
OAS2IRF7SP1100.863904
IFIT5RIG1CHMP50.863765
OAS2OAS3XIAP0.862892
OAS2OASLZBP10.862277
EPSTI1OAS3SP1100.861466
IRF7RIGEZBP10.861372
OAS3PARP9SP1100.861136
EPSTI1RIG1RIGE0.860936
IFIT4SP110RIGE0.860801
RIG1RIGEXIAP0.860302
OAS2EPSTI1SP1100.860174
CIG5RIGEZBP10.859596
OAS2SP110XIAP0.858564
EPSTI1OASLRIGE0.857914
OAS2RIG1OASL0.857565
OASLRIGEXIAP0.857553
OAS2CIG5OAS30.857493
IRF7OAS3SP1100.857288
OAS3SP110XIAP0.856743
RIG1IFI44CHMP50.855689
OAS2RIG1ZBP10.85545
RIG1PARP9SP1100.855367
OAS2CIG5SP1100.854157
OAS2EPSTI1RIGE0.852592
PARP9RIGEZBP10.852095
OASLCIG5RIGE0.850683
RIG1CIG5RIGE0.850622
OASLIRF7RIGE0.849649
CIG5OAS3SP1100.849016
OAS2RIGEXIAP0.848472
OASLPARP9RIGE0.847797
RIG1IRF7RIGE0.847049
OAS2PARP9RIGE0.84672
OAS2IRF7RIGE0.844908
OASLOAS3ZBP10.843861
OAS2CIG5RIGE0.84326
EPSTI1OAS3RIGE0.843087
OASLSP110ZBP10.840384
OAS3RIGEXIAP0.835809
RIG1OAS3ZBP10.835232
CIG5OAS3RIGE0.830689
IRF7OAS3RIGE0.830055
RIG1OASLOAS30.829875
OAS3PARP9RIGE0.829849
RIG1PARP9RIGE0.827293
RIG1SP110ZBP10.827103
OAS2OAS3ZBP10.825923
OAS2OASLOAS30.825647
EPSTI1SP110RIGE0.824627
SP110RIGEXIAP0.823548
OASLRIGEZBP10.821675
OAS2SP110ZBP10.821066
OAS2OASLSP1100.820454
CIG5SP110RIGE0.819918
RIG1OASLSP1100.818533
OAS3SP110ZBP10.814438
IRF7SP110RIGE0.814248
PARP9SP110RIGE0.812561
OAS2RIGEZBP10.810229
OASLOAS3SP1100.809037
RIG1RIGEZBP10.806619
OAS2OASLRIGE0.804693
OAS2RIG1OAS30.803515
OAS3RIGEZBP10.79653
RIG1OASLRIGE0.79316
OASLOAS3RIGE0.789533
OAS2OAS3SP1100.789077
OAS2RIG1SP1100.78802
RIG1OAS3SP1100.785883
SP110RIGEZBP10.781728
OAS2RIG1RIGE0.777652
OAS2OAS3RIGE0.7757
OASLSP110RIGE0.772656
RIG1OAS3RIGE0.761256
OAS2SP110RIGE0.75784
OAS3SP110RIGE0.7529
RIG1SP110RIGE0.725531