WO2007127756A2 - Methods and compositions for detecting autoimmune disorders - Google Patents

Abstract

The invention provides methods and compositions useful for detecting, prognosing and monitoring autoimmune disorders, such as systemic lupus erythematous (SLE), by detecting a greater level of expression of interferone-inducible genes as compared with a reference sample.

Description

METHODS AND COMPOSITIONS FOR DETECTING AUTOIMMUNE DISORDERS RELATED APPLICATION

This application is a non-provisional application filed under 37 CFR 1.53(b)(l), claiming priority under 35 USC 119(e) to provisional application number 60\794,393 filed April 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. Moreoever, 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 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 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 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 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 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 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 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 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 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 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, OASl, and MXl; or (2) OASL, CHMP5, and ZBPl; or (3) IFI44L, OASL, and CIG5; or (4) IFI44L,

CIG5, and ZBPl; or (5) EPSTIl, TYKI, and MXl; or (6) IFIT4, HERC5, and TYKI; or (7) IFIT4, TYKI, and XIAP; or (8) IFI44L, OASL, and ZBPl; or (9) IFI44L, IFIT4, and OASL; or (10) IFI4, OASl, and IFITl; or (11) EPSTIl, HERC5, and TYKI; or (12) IFI44L, EPSTIl, and OASL; or (13) IFI44L, EPSTIl, and OAS3; or (14) EPSTIl, TYKI, and IFITl; or (15) G1P2, SAMD9L, and SPl 10. 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 Ll 9 (RPL 19; NP 000972), glyceraldehyde-3- phosphate dehydrogenase (GAPDH), actins (e.g. β-actin), tubulins, hypoxantine phsophoribosyltransferase (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 invidual 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 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

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

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

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

Figure 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 1.5X, 1.75X, 2X, 3X, 4X, 5X, 6X, 7X, 8X, 9X or 1OX 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, T- 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 (—0—) 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 disoder. 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. Patent 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. MoI. 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, 1¹³¹, 1¹²⁵, 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 (ITP) 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. MoI. 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-αC (IFN-αlO), IFN-αD (IFN-αl), IFN-αE (IFN-α22), IFN-αF (IFN-α21), IFN-αG (IFN- α5), IFN-αl6, IFN-αl7, IFN-α4, IFN-α6, IFN-α7, and IFN-αH (IFN-αl4), and pseudogenes having at least 80% homology. The second subfamily, απ or ω, contains at least 5 pseudogenes and 1 functional gene (denoted herein as "IFN-απl" 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", "hlFNARl", "IFNARl", and "Uze chain" are defined as the 557 amino acid receptor protein cloned by Uze et ah, 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 IFNARl that contain the extracellular domain (ECD) (or fragments of the ECD) of IFNARl. 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 (NP 000972), glyceraldehyde-3- phosphate dehydrogenase (GAPDH), Cypl, albumin, actins(e.g. β-actin), tubulins, cyclophilin, hypoxantine phosphoribosyltransferase (HRPT), ribosomal protein L32

(NP OO 1007075), 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 glyco lipid, 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/pbrownl .

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," 3^rd 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 deparaffmized and rehydrated to water. The tissue sections may be deparaffmized 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 deparaffmizing non-organic agents such as

Hemo-De7 (CMS, Houston, Texas) 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, ¹²⁵1, 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, New York, 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. Patent 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. Patent 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. Patent 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 exmple, staining intensity criteria may be evaluated as follows:

TABLE A

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 40⁰C 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 October 11, 2001; (See, for example, U.S. 5,700,637, U.S. Patent 5,445,934, and U.S. Patent 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 commerically 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, intraarticular, 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 ng/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, MN).

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, CA) and hybridized to WHG oligonucleotide microarray chips from Agilent (Palo Alto, CA). 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 Iog2 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, NC) and Excel (Microsoft, Redmond, WA).

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 x 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 (Figure 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 (Figure 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 (Figure 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. probeid accession gene symbol gene description

NM 00103273

A_ 24 P343929 1 OAS2 2'-5'-oligoadenylate synthetase 2

A 24 P395966 NM 030776 ZBPl Z-D binding protein 1

A_ 23 P259141 NM 030776 ZBPl Z-D binding protein 1

A_ 23 P139786 NM 003733 OASL 2'-5 '-oligoadenylate synthetase-like

RSAD2 radical S-adenosyl methionine domain

A 24 P316965 NM 080657 (CIG5) containing 2

A_ 23 P 17663 NM 002462 MXl myxovirus resistance 1

A_ 24 P378019 NM 001572 IRF7 interferon regulatory factor 7

NM 00103240

A_ 23 _P64828 9 OASl 2',5 '-oligoadenylate synthetase 1

NM 00100226

A_ 24 P943205 4 EPSTIl epithelial stromal interaction 1

A_ 23 P23074 NM 006417 IFI44 interferon-induced protein 44

A_ 23 _P45871 NM 006820 IFI44L interferon-induced protein 44-like interferon, alpha-inducible protein IFI-

A_ 23 P819 NM 005101 G1P2 15K

RSAD2 radical S-adenosyl methionine domain

A_ 24 _P28722 NM 080657 (CIG5) containing 2

A_ 24 P917810 NM 000059 BRCA2 breast cancer 2, early onset

NM 00100188 interferon-induced protein with

A_ 23 P52266 7 IFITl tetratricopeptide repeats 1

A_ 23 P110196 NM 016323 HERC5 hect domain and RLD 5

A_ 23 _P47955 NM 006187 OAS3 2'-5 '-oligoadenylate synthetase 3

NM 00103168 interferon-induced protein with

A_ 23 P35412 3 IFIT3 tetratricopeptide repeats 3

A_ 24 P557479 NM _017523 HSXIAPAFl XIAP associated factor- 1

A_ 23 _P4283 NM _017523 HSXIAPAFl XIAP associated factor- 1

A_ 32 P 132206 NM 017414 USP 18 ubiquitin specific peptidase 18

A_ 24 P317762 NM 002346 RIG-E lymphocyte antigen 6 complex, locus E

A_ 24 _P316257 NM 145270 FLJ36208 hypothetical protein FLJ36208

NM 00100226

A_ 23 P 105794 4 EPSTIl epithelial stromal interaction 1

A_ 23 P 166797 NM _022147 TMEM7 28kD interferon responsive protein poly (ADP-ribose) polymerase family,

A_ 23 Pl 11804 NM 022750 PARP 12 member 12

NM 00101300 hect domain and RLD 6, transcript

A_ 23 P250353 0 HERC6 variant 3

A_ 24 P334361 NM 017631 SGRA12061 hypothetical protein FLJ20035

A_ 23 _P384355 NM _207315 TYKI thymidylate kinase family LPS-inducible interferon-induced protein with

A_ 24 P30194 NM 012420 IFIT5 tetratricopeptide repeats 5

XIAP associated factor- 1, transcript

A 23 P4286 NM _017523 HSXIAPAFl variant 1

A_ 32 _P227059 AA977193 (no symbol) (no known gene) eukaryotic translation initiation factor 2- A_23_P142750 NM_002759 EIF2AK2 alpha kinase 2 poly (ADP-ribose) polymerase family, A_24_P161018 NM_017554 PARP14 member 14

A_24_P335305 NM_006187 OAS3 2'-5'-oligoadenylate synthetase 3

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. 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, CA) and hybridized to HGUl 33 oligonucleotide microarray chips from Affymetrix, Inc. (Santa Clara, CA). 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 Iog2 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, NC). 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 (Figure 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 HGUl 33), or real-time PCR (e.g. Taqman).

Probe Rho Accession Symbol Name

226603_ at 0.9760 NM_152703 SAMD9L sterile alpha motif domain containing 9-like

230036_ at 0.9754 NM _152703 SAMD9L sterile alpha motif domain containing 9-like

226702_ at 0.9747 NM _207315 TYKI Thymidylate kinase family

LPS-inducible

242625_ at 0.9733 NM 080657 RSAD2 radical S-adenosyl methionine (CIG5) domain containing 2 223220_ s at 0.9725 NM 031458 PARP9 poly ADP-ribose polymerase family, member 9

213797_ at 0.9679 NM 080657 RSAD2 radical S-adenosyl methionine (CIG5) domain containing 2 204747_ at 0.9664 NM 001031683 IFIT3 interferon-induced protein with tetratricopeptide repeats 3

203153_ at 0.9586 NM 001001887 IFITl interferon-induced protein with tetratricopeptide repeats 1

226757_ at 0.9582 NM 001547 IFIT2 interferon-induced protein with tetratricopeptide repeats 2

229450_ at 0.9572 NM 001031683 IFIT3 interferon-induced protein with tetratricopeptide repeats 3

208436 s at 0.9568 NM 001572 IRF7 interferon regulatory factor 7 219062_ s at 0.9544 NM _017742 ZCCHC2 zinc finger, CCHC domain containing 2

224701_ at 0.9531 NM _017554 PARP 14 poly ADP-ribose polymerase family, member 14

205483_ s at 0.9511 NM 005101 G1P2 interferon, alpha-inducible protein clone IFI- 15K

218943_ s at 0.9495 NM 014314 DDX58 DEAD Asp-Glu- Ala-Asp box (RIGl) polypeptide 58

219863 at 0.9462 NM 016323 HERC5 hect domain and RLD 5 227609_ at 0.9458 NM 001002264 EPSTIl epithelial stromal interaction 1 breast

219356 s at 0.9456 NM 016410 CHMP5 chromatin modifying protein 5 203596_ s at 0.9456 NM 012420 IFIT5 interferon-induced protein with tetratricopeptide repeats 5

228152_ s at 0.9422 XM 037817 LCGE2279 FLJ31033 y

228531 at 0.9417 NM 017654 SAMD9 sterile alpha motif domain containing 9 203595 s at 0.9406 NM 012420 IFIT5 interferon-induced protein with tetratricopeptide repeats 5

202446 s at 0 .9383 NM 021105 PLSCR2 phospholipid scramblase 2

228617_ at 0.9379 NM _017523 HSXIAPAF XIAP associated factor- 1

1

232222_ at 0 .9374 NM _017742 ZCCHC2 zinc finger, CCHC domain

O O O O containing 2

204439_ at 0 .9356 NM 006820 IFI44L interferon-induced protein 44- like

212657_ s at 0 .9346 NM 000577 ILlRN interleukin 1 receptor antagonist

210797_ s at 0 .9341 NM 003733 OASL 2'-5'-oligoadenylate synthetase- like

213294_ at 0 .9334 P ADB 12769 PRKR dsRNA-dependent protein kinase

211012 s at 0 .9311 NM 002675 PML promyelocytic leukemia 202086_ at 0.9302 NM 002462 MXl myxovirus influenza virus resistance 1

223502_ s at 0 .9300 NM 006573 TNFSF13B tumor necrosis factor ligand superfamily, member 13b

227807_ at 0 .9295 NM 031458 PARP9 poly ADP-ribose polymerase family, member 9

214453 s at 0 .9278 NM 006417 IFI44 interferon-induced protein 44 205660_ at 0.9275 NM 003733 OASL 2'-5'-oligoadenylate synthetase- like

228230_ at 0 .9273 NM 033405 PRIC285 peroxisomal proliferator- activated receptor A

218400_ at 0 .9253 NM 006187 OAS3 2'-5'-oligoadenylate synthetase

3

223501_ at 0 .9227 NM 006573 TNFSF13B tumor necrosis factor ligand superfamily, member 13b

214059 at .9186 NM 006417 IFI44 interferon-induced protein 44 202687 s at .9178 NM 003810 Apo-2L Apo-2 Ligand 202863 at .9176 NM 003113 SP140 SP 140 nuclear body protein 217502_ at .9158 NM 001547 IFIT2 interferon-induced protein with tetratricopeptide repeats 2

218085 at 0 .9130 NM 016410 CHMP5 chromatin modifying protein 5 228439_ at 0.9123 NM 138456 BATF2 basic leucine zipper transcription factor, ATF-like 2

209593_ s at 0 .9089 NM 014506 TORlB torsin family 1 , member B torsin B

222793_ at 0 .9079 NM 014314 DDX58 DEAD Asp-Glu- Ala-Asp box (RIGl) polypeptide 58 204994_ at 0.9061 NM 002463 MX2 myxovirus influenza virus resistance 2 mouse

219691 at 0 .9029 NM 017654 SAMD9 sterile alpha motif domain containing 9

208087 s at 0. 9027 NM 030776 ZBPl Z-D binding protein 1

202270 at 0. 9008 NM 002053 GBPl guanylate binding protein 1 , interferon-inducible, 67kDa

231577 s at 0.9007 NM 002053 GBPl guanylate binding protein 1 , interferon-inducible, 67kDa

219209 at 0.9004 NM 022168 IFIHl interferon induced with helicase C domain 1

200986 at 0.8978 NM 000062 SERPINGl Serine/cysteine proteinase inhibitor, clade G Cl inhibitor, 1

204972 at 0.8964 NM 001032731 OAS2 2'-5'-oligoadenylate synthetase

2, 69/7IkDa

242020 s at 0. 8948 NM 030776 ZBPl Z-D binding protein 1

209498_ at 0. 8933 NM 001024912 CEACAMl carcino embryonic antigen- related cell adhesion molecule 1

235276_ at 0. 8931 NM 001002264 EPSTIl epithelial stromal interaction 1 breast

219211 at 0. 8925 NM 017414 USP 18 ubiquitin specific protease 41

239277 at 0. 8897 NM 001033583 ACOT9 acyl-CoA thioesterase 9

243271_ at 0. 8892 NM _152703 SAMD9L sterile alpha motif domain containing 9-like

205098 at 0. 8887 NM 001295 CCRl chemokine C-C motif receptor 1

202430_s_at 0.8859 NM 021105 PLSCR2 phospholipid scramblase 2

209417_s_at 0.8837 NM 005533 IFI35 interferon-induced protein 35

205552_s_at 0.8789 NM 001032409 OASl 2',5'-oligoadenylate synthetase l, 40/46kDa

231769_at 0.8783 NM 018438 FBXO6 F-box protein 6

241916_at 0.8782 NM 021105 PLSCR2 phospholipid scramblase 2

233425 at 0.8778 NM 017742 ZCCHC2 zinc finger, CCHC domain containing 2

218543 s at 0.8762 NM 022750 PARP12 poly ADP-ribose polymerase family, member 12

202307 s at 0.8742 NM 000593 TAPl transporter 1 , ATP -binding cassette, sub-family B

204698 at 0.8735 NM 002201 ISG20 interferon stimulated gene 2OkDa

202269 x at 0.8730 NM 002053 GBPl guanylate binding protein 1 , interferon-inducible, 67kDa

232666 at 0.8711 NM 006187 OAS3 2'-5'-oligoadenylate synthetase

3, 10OkDa

218986 s at 0.8703 NM 017631 SGRA1206 Hypothetical protein FLJ20035

1 FLJ20035

205569_ at 0. 8675 NM_014398 LAMP3 lysosomal-associated membrane protein 3

202145_ at 0. 8672 NM 002346 LY6E lymphocyte antigen 6 complex,

(RIGE) locus E

219352 at 0. 8671 NM 001013000 HERC6 hect domain and RLD 6

239979 at 0. 8665 NM 001002264 EPSTIl epithelial stromal interaction 1 breast 223599_ at 0.8664 NM 001003818 TRIMPl tripartite motif-containing pseudogene 1

230866 at 0 .8656 NM 006639 CYSLTRl cysteinyl leukotriene receptor 1

216565_ x at 0 .8650 XM 497663 LOC391020 similar to Interferon-induced transmembrane protein 3

212659_ s at 0 .8635 NM 000577 ILlRN interleukin 1 receptor antagonist

202869_ at 0 .8634 NM 001032409 OASl 2',5'-oligoadenylate synthetase l, 40/46kDa

223952_ x at 0 .8623 NM 005771 DHRS9 dehydrogenase/reductase SDR family member 9

205241_ at 0 .8614 NM 001953 SCO2 SCO cytochrome oxidase deficient homolog 2 yeast

227458_ at 0 .8601 NM 014143 PDL1/B7- programmed cell death 1

Hl ligand 1

231747 at 0 .8600 NM 006639 CYSLTRl cysteinyl leukotriene receptor 1

209969_ s at 0 .8576 NM 007315 STATl signal transducer and activator of transcription 1, 9IkDa

218999 at 0 .8561 NM 018295 AGPR4538 hypothetical protein MGC5242

224009_ x at 0 .8535 NM 005771 DHRS9 dehydrogenase/reductase SDR family member 9

228607_ at 0 .8529 NM 001032731 OAS2 2'-5'-oligoadenylate synthetase

2, 69/7IkDa

205099_ s at 0 .8516 NM 001295 CCRl chemokine C-C motif receptor

1

219799_ s at 0 .8479 NM 005771 DHRS9 dehydrogenase/reductase SDR family member 9

206133_ at 0 .8420 NM _017523 HSXIAPAF XIAP associated factor- 1

1

211889_ x at 0 .8386 NM 001024912 CEACAMl carcino embryonic antigen- related cell adhesion molecule 1

222154_ s at 0 .8365 NM 015535 DNAPTP6 DNA polymerase- transactivated protein 6

225291_ at 0 .8350 NM 033109 PNPTl polyribonucleotide nucleotidyltransferase 1

202864 s at 0 .8347 NM 003113 SP140 SP 140 nuclear body protein

210705 s at 0 .8341 NM 033034 TRIM5 tripartite motif-containing 5

223167 s at 0 .8334 NM 013396 USP25 ubiquitin specific protease 25

229625 at 0 .8324 NM 004120 GBP5 guanylate binding protein 5

202837_ at 0 .8278 NM 006700 TRAFDl TRAF-type zinc finger domain containing 1

216243_ s at 0 .8185 NM 000577 ILlRN interleukin 1 receptor antagonist

223849_ s at 0 .8180 NM 020963 MOVlO MovlO, Moloney leukemia virus 10, homolog mouse

222498 at 0 .8175 NM 022461 AZI2 5-azacytidine induced 2

238581 at 0 .8173 NM 004120 GBP5 guanylate binding protein 5

217933 s at 0 .8138 NM 015907 LAP3 leucine aminopeptidase 3 219519 s at 0.8108 NM 023068 SIGLECl sialoadhesin

208392 x at 0 .8084 NM 004509 SPI lO SPl 10 nuclear body protein

239988 at 0 .8079 NM 017912 SKKS3063 Hect domain and RLD 6

H I

230314 at 0 .8074 P ADH28842 CMLMI lO chronic myelogenous leukaemia (CML) gene marker #110

206576 s at 0 .8072 NM 001024912 CEACAMl carcinoembryonic antigen- related cell adhesion molecule 1

227347 x at 0 .8047 NM 021170 HES4 hairy and enhancer of split 4 Drosophila

202411 at 0 .8038 NM 005532 IFI27 interferon, alpha-inducible protein 27

219684 at 0 .7998 NM 022147 TMEM7 transmembrane protein 7

205003 at 0 .7974 NM 014705 DOCK4 dedicator of cytokinesis 4

212185 x at 0 .7969 NM 005953 MT2A metallothionein 2A

235256 s at 0 .7957 NM 138801 GALM galactose mutarotase aldose 1- epimerase

242234 at 0 .7948 NM _017523 HSXIAPAF XIAP associated factor- 1

1

211883 x at 0 .7916 NM 001024912 CEACAMl carcinoembryonic antigen- related cell adhesion molecule 1

206513 at 0 .7891 NM 004833 AIM2 absent in melanoma 2

44673 at 0 .7884 NM 023068 SIGLECl sialoadhesin

209546 s at 0 .7869 NM 003661 APOLl apolipoprotein L, 1

204415 at 0 .7838 NM 002038 G1P3 interferon, alpha-inducible protein clone IFI-6-16

206553 at 0 .7821 NM 001032731 OAS2 2'-5'-oligoadenylate synthetase 2, 69/7IkDa

206461 x at 0 .7758 NM 005946 MT2A metallothionein 2A

226169 at 0 .7746 NM 030962 SBF2 SET binding factor 2

244398 x at 0 .7742 NM 152373 ZNF684 zinc finger protein 684

238439 at 0 .7659 NM 144590 ANKRD22 ankyrin repeat domain 22

227649 s at 0 .7646 NM 015326 SRGAP2 SLIT-ROBO Rho GTPase activating protein 2

220998 s at 0 .7644 NM 030930 UNC93B1 unc-93 homolog Bl C. elegans

204211 x at 0 .7628 NM 002759 EIF2AK2 eukaryotic translation initiation factor 2-alpha kinase 2

224973 at 0 .7612 NM 017633 FAM46A family with sequence similarity 46, member A

234974 at 0 .7601 NM 138801 GALM galactose mutarotase aldose 1- epimerase

242898 at 0 .7588 NM 002759 EIF2AK2 eukaryotic translation initiation factor 2-alpha kinase 2

232034 at 0 .7581 BC080605 LOC203274 hypothetical protein LOC203274

231455 at 0 .7560 NM 001001695 FLJ42418 FLJ42418 208581 x at 0.7546 NM 005952 MTlX metallothionein IX

224225_ s at 0 .7545 NM 016135 ETV7 ets variant gene 7 (TEL2 oncogene)

205875_ s at 0 .7543 NM 016381 TREXl three prime repair exonuclease 1

209286_ at 0 .7522 NM 006449 CDC42EP3 CDC42 effector protein Rho GTPase binding 3

205715_ at 0 .7472 NM 004334 BSTl bone marrow stromal cell antigen 1

223834_ at 0 .7465 NM 014143 PDL1/B7- programmed cell death 1

Hl ligand 1

212285 s at 0 .7414 NM 198576 AGRN agrin

230695_ s at 0 .7381 NM _152732 C6orf206 chromosome 6 open reading frame 206

219364_ at 0 .7381 NM 024119 LGP2 likely ortholog of mouse Dl llgp2

238455 at 0 .7371 NM 032812 PLXDC2 Plexin domain containing 2

201641 at 0 .7343 NM 004335 BST2 Bone marrow stromal antigen 2

219439_ at 0 .7273 NM 020156 ClGALTl core 1 synthase, glyc-N- acetylgal 3-beta-galtransferase, 1

224503_ s at 0 .7231 NM _017742 ZCCHC2 zinc finger, CCHC domain containing 2

234942_ s at 0 .7226 NM 052951 DNTTIPl deoxynucleotidyltransferase, terminal, interacting protein 1

214933_ at 0 .7212 NM 000068 CAClA calcium channel, voltage- dependent, P/Q type, alpha IA

219055 at 0 .7189 NM 018079 SRBDl S 1 RNA binding domain 1

225447_ at 0 .7179 NM 000408 GPD2 glycerol-3 -phosphate dehydrogenase 2 mitochondrial

236285_ at 0 .7173 P_AAF17573 SYN22A2 Breast cancer associated SYN22A2 coding sequence

217165 x at 0 .7168 NM 005946 MT2A metallothionein 2A

200923_ at 0 .7164 NM 005567 LGALS3BP lectin, galactoside-binding, soluble, 3 binding protein

220104_ at 0 .7159 NM 020119 ZC3HAV1 zinc finger CCCH-type, antiviral 1

216950_ s at 0 .7133 NM 000566 FCGRlA Fc fragment of IgG, high affinity Ia, receptor CD64

227905 s at 0 .7115 NM 022461 AZI2 5-azacytidine induced 2

230997_ at 0 .7109 NM 145755 TTC21A tetratricopeptide repeat domain 21A

210889_ s at 0 .7099 NM 001002273 FCGR2B Low affinity immunoglobulin gamma fc receptor ii-b

214511_ x at 0 .7050 NM 000566 FCGRlA Fc fragment of IgG, high affinity Ia, receptor (CD64)

211456_ x at 0 .7045 NM 001039954 MT1P2 metallothionein 1 pseudogene 2

232563 at 0 .7017 NM 152373 ZNF684 zinc finger protein 684 235456_at 0.6926 NM_021063 HIST1H2B histone 1 , H2bd

D

229194 at 0 .6917 NM 032373 PCGF5 polycomb group ring finger 5

235157_at 0 .6859 NM_017554 PARP 14 poly ADP-ribose polymerase family, member 14

230333_at 0 .6851 NM_002970 SAT Spermidine/spermine Nl- acetyltransferase

231956 at 0 .6813 NM 020954 KIAA1618 KIAA1618

235175 at 0 .6803 NM 052941 GBP4 guanylate binding protein 4

232149_s_at 0 .6777 NM_003580 NSMAF neutral sphingomyelinase N-

SMase activation assoc factor

235331 x at 0 .6769 NM 032373 PCGF5 polycomb group ring finger 5

221653 x at 0 .6762 NM 030882 APOL2 apolipoprotein L, 2

219716 at 0 .6689 NM 030641 APOL6 apolipoprotein L, 6

214909_s_at 0 .6669 NM_013974 DDAH2 dimethylarginine dimethylaminohydrolase 2

207500_at 0 .6654 NM_004347 CASP5 caspase 5, apoptosis-related cysteine protease

23208 l_at 0 .6648 NM_004915 ABCGl ATP -binding cassette, subfamily G WHITE, member 1

241812_at 0 .6584 NM_015535 DNAPTP6 DNA polymerase- transactivated protein 6

230166 at 0 .6571 NM 133465 KIAA1958 KIAA1958

239143 x at 0 .6554 NM 016271 RNF138 ring finger protein 138

217823_s_at 0 .6543 NM_016021 UBE2J1 ubiquitin-conjugating enzyme

E2, Jl UBC6 homolog, yeast

242109_at 0 .6501 NM 006519 TCTELl t-complex-associated-testis- expressed 1 -like 1

206175 x at 0 .6420 NM 013360 ZNF230 zinc finger protein 230

215537_x_at 0 .6366 NM_013974 DDAH2 dimethylarginine dimethylaminohydrolase 2

220252_x_at 0 .6318 NM_025159 CXorf21 chromosome X open reading frame 21

227268 at 0 .6213 NM 016125 PLFL4625 PTDO 16 protein

216336 x at 0 .6153 NM 153341 IBRDC3 IBR domain containing 3

229804 x at 0 .6077 NM 018491 CBWDl COBW domain containing 1

236013_at 0 .6011 NM_000721 CAClE calcium channel, voltage- dependent, alpha IE subunit

227004 at 0 .5968 NM 003159 CDKL5 cyclin-dependent kinase-like 5

226099_at 0 .5788 NM_012081 ELL2 elongation factor, R polymerase II, 2

227947_at 0 .5761 NM_014721 PHACTR2 phosphatase and actin regulator

Z

210985 s at 0 .5722 NM 003113 SP140 SP 140 nuclear body protein

204326 x at 0 .5699 NM 005952 MTlX metallothionein IX

233264 at 0.5515 AK022088 FLJ 12026 HEMBB1001816

212859_x_at 0.5285 NM_005953 MTlX metallothionein IX chromosome 13 open reading

235348 at 0.5251 NM 032859 C13orf6 frame 6 225872_ at 0.5053 NM_025181 SLC35F5 solute carrier family 35, member F5

235681_ at 0.4913 NM_021063 HIST1H2B histone l, H2bd

L)

207291_ at 0.4851 NM_024081 PRRG4 proline rich GIa G- carboxyglutamic acid 4 transmembrane

234997_ x at 0.4617 CD684982 EST1502 human spermidine/spermine

Nl acetyl transferase

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.

Probe Rho Accession Symbol Name

228152_s_at 0.9422 XM_037817 LCGE22799 FLJ31033 202446_s_at; 0.9383; NM 021105 PLSCR2 phospholipid scramblase 202430_s_at; 0.8859; 2 241916_at 0.8782 213294_at 0.9334 P ADB 12769 PRKR dsRNA-dependent protein kinase

211012_s_at 0.9311 NM_002675 PML promyelocytic leukemia 228230_at 0.9273 NM_033405 PRIC285 peroxisomal proliferator- activated receptor A

202687_s_at 0.9178 NM_003810 Apo-2L Apo-2 Ligand

202863_at; 0.9176; NM 003113 SP140 SP 140 nuclear body protein

202864_s_at; 0.8347;

210985_s_at 0.5722

209498_at; 0.8933; NM 001024912 CEACAMl carcinoembryonic antigen-

211889_x_at; 0.8386; related cell adhesion

206576_s_at; 0.8072; molecule 1

211883_x_at 0.7916

239277_at 0.8897 NM_001033583 ACOT9 acyl-CoA thioesterase 9

231769_at 0.8783 NM_018438 FBXO6 F-box protein 6

202307_s_at 0.8742 NM 000593 TAPl transporter 1 , ATP-binding cassette, sub-family B

204698 at 0.8735 NM 002201 ISG20 interferon stimulated gene 2OkDa

218986 s at 0.8703 NM 017631 SGRA12061 Hypothetical protein FLJ20035 FLJ20035

205569 at 0.8675 NM 014398 LAMP3 lysosomal-associated membrane protein 3

223599 at 0.8664 NM 001003818 TRIMPl tripartite motif-containing pseudogene 1

230866 at 0. 8656; NM 006639 CYSLTRl cysteinyl leukotriene

231747 at 0. 8600 receptor 1

216565 X at 0. 8650 XM 497663 LOC391020 similar to Interferon- induced transmembrane protein 3

223952 X at; 0 .8623; NM_ 005771 DHRS9 dehydrogenase/reductase

224009 X _at; 0 .8535; SDR family member 9

219799 S at 0 .8479

205241 at 0 .8614 NM_ 001953 SCO2 SCO cytochrome oxidase deficient homolog 2 yeast

227458 at 0 .8601; NM_ 014143 PDL1/B7-H1 programmed cell death 1

223834 at 0 .7465 ligand 1

209969 _s_ at 0 .8576 NM_ 007315 STATl signal transducer and activator of transcription 1,

9IkDa

218999 at 0 .8561 NM_ 018295 AGPR4538 hypothetical protein

MGC5242

210705 _s_ at 0 .8341 NM 033034 TRIM5 tripartite motif-containing 5

223167 S at 0 .8334 NM_ 013396 USP25 ubiquitin specific protease

25

229625 at •> 0 .8324; NM_ 004120 GBP5 guanylate binding protein 5

238581 at 0 .8173

202837 at 0 .8278 NM_ 006700 TRAFDl TRAF-type zinc finger domain containing 1

223849 _s_ at 0 .8180 NM_ 020963 MOVlO MovlO, Moloney leukemia virus 10, homolog mouse

222498 at 0 .8175; NM_ 022461 AZI2 5-azacytidine induced 2

227905 S at 0 .7115

217933 _s_ at 0 .8138 NM 015907 LAP3 leucine aminopeptidase 3

219519 _s_ at; 0 .8108; NM_ 023068 SIGLECl sialoadhesin

44673 at 0 .7884

208392 X at 0 .8084 NM 004509 SPI lO SPl 10 nuclear body protein

239988 at 0 .8079 NM 017912 SKKS30637 Hect domain and RLD 6

230314 at 0 .8074 P ADH28842 CMLMI lO chronic myelogenous leukaemia (CML) gene marker #110

227347 x at 0.8047 NM 021170 HES4 hairy and enhancer of split 4

Drosophila

202411_ at 0 .8038 NM_ 005532 IFI27 interferon, alpha-mducible protein 27

205003 at 0 .7974 NM 014705 DOCK4 dedicator of cytokinesis 4

212185 x_at; 0 .7969; NM_ 005953 MT2A metallothionein 2A

206461 x_at; 0 .7758;

217165 x at 0 .7168

235256 s at; 0 .7957; NM_ 138801 GALM galactose mutarotase aldose

234974 at 0 .7601 1-epimerase

206513 at 0 .7891 NM 004833 AIM2 absent in melanoma 2

209546 s at 0 .7869 NM 003661 APOLl apolipoprotein L, 1

204415_ at 0 .7838 NM_ 002038 G1P3 interferon, alpha-inducible protein clone IFI-6-16

206553_ at 0 .7821 NM_ 001032731 OAS2 2'-5 '-oligoadenylate synthetase 2, 69/7IkDa

226169 at 0 .7746 NM 030962 SBF2 SET binding factor 2

244398 X _.at; 0 .7742; NM_ 152373 ZNF684 zinc finger protein 684

232563 at 0 .7017

238439 at 0 .7659 NM 144590 ANKRD22 ankyrin repeat domain 22

227649 S at 0 .7646 NM 015326 SRGAP2 SLIT-ROBO Rho GTPase activating protein 2

220998 s at 0.7644 NM 030930 UNC93B1 unc-93 homo log Bl C. elegans

224973 at 0.7612 NM 017633 FAM46A family with sequence similarity 46, member A

232034 at 0 .7581 LOC203274

231455 at 0 .7560 NM OOIOOK FLJ42418 FLJ42418

208581 X at; 0 .7546; NM_ 005952 MTlX metallothionein IX

204326 X _.at; 0 .5699;

212859 X at 0 .5285

224225 S at 0 .7545 NM 016135 ETV7 ets variant gene 7 (TEL2 oncogene)

205875 s at 0.7543 NM 016381 TREXl three prime repair exonuclease 1

209286 at 0.7522 NM 006449 CDC42EP3 CDC42 effector protein Rho

GTPase binding 3

205715 at 0.7472 NM 004334 BSTl bone marrow stromal cell antigen 1

212285_s_at 0.7414 NMJ98576 AGRN agrin 230695 s at 0.7381 NM 152732 C6orf206 chromosome 6 open readine frame 206

219364 at 0.7381 NM 024119 LGP2 likely ortholog of mouse Dl llgp2

238455 at 0 .7371 NM 032812 PLXDC2 Plexin domain containing 2

201641_ at 0 .7343 NM_ 004335 BST2 Bone marrow stromal antigen 2

219439_ at 0 .7273 NM_ 020156 ClGALTl core 1 synthase, glyc-N- acetylgal 3-beta- galtransferase, 1

234942 s at 0 .7226 NM 052951 DNTTIPl deoxynucleotidyltransferase, terminal, interacting protein 1

214933 at 0.7212 NM 000068 CAClA calcium channel, voltage- dependent, P/Q type, alpha IA

219055_at 0.7189 NM O 18079 SRBDl S 1 RNA binding domain 1

225447 at 0.7179 NM 000408 GPD2 glycerol-3 -phosphate dehydrogenase 2 mitochondrial

236285 at 0.7173 P AAF17573 SYN22A2 Breast cancer associated SYN22A2 coding sequence

200923 at 0.7164 NM 005567 LGALS3BP lectin, galactoside-binding, soluble, 3 binding protein 220104 at 0.7159 NM 020119 ZC3HAV1 zinc finger CCCH-type, antiviral 1

216950_s_at; 0.7133; NM 000566 FCGRlA Fc fragment of IgG, high

21451 l x at 0.7050 affinity Ia, receptor CD64

230997_at 0.7109 NMJ45755 TTC21A tetratricopeptide repeat domain 21 A

210889 s at 0.7099 NM 001002273 FCGR2B Low affinity immunoglobulin gamma fc receptor ii-b

211456 x at 0.7045 NM 001039954 MT1P2 metallothionein 1 pseudogene 2

235456 at; 0 .6926; NM_ 021063 HIST1H2BD histone 1 , H2bd

235681 at 0 .4913

229194 at; 0 .6917; NM_ 032373 PCGF5 polycomb group ring finger

235331 x at 0 .6769 5

230333_at 0 .6851 NM_ 002970 SAT Spermidine/spermine Nl- acetyltransferase

231956 at 0 .6813 NM 020954 KIAA1618 KIAA1618

235175 at 0 .6803 NM 052941 GBP4 guanylate binding protein 4

232149 s at 0 .6777 NM 003580 NSMAF neutral sphingomyelinase N-SMase activation assoc factor

221653 X at 0 .6762 NM 030882 APOL2 apolipoprotein L, 2

219716 at 0 .6689 NM 030641 APOL6 apolipoprotein L, 6

214909 S at; 0 .6669; NM_ 013974 DDAH2 dimethylarginine

215537 X at 0 .6366 dimethylaminohydrolase 2

207500 at 0 .6654 NM 004347 CASP5 caspase 5, apoptosis-related cysteine protease

232081 at 0.6648 NM 004915 ABCGl ATP-binding cassette, subfamily G WHITE, member 1

230166 at 0 .6571 NM 133465 KIAA1958 KIAA1958

239143 X at 0 .6554 NM^" 016271 RNF138 ring finger protein 138

217823 S at 0 .6543 NM^{" "}016021 UBE2J1 ubiquitin-conjugating enzyme E2, Jl UBC6 homolog, yeast

242109 at 0.6501 NM 006519 TCTELl t-complex-associated-testis- expressed 1 -like 1

206175_x_at 0.6420 NM O 13360 ZNF230 zinc finger protein 230 220252 x at 0.6318 NM 025159 CXorf21 chromosome X open reading frame 21

227268 at 0 .6213 NM 016125 PLFL4625 PTDO 16 protein

216336 X at 0 .6153 NM 153341 IBRDC3 IBR domain containing 3

229804 X at 0 .6077 NM 018491 CBWDl COBW domain containing 1

236013_at 0 .6011 NM_ 000721 CAClE calcium channel, voltage- dependent, alpha IE subunit

227004 at 0 .5968 NM 003159 CDKL5 cyclin-dependent kinase-like

5

226099 at 0.5788 NM 012081 ELL2 elongation factor, R polymerase II, 2

227947_ at 0.5761 NM_014721 PHACTR2 phosphatase and actin regulator 2

233264 at 0.5515 AK022088 FLJ 12026 HEMBB1001816

235348_ at 0.5251 NM_032859 C13orf6 chromosome 13 open reading frame 6

225872_ at 0.5053 NM_025181 SLC35F5 solute carrier family 35, member F5

207291_ at 0.4851 NM_024081 PRRG4 proline rich GIa G- carboxyglutamic acid 4 transmembrane

234997 x at 0.4617 CD684982 EST1502 human spermidine/spermine Nl 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.

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, CA) 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, CA) 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, CA). 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 Figure 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. EPSTIl NM 001002264

RIGl

(DDX58) NM 014314

OAS3 NM 006187

HERC5 NM 016323

PARP9 NM 031458

SAMD9L NM 152703

TYKI NM 207315

CHMP5 NM 016410

ZBPl NM 030776

CIG5

(RS AD2) NM 080657

IFI44 NM 006417

IFI44L NM 006820

IFITl NM 001548

IFIT4

(IFIT3) NM 001549

IFIT5 NM 012420

IRF7 NM 004029

G1P2 NM 005101

MXl NM 002462

OASl NM 002534

OAS2 NM 002535

OASL NM 003733

SPI lO NM 004509

RIGE

(LY6E) NM 002346

XIAP NM 001167

Table 4A. List of selected 24 genes, with corresponding RefSeq ID.

Pearson

Genel Gene2 Gene3 Correlation

IFIT4 OASl MXl 0.996514

OASL CHMP5 ZBPl 0.996478

IFI44L OASL CIG5 0.996391

IFI44L CIG5 ZBPl 0.995869

EPSTIl TYKI MXl 0.995702

IFIT4 HERC5 TYKI 0.995611

IFIT4 TYKI XIAP 0.995609

IFI44L OASL ZBPl 0.995602

IFI44L IFIT4 OASL 0.995504

IFIT4 OASl IFITl 0.995422

EPSTIl HERC5 TYKI 0.995392

IFI44L EPSTIl OASL 0.995385 IFI44L EPSTIl 0AS3 0.995345

EPSTIl TYKI IFITl 0.99515

G1P2 SAMD9L SPI lO 0.99489

IRF7 HERC5 TYKI 0.994867

IFIT5 CIG5 ZBPl 0.994863

IFI44L EPSTIl ZBPl 0.994776

IFI44L SPI lO ZBPl 0.994649

PJGl IRF7 HERC5 0.994588

TYKI IFITl XIAP 0.994564

IFIT4 TYKI MXl 0.994522

OASL IFI44 ZBPl 0.994503

EPSTIl G1P2 SAMD9L 0.994402

IRF7 SAMD9L MXl 0.99428

IFI44L OAS2 OASL 0.994232

IFI44L CIG5 SPI lO 0.994183

TYKI MXl XIAP 0.994176

IFI44L OASL IRF7 0.994168

IFIT5 IFIT4 OAS3 0.994107

IRF7 HERC5 SAMD9L 0.994056

OASL CIG5 CHMP5 0.994043

IRF7 TYKI IFITl 0.993998

TYKI IFITl SPI lO 0.993932

IFIT4 TYKI IFITl 0.993875

CIG5 HERC5 TYKI 0.993865

IFIT5 IFIT4 ZBPl 0.993786

OAS2 OASL CHMP5 0.993676

IFI44L IFIT4 RIGE 0.993594

EPSTIl 0AS3 CHMP5 0.993546

IFI44L IFIT4 OAS3 0.993513

EPSTIl G1P2 TYKI 0.993511

EPSTIl G1P2 HERC5 0.99349

OASl IRF7 IFITl 0.99348

IRF7 TYKI MXl 0.993472

IFIT5 0AS2 ZBPl 0.993459

IRF7 HERC5 IFITl 0.99345

IFI44L OASL XIAP 0.993443

OASl CIG5 IFITl 0.993431

IFIT4 IRF7 TYKI 0.993429

HERC5 TYKI SPI lO 0.993356

IFIT4 RIGl TYKI 0.993297

OASl IRF7 MXl 0.993259

IFIT5 IRF7 ZBPl 0.993164

IFIT4 G1P2 OASl 0.993068

G1P2 IRF7 HERC5 0.992975

IFI44L 0AS2 CIG5 0.992931

CIG5 TYKI 0.992894 SAMD9L

IRF7 HERC5 MXl 0.99289

OAS2 OASL IFI44 0.992876

HERC5 TYKI XIAP 0.992863

OASL CIG5 IFI44 0.992852

CIG5 IFI44 ZBPl 0.992827

IFIT5 0AS2 IRF7 0.992666

IFI44L IRF7 CIG5 0.992636

TYKI MXl SPI lO 0.992558

IFI44L OASL MXl 0.992556

OASl CIG5 MXl 0.992546

EPSTIl IFI44 0AS3 0.992546

G1P2 CIG5 SAMD9L 0.992522

EPSTIl RIGl TYKI 0.99252

OASL SAMD9L IFITl 0.992509

IFIT5 EPSTIl ZBPl 0.992466

IFI44L HERC5 RIGE 0.992413

CIG5 TYKI IFITl 0.992392

IFI44L IRF7 ZBPl 0.992374

G1P2 IRF7 SAMD9L 0.992327

IFIT4 SAMD9L TYKI 0.992311

IFI44L OASL SPI lO 0.992307

IFIT5 0AS2 CIG5 0.992229

IFI44L IFITl RIGE 0.992209

IFI44L IFIT4 ZBPl 0.992195

IFI44L CIG5 XIAP 0.992193

IFIT5 EPSTIl OAS3 0.99217

IFI44L 0AS2 EPSTIl 0.992154

IFI44L EPSTIl CIG5 0.992137

IFI44L 0AS2 SPI lO 0.99207

EPSTIl SAMD9L TYKI 0.99207

IFI44L MXl RIGE 0.992058

OASL CHMP5 XIAP 0.992049

G1P2 HERC5 XIAP 0.992014

IFI44L OASL IFITl 0.992005

G1P2 SAMD9L ZBPl 0.991994

IFI44L EPSTIl RIGE 0.991991

IFIT5 0AS2 MXl 0.991941

IRF7 SAMD9L IFITl 0.991891

IFI44L IRF7 OAS3 0.991715

IFIT4 EPSTIl TYKI 0.991674

EPSTIl G1P2 OASl 0.991603 IFI44L 0AS2 ZBPl 0.991594

EPSTIl OASl MXl 0.991562

CIG5 HERC5 SAMD9L 0.99156

IFIT5 0AS3 IFITl 0.991555

IFIT5 OASL MXl 0.991528

OASl IFITl MXl 0.991486

IFIT4 G1P2 SAMD9L 0.991439

IFIT5 CIG5 XIAP 0.991397

OAS2 IFI44 ZBPl 0.991331

EPSTIl OASL CHMP5 0.991303

HERC5 IFITl XIAP 0.991268

G1P2 HERC5 SPI lO 0.99125

CIG5 TYKI MXl 0.991247

OASL SAMD9L MXl 0.991199

IFIT5 IFIT4 0AS2 0.991186

IFIT5 IRF7 0AS3 0.991178

IFI44L 0AS2 IRF7 0.991172

IFIT5 IFIT4 OASL 0.991098

IFIT5 IRF7 CIG5 0.991095

IFI44L OASL HERC5 0.991094

IFI44L RIGE XIAP 0.99101

OASL IRF7 CHMP5 0.990968

IFIT4 SAMD9L MXl 0.990947

IFIT5 0AS3 MXl 0.990942

IFIT4 G1P2 HERC5 0.990937

G1P2 OASl CIG5 0.990933

G1P2 IFITl XIAP 0.990886

SAMD9L MXl XIAP 0.990878

0AS3 CHMP5 SPI lO 0.990877

G1P2 TYKI SPI lO 0.990867

EPSTIl OASl IFITl 0.990838

G1P2 OASL SAMD9L 0.990826

IFI44L CIG5 RIGE 0.990812

SAMD9L TYKI SPI lO 0.990776

IFIT5 CIG5 MXl 0.990775

CHMP5 RIGE XIAP 0.990758

OASL TYKI IFITl 0.990748

HERC5 MXl XIAP 0.990729

EPSTIl G1P2 IFITl 0.9907

IRF7 0AS3 CHMP5 0.990687

EPSTIl OASL IFI44 0.990632

G1P2 OASl IFITl 0.990614

IFIT5 XIAP ZBPl 0.990611

IFIT4 OASl HERC5 0.990512 IFIT4 HERC5 SAMD9L 0.990506

EPSTIl IFI44 ZBPl 0.990464

OASL CHMP5 SPI lO 0.990463

IFIT5 OASL IFITl 0.990412

EPSTIl TYKI XIAP 0.990325

EPSTIl IRF7 TYKI 0.990315

G1P2 SAMD9L XIAP 0.990306

IFI44L CIG5 OAS3 0.990281

IFIT5 0AS2 EPSTIl 0.990115

CIG5 SAMD9L MXl 0.990079

SAMD9L TYKI ZBPl 0.989993

OAS2 TYKI IFITl 0.989986

EPSTIl SAMD9L MXl 0.989945

IFI44 RIGE ZBPl 0.989942

IFIT5 MXl RIGE 0.989937

IFI44L 0AS3 SPI lO 0.989929

IFIT5 MXl ZBPl 0.98985

IFI44L SAMD9L RIGE 0.989814

CIG5 IFI44 RIGE 0.989794

OAS2 CIG5 IFI44 0.989763

OASL HERC5 SAMD9L 0.989717

IFIT4 IRF7 SAMD9L 0.989667

IFIT5 IFITl RIGE 0.989587

IFIT4 IRF7 HERC5 0.989574

IFIT5 OASL ZBPl 0.989563

TYKI IFITl ZBPl 0.989561

G1P2 CIG5 HERC5 0.989534

HERC5 TYKI MXl 0.9895

EPSTIl IFI44 RIGE 0.989498

G1P2 OASl MXl 0.989491

IRF7 SAMD9L TYKI 0.989455

CIG5 IFI44 OAS3 0.989384

IFIT5 OASL CIG5 0.989345

IFIT4 G1P2 TYKI 0.989323

IFI44L 0AS3 HERC5 0.989322

IFIT4 TYKI ZBPl 0.989292

IFIT5 SPI lO ZBPl 0.98929

IFI44 SPI lO ZBPl 0.989289

IFI44L XIAP ZBPl 0.989258

HERC5 TYKI IFITl 0.989244

IFIT5 OAS2 IFITl 0.989239 EPSTIl G1P2 MXl 0.98921

G1P2 IRF7 IFITl 0.989159

IFI44L IFIT4 0AS2 0.989146

OAS3 CHMP5 XIAP 0.989141

OASL 0AS3 CHMP5 0.989136

OASL IFI44 XIAP 0.989112

IFI44L EPSTIl SPI lO 0.989091

IFI44L IRF7 SPI lO 0.989077

IFI44L IFIT4 CIG5 0.989073

CIG5 0AS3 CHMP5 0.989057

IFI44 RIGE XIAP 0.989037

CIG5 SAMD9L IFITl 0.989029

IFI44L CIG5 HERC5 0.989011

IFIT5 0AS3 HERC5 0.988963

IFIT4 HERC5 XIAP 0.988945

IFIT4 HERC5 MXl 0.988925

IFIT5 0AS3 XIAP 0.988891

IFI44L IFIT4 SPI lO 0.988869

IFI44L 0AS3 XIAP 0.988845

CHMP5 RIGE ZBPl 0.988767

CIG5 CHMP5 RIGE 0.988756

IFI44L 0AS3 IFITl 0.988746

PJGl IRF7 SAMD9L 0.988717

IFI44 MXl RIGE 0.988705

SAMD9L IFITl XIAP 0.988634

EPSTIl CHMP5 RIGE 0.988543

IFI44L CIG5 MXl 0.988509

IFIT5 MXl SPI lO 0.988438

HERC5 TYKI ZBPl 0.988437

OASl IFITl ZBPl 0.988433

IFIT4 HERC5 IFITl 0.988422

IRF7 TYKI XIAP 0.988382

IFIT5 IFITl ZBPl 0.988359

IFIT5 0AS2 OASL 0.988341

IFIT5 IFIT4 CIG5 0.988316

SAMD9L IFITl ZBPl 0.988312

G1P2 IFITl SPI lO 0.988303

OASl IFITl XIAP 0.9883

OASL SAMD9L TYKI 0.988278

HERC5 CHMP5 RIGE 0.988269

IFIT4 OASl TYKI 0.988268

0AS2 OASl IFITl 0.988248

G1P2 MXl XIAP 0.988232

OASl HERC5 MXl 0.988215

OASl CIG5 HERC5 0.988211

HERC5 ZBPl 0.988167 SAMD9L

OAS2 HERC5 TYKI 0.988163

IFI44 0AS3 ZBPl 0.988139

CIG5 CHMP5 ZBPl 0.988136

IFI44L IRF7 RIGE 0.988106

IFIT4 IFI44 0AS3 0.988101

OAS2 SAMD9L TYKI 0.988081

IFIT5 CIG5 IFITl 0.988073

IFIT5 EPSTIl CIG5 0.988072

IFIT4 OASL IFI44 0.98801

IFI44 HERC5 RIGE 0.987984

IFIT4 G1P2 XIAP 0.987951

IFI44L MXl SPI lO 0.98795

OASl MXl XIAP 0.987945

RIGl IRF7 IFITl 0.987936

IFIT4 RIGl HERC5 0.987933

IFIT4 SAMD9L IFITl 0.987928

IFI44L EPSTIl IRF7 0.987927

IFIT4 OASl IRF7 0.987914

IFIT5 OASL XIAP 0.987913

IFIT4 IFI44 RIGE 0.987912

IFIT5 CIG5 0AS3 0.987904

IFIT4 SAMD9L XIAP 0.987896

OAS2 G1P2 SAMD9L 0.987775

OASL HERC5 IFITl 0.987735

IRF7 IFI44 0AS3 0.987734

IFIT5 CIG5 HERC5 0.98773

EPSTIl HERC5 MXl 0.987723

G1P2 CIG5 TYKI 0.98772

IFIT5 IFIT4 RIGE 0.987715

IFI44L RIGE ZBPl 0.987715

IFIT5 OASL IRF7 0.987699

OASl HERC5 IFITl 0.987696

EPSTIl HERC5 SAMD9L 0.987685

OASL IRF7 IFI44 0.98768

IFI44L RIGl OASL 0.987635

EPSTIl RIGl G1P2 0.987607

IFIT4 CIG5 TYKI 0.987605

0AS2 EPSTIl IFI44 0.987589

IFIT5 0AS2 XIAP 0.987588

0AS2 TYKI MXl 0.987555

OASL IFI44 MXl 0.987554

CHMP5 MXl RIGE 0.987534

IFI44L 0AS3 MXl 0.987521

IFI44 0AS3 SPI lO 0.987441 EPSTIl HERC5 IFITl 0.987435

G1P2 HERC5 IFITl 0.987431

IFIT4 TYKI SPI lO 0.9874

OAS2 IFI44 RIGE 0.987335

IRF7 HERC5 XIAP 0.987327

OAS3 CHMP5 ZBPl 0.987314

HERC5 SAMD9L XIAP 0.987305

G1P2 HERC5 SAMD9L 0.987303

OASL HERC5 TYKI 0.987292

RIGl IRF7 TYKI 0.987272

IFI44 0AS3 XIAP 0.987263

OASL TYKI MXl 0.987226

SAMD9L MXl ZBPl 0.987216

G1P2 TYKI XIAP 0.987186

RIGl IFITl XIAP 0.987143

CIG5 HERC5 IFITl 0.987143

OASL CHMP5 MXl 0.987113

IFIT5 CIG5 SPI lO 0.987103

HERC5 SAMD9L MXl 0.987078

EPSTIl SAMD9L IFITl 0.987021

IFI44L EPSTIl XIAP 0.986996

IFIT4 G1P2 IFITl 0.986962

IFIT5 0AS2 SPI lO 0.986961

TYKI IFITl MXl 0.986955

IFI44 IFITl RIGE 0.98694

G1P2 OASl IRF7 0.986929

RIGl TYKI XIAP 0.986927

IFI44L SPI lO XIAP 0.986913

IFIT5 EPSTIl OASL 0.986895

OASL IFI44 SPI lO 0.986847

SAMD9L MXl SPI lO 0.986839

IFIT4 IFITl XIAP 0.986801

G1P2 SAMD9L MXl 0.986792

SAMD9L TYKI MXl 0.986776

IFITl MXl XIAP 0.986772

RIGl HERC5 XIAP 0.986653

IFIT4 SAMD9L ZBPl 0.986638

CIG5 IFI44 SPI lO 0.986615

RIGl TYKI MXl 0.986584

IFI44L CIG5 IFITl 0.986574

CIG5 TYKI XIAP 0.986567

SAMD9L TYKI XIAP 0.986554

IFI44L RIGl RIGE 0.986514 IFIT4 OASL CHMP5 0.986483

IFI44L 0AS2 MXl 0.986478

CIG5 IFI44 XIAP 0.98647

IFI44L G1P2 RIGE 0.986469

IRF7 IFI44 ZBPl 0.986437

EPSTIl CIG5 IFI44 0.986418

RIGl CIG5 TYKI 0.986387

RIGl TYKI IFITl 0.986336

IFIT5 EPSTIl MXl 0.986313

IRF7 IFITl XIAP 0.986307

IFIT4 MXl XIAP 0.98627

IFIT4 0AS3 CHMP5 0.986258

G1P2 IRF7 MXl 0.986258

OAS2 IFI44 SPI lO 0.986255

IFIT5 G1P2 CIG5 0.986247

IFI44L HERC5 SPI lO 0.986229

G1P2 OASL IFITl 0.986183

G1P2 SAMD9L IFITl 0.986168

TYKI MXl ZBPl 0.986151

CHMP5 IFITl RIGE 0.986136

OASl IRF7 HERC5 0.986057

IRF7 IFITl MXl 0.986039

IFIT5 HERC5 RIGE 0.985983

IFIT5 0AS2 HERC5 0.985946

RIGl IRF7 MXl 0.985944

IFI44 XIAP ZBPl 0.985944

IFI44L G1P2 OASL 0.985941

IFIT5 OASL HERC5 0.98592

G1P2 HERC5 MXl 0.985913

OAS2 OASl MXl 0.98591

IFIT5 G1P2 ZBPl 0.985875

OASl CIG5 TYKI 0.985852

RIGl G1P2 HERC5 0.985831

OASl OASL IFITl 0.985827

G1P2 CIG5 IFITl 0.985799

IFI44L 0AS3 ZBPl 0.985763

IFI44L 0AS2 XIAP 0.985746

IFIT5 HERC5 ZBPl 0.985738

RIGl HERC5 MXl 0.985734

IRF7 CIG5 TYKI 0.985724

CIG5 HERC5 MXl 0.985709

IFIT4 RIGl SAMD9L 0.985702

0AS2 SAMD9L MXl 0.985696

0AS3 HERC5 CHMP5 0.985677

OASL HERC5 CHMP5 0.985675

EPSTIl G1P2 XIAP 0.985614 IFIT4 G1P2 MXl 0.985575

OAS2 SAMD9L IFITl 0.985558

IFI44 0AS3 HERC5 0.985493

IFIT4 OASL TYKI 0.985491

IFIT5 0AS2 G1P2 0.985467

CHMP5 SPI lO ZBPl 0.985431

RIGl MXl XIAP 0.985418

IFI44L HERC5 ZBPl 0.985411

G1P2 HERC5 ZBPl 0.985399

IFI44L MXl ZBPl 0.985399

RIGl HERC5 IFITl 0.985388

OASL IFI44 IFITl 0.985349

RIGl OASl MXl 0.985314

IFIT4 IFI44 ZBPl 0.985306

IFIT4 OASL SAMD9L 0.985271

OASL IFI44 HERC5 0.985262

IFIT4 0AS2 TYKI 0.985259

IRF7 CHMP5 RIGE 0.985241

G1P2 IRF7 TYKI 0.98524

RIGl SAMD9L MXl 0.985203

G1P2 OASL HERC5 0.985184

IFI44L IFIT4 EPSTIl 0.985167

SAMD9L IFITl SPI lO 0.985161

HERC5 SAMD9L SPI lO 0.985136

IFI44L EPSTIl MXl 0.985133

IFIT4 CHMP5 RIGE 0.985089

IFI44L IFITl SPI lO 0.985074

OASL CHMP5 IFITl 0.985052

IFI44L 0AS2 RIGE 0.985038

OASl MXl ZBPl 0.985036

IFIT5 G1P2 SPI lO 0.985035

RIGl HERC5 TYKI 0.98502

IFI44L 0AS2 HERC5 0.985013

OASL IFI44 OAS3 0.984994

IFIT5 0AS3 ZBPl 0.984992

IRF7 CIG5 IFI44 0.984947

EPSTIl CHMP5 ZBPl 0.984947

IFI44L G1P2 SPI lO 0.984929

IFIT5 IFIT4 SPI lO 0.984889

IFI44 0AS3 MXl 0.984882

IFIT5 IFIT4 XIAP 0.984858

G1P2 OASl ZBPl 0.984857

IFI44L 0AS2 IFITl 0.984833

IFIT5 EPSTIl IRF7 0.984785

IFI44L IFITl ZBPl 0.984771 G1P2 OASl HERC5 0.984751

IFI44L OAS3 SAMD9L 0.984637

IFIT5 EPSTIl XIAP 0.984622

OAS2 IRF7 IFI44 0.984619

IFIT4 IRF7 IFITl 0.984565

IFIT5 IFITl SPI lO 0.984547

SAMD9L TYKI IFITl 0.984535

HERC5 SAMD9L IFITl 0.984528

IFI44L CIG5 TYKI 0.984518

RIGl OASl IFITl 0.984505

IFI44L OASL SAMD9L 0.984455

IRF7 IFI44 RIGE 0.984421

IFI44L G1P2 CIG5 0.98441

OAS2 CHMP5 RIGE 0.98438

G1P2 TYKI IFITl 0.984362

IFIT5 G1P2 OASL 0.98435

SAMD9L CHMP5 RIGE 0.98435

IFIT4 OASl CIG5 0.984347

OAS2 HERC5 SAMD9L 0.98434

IFIT4 G1P2 IRF7 0.984323

G1P2 HERC5 TYKI 0.984302

IRF7 CIG5 SAMD9L 0.984261

EPSTIl G1P2 IRF7 0.984258

OASl TYKI MXl 0.984212

IFI44L RIGl CIG5 0.984189

IFI44 0AS3 IFITl 0.984148

OASl CIG5 SAMD9L 0.984088

IRF7 SAMD9L XIAP 0.984046

IFIT4 OASl XIAP 0.983986

G1P2 MXl SPI lO 0.983965

OASl TYKI IFITl 0.983952

IFIT4 OASl SAMD9L 0.983939

IRF7 MXl XIAP 0.983917

G1P2 IFI44 RIGE 0.983911

EPSTIl OASl TYKI 0.983904

IFI44L OASL TYKI 0.983891

IFIT5 0AS2 PARP9 0.983888

RIGl G1P2 XIAP 0.983881

IFIT5 G1P2 RIGE 0.983874

OAS2 CHMP5 ZBPl 0.983861

IFIT4 RIGl OASl 0.983828 G1P2 IFITl ZBPl 0.983828

IFIT4 IRF7 MXl 0.983803

OASL HERC5 MXl 0.983775

RIGl CIG5 SAMD9L 0.983728

IFIT5 RIGE XIAP 0.983696

HERC5 IFITl SPI lO 0.983625

IFIT5 CIG5 PARP9 0.983607

OASL CHMP5 RIGE 0.983598

IFI44L IFIT4 XIAP 0.983588

IRF7 SAMD9L ZBPl 0.983584

IFIT5 0AS3 SAMD9L 0.983578

G1P2 TYKI ZBPl 0.983567

EPSTIl OASl HERC5 0.983564

HERC5 IFITl MXl 0.983432

IFIT4 EPSTIl G1P2 0.98341

IFIT5 MXl XIAP 0.983401

SAMD9L IFITl MXl 0.983359

OAS3 CHMP5 MXl 0.983261

OAS2 IFI44 0AS3 0.983253

IFIT4 OASl ZBPl 0.983249

G1P2 IRF7 XIAP 0.983205

OAS3 CHMP5 IFITl 0.983177

HERC5 IFITl ZBPl 0.983163

IFIT5 IFIT4 EPSTIl 0.983135

IFIT5 0AS3 SPI lO 0.983121

OASl IFITl SPI lO 0.983118

0AS2 CIG5 CHMP5 0.983111

IFI44L OASL OAS3 0.983103

G1P2 OASl SPI lO 0.983094

G1P2 OASl XIAP 0.983073

EPSTIl IRF7 HERC5 0.983059

IFIT5 EPSTIl G1P2 0.983057

IFIT5 IFIT4 IRF7 0.983047

IFI44L EPSTIl HERC5 0.982974

0AS2 G1P2 OASl 0.982973

IFIT4 RIGl G1P2 0.98284

EPSTIl IRF7 SAMD9L 0.982832

0AS3 SAMD9L IFITl 0.98283

G1P2 TYKI MXl 0.982823

IFIT5 IRF7 MXl 0.982823

CIG5 IFI44 MXl 0.982815

IFIT5 IRF7 SPI lO 0.982806

EPSTIl IFITl MXl 0.982804

0AS2 G1P2 HERC5 0.982779 HERC5 SAMD9L TYKI 0.982773

OASL TYKI CHMP5 0.98276

OASl SAMD9L MXl 0.982709

IFI44L TYKI RIGE 0.982691

IFI44L RIGl OAS3 0.982688

IFIT4 IFITl MXl 0.982616

EPSTIl CIG5 TYKI 0.982605

G1P2 CIG5 MXl 0.982585

TYKI CHMP5 RIGE 0.982585

IFI44L IFIT4 IRF7 0.982564

IFIT5 CIG5 TYKI 0.982489

G1P2 CHMP5 RIGE 0.98248

IFIT5 0AS3 PARP9 0.982456

IFIT4 EPSTIl OASl 0.98245

CIG5 CHMP5 XIAP 0.982444

IRF7 CHMP5 ZBPl 0.982443

IFIT5 SAMD9L RIGE 0.982442

CIG5 CHMP5 SPI lO 0.982432

IFIT5 EPSTIl IFITl 0.982364

IFIT5 G1P2 OAS3 0.982346

OAS2 IFI44 XIAP 0.982312

CIG5 IFI44 HERC5 0.982284

OAS2 G1P2 TYKI 0.982279

RIGl G1P2 IFITl 0.982209

IFI44L EPSTIl G1P2 0.982198

OASL IFITl MXl 0.982165

OASl OASL MXl 0.982158

IFIT4 RIGl MXl 0.982123

IFI44L TYKI SPI lO 0.982105

IFIT5 RIGl ZBPl 0.982033

IFI44L SPI lO RIGE 0.982032

IFI44L EPSTIl IFITl 0.982017

IFIT4 CIG5 SAMD9L 0.981999

IFIT5 IFIT4 MXl 0.981994

IFIT5 RIGl OAS3 0.981987

0AS2 IFI44 MXl 0.981967

0AS2 G1P2 IFITl 0.981944

IFIT4 OAS2 IFI44 0.981942

IFIT5 CIG5 RIGE 0.981929

RIGl G1P2 SAMD9L 0.981924

EPSTIl TYKI ZBPl 0.981909

IFIT5 RIGl CIG5 0.9819

IFI44L G1P2 ZBPl 0.981887

0AS2 HERC5 IFITl 0.981886 G1P2 OASL IFI44 0.981878

IFI44 SAMD9L RIGE 0.981874

IFIT5 SPI lO XIAP 0.981729

CIG5 PARP9 SAMD9L 0.981712

OAS3 HERC5 SAMD9L 0.981703

EPSTIl RIGl HERC5 0.981663

IFIT5 EPSTIl RIGE 0.981653

PJGl SAMD9L ZBPl 0.981639

HERC5 MXl SPI lO 0.981627

IFIT5 IRF7 XIAP 0.981625

IFIT4 RIGl IFITl 0.981605

IFI44 MXl ZBPl 0.9816

RIGl G1P2 IRF7 0.98159

IFI44L CIG5 PARP9 0.981588

IRF7 TYKI ZBPl 0.981572

IFI44L OASl CIG5 0.981535

OASl MXl SPI lO 0.981522

IRF7 CIG5 HERC5 0.981504

OASL IFI44 RIGE 0.98145

IFIT5 HERC5 SPI lO 0.981389

IFIT4 CIG5 IFI44 0.981344

EPSTIl PARP9 TYKI 0.981338

IFI44L IRF7 XIAP 0.981327

G1P2 IFITl MXl 0.981177

SAMD9L IFITl RIGE 0.981164

CHMP5 XIAP ZBPl 0.981034

IRF7 CIG5 CHMP5 0.98102

IFI44L CIG5 SAMD9L 0.980991

G1P2 OASL TYKI 0.980952

IFIT4 EPSTIl SAMD9L 0.980931

CIG5 SAMD9L XIAP 0.98087

IFI44L RIGl ZBPl 0.980847

G1P2 OASL CHMP5 0.98084

RIGl CIG5 HERC5 0.980836

IFI44L OAS2 G1P2 0.980731

IFI44L OAS2 TYKI 0.980703

IFIT5 OAS2 RIGl 0.980656

IFI44L EPSTIl TYKI 0.980647

RIGl TYKI SPI lO 0.980579

EPSTIl IFITl XIAP 0.980575

IFI44 SPI lO RIGE 0.980565

IFI44 HERC5 ZBPl 0.980564 EPSTIl CIG5 CHMP5 0.980544

EPSTIl IFI44 XIAP 0.980516

IFIT5 0AS2 TYKI 0.980487

EPSTIl IRF7 IFITl 0.980474

IFI44L TYKI ZBPl 0.98047

IFI44L 0AS2 0AS3 0.980469

EPSTIl IFI44 SPI lO 0.980453

OASl 0AS3 IFITl 0.980399

G1P2 OASL MXl 0.980398

OASl CHMP5 RIGE 0.980281

IFIT5 EPSTIl HERC5 0.98028

OASl SAMD9L IFITl 0.980165

0AS3 TYKI CHMP5 0.980145

IFIT4 EPSTIl HERC5 0.980116

0AS2 EPSTIl CHMP5 0.980093

IFI44L 0AS3 TYKI 0.980031

EPSTIl HERC5 XIAP 0.980031

RIGl SAMD9L IFITl 0.98002

IFI44L OASl RIGE 0.980003

G1P2 SAMD9L RIGE 0.979981

IFIT5 IFITl XIAP 0.979977

IFI44L OASL PARP9 0.979964

CHMP5 SPI lO RIGE 0.979922

0AS2 0AS3 CHMP5 0.979909

IFIT5 EPSTIl SPI lO 0.97989

RIGl HERC5 SAMD9L 0.97989

0AS2 CHMP5 SPI lO 0.979884

G1P2 SAMD9L TYKI 0.979881

IFIT5 0AS2 OAS3 0.979865

CIG5 IFITl MXl 0.97981

IFI44L G1P2 OAS3 0.979733

IFIT5 TYKI ZBPl 0.97972

CIG5 IFI44 IFITl 0.979594

0AS2 IFI44 HERC5 0.979577

IFIT4 PARP9 TYKI 0.979539

OASl 0AS3 CHMP5 0.979509

IFIT5 IRF7 RIGE 0.979509

TYKI XIAP ZBPl 0.979497

EPSTIl MXl XIAP 0.979484

CIG5 HERC5 XIAP 0.979467

IFIT5 RIGE ZBPl 0.979447

0AS3 SAMD9L CHMP5 0.979429

IFIT5 IRF7 IFITl 0.979416 EPSTIl IRF7 IFI44 0.979334

G1P2 CIG5 IFI44 0.979329

IFIT4 G1P2 ZBPl 0.979297

IFIT4 OASL IFITl 0.979261

EPSTIl IRF7 MXl 0.979237

IFI44 IFITl ZBPl 0.979214

IFI44L MXl XIAP 0.979195

HERC5 MXl ZBPl 0.979186

IFI44L IRF7 MXl 0.979186

OASl PARP9 IFITl 0.979168

OAS2 IRF7 TYKI 0.979158

EPSTIl RIGl IFITl 0.979136

EPSTIl RIGl MXl 0.979132

IFI44L 0AS3 PARP9 0.979131

IFI44 MXl SPI lO 0.979127

OASl IRF7 CIG5 0.979073

IFIT4 PARP9 SAMD9L 0.979062

IFIT4 HERC5 ZBPl 0.979058

RIGl CHMP5 RIGE 0.979057

G1P2 CIG5 XIAP 0.979049

OASl HERC5 ZBPl 0.979026

IFI44L OASL RIGE 0.979004

0AS2 IRF7 CHMP5 0.978997

EPSTIl RIGl SAMD9L 0.978996

OASL IRF7 SAMD9L 0.978946

0AS2 HERC5 MXl 0.978889

HERC5 SAMD9L RIGE 0.978849

IFIT4 CIG5 HERC5 0.978822

IFIT4 OASL HERC5 0.978804

RIGl G1P2 MXl 0.978789

IFIT5 CIG5 SAMD9L 0.978769

IFI44L OASl 0AS3 0.978759

0AS3 SAMD9L MXl 0.978718

RIGl TYKI ZBPl 0.978668

G1P2 IFI44 ZBPl 0.978638

EPSTIl IFI44 MXl 0.97863

0AS2 IFI44 IFITl 0.978619

CIG5 PARP9 TYKI 0.978512

EPSTIl PARP9 SAMD9L 0.978467

EPSTIl SAMD9L XIAP 0.978424

IFIT5 0AS3 TYKI 0.978409 IFIT5 OASL SPI lO 0.978403

IFI44 SPI lO XIAP 0.978398

IFI44L IFIT4 MXl 0.978348

IFI44L OAS2 RIGl 0.978343

CIG5 IFITl XIAP 0.978337

RIGl OASL CHMP5 0.978325

IFI44L SAMD9L ZBPl 0.978297

IFIT5 IFIT4 IFITl 0.978296

OASl IRF7 TYKI 0.97822

IFIT5 OASL SAMD9L 0.978202

IRF7 TYKI SPI lO 0.978191

SAMD9L MXl RIGE 0.978177

IFIT5 OASL TYKI 0.978163

PARP9 SAMD9L XIAP 0.978139

G1P2 IFI44 OAS3 0.978119

OASl HERC5 XIAP 0.97802

IFIT4 0AS2 SAMD9L 0.978019

IFI44L IRF7 HERC5 0.978014

RIGl OASL SAMD9L 0.97801

G1P2 MXl ZBPl 0.977958

IFI44L 0AS2 PARP9 0.977945

OAS3 SAMD9L TYKI 0.977935

PARP9 IFITl XIAP 0.977901

G1P2 OASl OASL 0.977848

IFIT4 0AS2 OASl 0.977813

IFI44 0AS3 SAMD9L 0.977801

IFI44 TYKI RIGE 0.97779

IFIT5 SAMD9L ZBPl 0.977734

OAS2 EPSTIl TYKI 0.977724

PARP9 SAMD9L IFITl 0.977718

RIGl SAMD9L XIAP 0.977704

OAS3 TYKI IFITl 0.977699

IFIT5 RIGl OASL 0.977613

TYKI SPI lO XIAP 0.977603

PARP9 TYKI IFITl 0.977602

G1P2 OASl SAMD9L 0.977585

PARP9 TYKI XIAP 0.977542

OASL IFI44 TYKI 0.977504 IFIT5 IRF7 HERC5 0.977473

IRF7 IFI44 SPI lO 0.977459

IFIT5 EPSTIl TYKI 0.977454

IRF7 CIG5 IFITl 0.977446

OAS2 OASl HERC5 0.977433

CIG5 TYKI CHMP5 0.977361

IFIT5 IFIT4 HERC5 0.977353

IFIT4 EPSTIl MXl 0.977281

IFI44L RIGl SPI lO 0.977267

IFIT5 OASL PARP9 0.977265

IFIT4 EPSTIl IFITl 0.977256

RIGl IFITl MXl 0.977255

IFI44L IFIT4 HERC5 0.977207

IFIT4 G1P2 CIG5 0.977176

CIG5 IFI44 TYKI 0.9771

OASl TYKI ZBPl 0.977098

OAS2 G1P2 IFI44 0.977092

OASL SAMD9L CHMP5 0.977068

IFIT4 IFI44 SPI lO 0.977067

G1P2 PARP9 SAMD9L 0.977067

IFIT4 CHMP5 ZBPl 0.977042

CIG5 HERC5 CHMP5 0.976966

IFIT4 G1P2 OASL 0.976916

OAS2 G1P2 MXl 0.976841

G1P2 IRF7 CIG5 0.97684

IFIT4 OASl PARP9 0.976808

OASl SAMD9L ZBPl 0.976794

IFIT4 0AS3 SAMD9L 0.976791

IFI44L IFITl XIAP 0.97677

IFI44L IRF7 IFITl 0.976769

IFIT4 IFITl ZBPl 0.976725

G1P2 IFI44 SPI lO 0.976722

0AS2 OASl TYKI 0.976711

IFIT5 0AS2 RIGE 0.976711

EPSTIl G1P2 PARP9 0.97671

IFIT5 TYKI SPI lO 0.976687

G1P2 0AS3 SAMD9L 0.976675

RIGl IFI44 RIGE 0.976614

IFIT4 EPSTIl IFI44 0.976597

RIGl 0AS3 CHMP5 0.976452

EPSTIl OASl SAMD9L 0.976439

RIGl G1P2 CIG5 0.976418

CIG5 CHMP5 MXl 0.976409 OASl IRF7 SAMD9L 0.976378

OAS3 HERC5 IFITl 0.976367

OAS2 IRF7 SAMD9L 0.976358

IFIT5 IFIT4 G1P2 0.976294

EPSTIl OASl IRF7 0.976291

IFI44 HERC5 SPI lO 0.976272

IFI44 0AS3 RIGE 0.976262

IFIT4 G1P2 SPI lO 0.976253

EPSTIl G1P2 IFI44 0.976186

OASL IFITl XIAP 0.976181

IRF7 PARP9 SAMD9L 0.976177

IRF7 HERC5 ZBPl 0.976154

OAS3 CHMP5 RIGE 0.976111

OASL TYKI XIAP 0.976092

IFI44L 0AS2 SAMD9L 0.976088

IFI44L OASl OASL 0.976054

IFITl MXl SPI lO 0.976025

IFI44L HERC5 XIAP 0.975972

IFIT5 G1P2 XIAP 0.975971

IFIT5 0AS2 SAMD9L 0.975959

IFIT5 HERC5 XIAP 0.975949

OASL IFI44 SAMD9L 0.975842

IFIT5 EPSTIl PARP9 0.975824

EPSTIl IFI44 HERC5 0.975738

SAMD9L TYKI RIGE 0.975714

IFI44 0AS3 TYKI 0.975702

IFIT5 TYKI RIGE 0.97567

RIGl CIG5 IFITl 0.975658

HERC5 PARP9 SAMD9L 0.975637

G1P2 0AS3 CHMP5 0.975579

OASl HERC5 TYKI 0.975575

IFIT5 OASL 0AS3 0.975559

IFI44L IFIT4 IFITl 0.975549

SAMD9L XIAP ZBPl 0.975489

EPSTIl OASL TYKI 0.975407

IFI44L EPSTIl PARP9 0.975398

OASL IRF7 IFITl 0.975396

RIGl OASl CIG5 0.975346

RIGl OASL IFITl 0.975344

IFIT4 OASl OASL 0.975331

0AS3 HERC5 TYKI 0.975303

OASl IFI44 RIGE 0.975295 OAS2 IFITl MXl 0.97529

IFITl MXl ZBPl 0.975252

CIG5 MXl XIAP 0.975204

OASl CIG5 PARP9 0.97518

IFIT5 PARP9 ZBPl 0.975163

IFI44L OASl ZBPl 0.97516

IFI44L EPSTIl RIGl 0.975122

IFIT4 OASL MXl 0.975118

OASL IRF7 TYKI 0.975116

OAS2 RIGl TYKI 0.97509

OAS2 CHMP5 XIAP 0.975079

OASL SAMD9L XIAP 0.975079

HERC5 PARP9 IFITl 0.975059

RIGl G1P2 OASl 0.975034

RIGl OASL IFI44 0.974999

IFI44 0AS3 PARP9 0.974929

IFIT4 IFI44 XIAP 0.974925

IRF7 IFITl ZBPl 0.974912

PARP9 SAMD9L MXl 0.97489

OASl IFITl RIGE 0.974859

EPSTIl SAMD9L ZBPl 0.974825

HERC5 PARP9 XIAP 0.974823

EPSTIl TYKI SPI lO 0.974822

IFIT4 CIG5 IFITl 0.974778

G1P2 OASl TYKI 0.974713

IFI44 IFITl SPI lO 0.974708

HERC5 PARP9 TYKI 0.9747

EPSTIl G1P2 ZBPl 0.974674

IFI44L 0AS2 OASl 0.974667

IFI44 TYKI ZBPl 0.974642

EPSTIl CHMP5 XIAP 0.974537

IFIT4 SAMD9L SPI lO 0.974501

TYKI CHMP5 ZBPl 0.974475

EPSTIl G1P2 CIG5 0.974468

OASl IFI44 0AS3 0.974458

EPSTIl IFI44 IFITl 0.974387

OASl 0AS3 MXl 0.974382

0AS2 TYKI XIAP 0.974363

OASl OASL HERC5 0.974357

IFIT5 G1P2 IRF7 0.974308

OASl OASL CHMP5 0.974297

TYKI IFITl RIGE 0.974282

OASl PARP9 MXl 0.974256

0AS2 IFI44 TYKI 0.974177

OASl CIG5 IFI44 0.974175 RIGl IFI44 0AS3 0.974125

IFI44L IFIT4 TYKI 0.974105

OASl CIG5 CHMP5 0.974105

OAS2 PARP9 SAMD9L 0.974104

IRF7 CIG5 MXl 0.974084

CHMP5 SPI lO XIAP 0.974042

EPSTIl CHMP5 SPI lO 0.973988

OASl TYKI XIAP 0.973951

HERC5 CHMP5 ZBPl 0.973937

CIG5 TYKI ZBPl 0.973936

IFI44L SAMD9L SPI lO 0.973933

IFIT4 HERC5 PARP9 0.973933

IFIT5 OASl CIG5 0.97391

G1P2 PARP9 XIAP 0.973887

OASl CIG5 XIAP 0.973886

CHMP5 MXl ZBPl 0.973864

TYKI CHMP5 SPI lO 0.973768

EPSTIl PARP9 IFITl 0.97373

IRF7 CHMP5 SPI lO 0.973693

CIG5 IFI44 PARP9 0.973655

G1P2 PARP9 IFITl 0.973599

EPSTIl CIG5 SAMD9L 0.973586

G1P2 IRF7 ZBPl 0.97357

EPSTIl IRF7 CHMP5 0.973555

OASL IFI44 PARP9 0.973554

0AS2 TYKI CHMP5 0.973542

RIGl G1P2 TYKI 0.973532

IRF7 IFI44 XIAP 0.973462

IFIT5 RIGl RIGE 0.973451

IFIT5 IFIT4 TYKI 0.973442

G1P2 HERC5 PARP9 0.97344

0AS2 CHMP5 MXl 0.973422

PARP9 SAMD9L TYKI 0.973386

IFI44 MXl XIAP 0.973355

RIGl SAMD9L TYKI 0.973328

CIG5 CHMP5 IFITl 0.973246

CIG5 HERC5 PARP9 0.973244

IFI44L IFIT4 G1P2 0.973197

OASL IRF7 HERC5 0.973112

IFIT4 CIG5 CHMP5 0.973104

0AS2 OASl SAMD9L 0.973103

G1P2 CIG5 CHMP5 0.973073

RIGl G1P2 SPI lO 0.973048 IFIT4 CIG5 MXl 0.973006

IFI44L EPSTIl OASl 0.973006

IFIT4 0AS3 TYKI 0.973003

G1P2 XIAP ZBPl 0.97295

OASL PARP9 SAMD9L 0.972938

EPSTIl HERC5 PARP9 0.972841

IFITl XIAP ZBPl 0.972814

IFIT4 PARP9 IFITl 0.972796

CHMP5 MXl SPI lO 0.972719

PARP9 TYKI MXl 0.972707

IFIT4 MXl ZBPl 0.972638

IFI44L EPSTIl SAMD9L 0.972539

IFIT5 IFITl MXl 0.972533

IFI44L G1P2 XIAP 0.972515

EPSTIl IFI44 TYKI 0.972495

IFIT4 0AS2 HERC5 0.97249

IFIT4 RIGl XIAP 0.97246

IFIT5 HERC5 MXl 0.972458

OASl TYKI SPI lO 0.972445

EPSTIl OASl CIG5 0.972368

CIG5 PARP9 IFITl 0.972329

IFIT4 0AS2 G1P2 0.972297

IFIT4 IRF7 IFI44 0.972137

HERC5 IFITl RIGE 0.97204

IFI44L PARP9 RIGE 0.971994

RIGl CIG5 MXl 0.971955

CIG5 IFI44 SAMD9L 0.971908

CHMP5 IFITl ZBPl 0.971907

CIG5 SAMD9L ZBPl 0.971889

G1P2 OASl PARP9 0.971807

IRF7 PARP9 IFITl 0.97179

OAS3 TYKI MXl 0.971782

OAS2 HERC5 CHMP5 0.97176

IRF7 HERC5 PARP9 0.971671

IFIT4 G1P2 PARP9 0.971625

EPSTIl TYKI CHMP5 0.971602

IRF7 IFI44 MXl 0.971595

OASl OASL SAMD9L 0.971575

IFIT4 0AS2 CHMP5 0.971528

IFI44L G1P2 IRF7 0.971506

OASl HERC5 SPI lO 0.971466

RIGl OASL TYKI 0.971392

IRF7 PARP9 TYKI 0.971348

IFIT4 OASl OAS3 0.971335 G1P2 CHMP5 ZBPl 0.971335

IFIT4 HERC5 SPI lO 0.971301

IFI44 TYKI SPI lO 0.971298

OAS2 IRF7 HERC5 0.97127

IFIT4 0AS2 IFITl 0.971233

IFI44L PARP9 SPI lO 0.971191

IFIT5 OASl 0AS3 0.971185

OAS2 IRF7 IFITl 0.971184

OAS2 IFI44 PARP9 0.971174

IFI44L PARP9 ZBPl 0.971145

G1P2 CHMP5 SPI lO 0.971088

OASl HERC5 SAMD9L 0.971083

G1P2 CIG5 PARP9 0.971042

IFIT5 PARP9 XIAP 0.971027

EPSTIl CHMP5 MXl 0.970954

G1P2 SPI lO XIAP 0.970897

OASL HERC5 XIAP 0.970881

PJGl IFITl ZBPl 0.97081

G1P2 OASL XIAP 0.970803

OAS2 PARP9 TYKI 0.970766

IFI44L IFIT4 OASl 0.970742

IFIT5 G1P2 MXl 0.970738

EPSTIl CIG5 HERC5 0.970734

EPSTIl OASl PARP9 0.970723

HERC5 TYKI RIGE 0.970716

OASl 0AS3 HERC5 0.970715

G1P2 IFITl RIGE 0.970712

IFIT4 IRF7 XIAP 0.970712

HERC5 CHMP5 SPI lO 0.970697

IFI44L 0AS3 RIGE 0.970693

RIGl CIG5 IFI44 0.970657

EPSTIl OASL SAMD9L 0.970657

RIGl G1P2 ZBPl 0.970629

RIGl HERC5 ZBPl 0.970593

IFI44 SAMD9L ZBPl 0.970587

OASl IRF7 XIAP 0.970567

IFIT4 IFI44 MXl 0.970564

OASl OASL TYKI 0.970536

OASl OASL IFI44 0.970435

OASl 0AS3 SAMD9L 0.970395

OASl IRF7 ZBPl 0.970393

IFI44L TYKI XIAP 0.970382

HERC5 XIAP ZBPl 0.970322

0AS2 CHMP5 IFITl 0.970286

EPSTIl OASl XIAP 0.970174 IFI44L IRF7 TYKI 0.970096

IFI44L HERC5 MXl 0.970092

PARP9 MXl XIAP 0.970089

IFIT5 EPSTIl RIGl 0.970015

IFIT5 IFIT4 PARP9 0.97001

G1P2 0AS3 IFITl 0.96993

OAS3 HERC5 MXl 0.969845

OASL MXl XIAP 0.969812

OASl IFI44 ZBPl 0.969803

G1P2 HERC5 RIGE 0.969762

IFIT5 PARP9 SPI lO 0.969753

G1P2 0AS3 HERC5 0.969712

OASl MXl RIGE 0.969615

HERC5 PARP9 MXl 0.969607

IFI44 IFITl XIAP 0.969589

RIGl OASL HERC5 0.969589

CIG5 TYKI SPI lO 0.969581

G1P2 IRF7 SPI lO 0.969568

IFIT5 IFI44L RIGE 0.969542

IFI44 HERC5 XIAP 0.96949

RIGl IFI44 ZBPl 0.969468

IFIT5 HERC5 IFITl 0.969441

IRF7 IFI44 HERC5 0.96943

RIGl OASl HERC5 0.969339

IFIT5 TYKI XIAP 0.969273

EPSTIl G1P2 OASL 0.969257

IFIT5 G1P2 IFITl 0.969226

TYKI MXl RIGE 0.969116

0AS3 PARP9 CHMP5 0.969112

EPSTIl G1P2 CHMP5 0.96899

IFIT4 SAMD9L RIGE 0.968926

IFIT4 OASl SPI lO 0.968908

0AS2 CIG5 TYKI 0.968886

EPSTIl CIG5 IFITl 0.968832

IFIT4 RIGl IRF7 0.968749

OASL IRF7 MXl 0.968693

IFIT4 IFITl SPI lO 0.968688

0AS2 OASl IFI44 0.968687

0AS2 RIGl SAMD9L 0.968678

IFIT5 EPSTIl SAMD9L 0.968673

OASl CHMP5 ZBPl 0.968667

IFI44L OASl SPI lO 0.968637

EPSTIl RIGl OASl 0.968633

G1P2 OASl OAS3 0.968589

IFIT4 IFI44 HERC5 0.968562

IFI44 PARP9 RIGE 0.96854 IRF7 SAMD9L SPI lO 0.96853

OASL CIG5 TYKI 0.968523

EPSTIl HERC5 CHMP5 0.96846

OAS2 G1P2 CHMP5 0.968446

IRF7 0AS3 SAMD9L 0.968439

G1P2 OASL IRF7 0.968413

EPSTIl OASL IFITl 0.968391

IFIT4 0AS3 HERC5 0.968353

IFIT5 IRF7 TYKI 0.968333

RIGl OASl IRF7 0.968329

EPSTIl IFITl ZBPl 0.968297

OASL CIG5 SAMD9L 0.968278

IRF7 MXl ZBPl 0.968177

OASl HERC5 PARP9 0.968172

G1P2 PARP9 TYKI 0.968154

CHMP5 IFITl SPI lO 0.968058

IFIT4 CHMP5 SPI lO 0.968014

IFI44L IFITl MXl 0.967969

IFIT4 0AS2 MXl 0.967961

IRF7 CHMP5 XIAP 0.967909

IFIT5 OASl ZBPl 0.967889

IRF7 IFI44 IFITl 0.967883

IFI44L HERC5 IFITl 0.967852

0AS2 IFI44 SAMD9L 0.967841

0AS2 G1P2 IRF7 0.967815

EPSTIl PARP9 MXl 0.967795

EPSTIl HERC5 ZBPl 0.967772

OASL PARP9 CHMP5 0.967676

G1P2 IFI44 XIAP 0.967671

PARP9 SAMD9L ZBPl 0.967633

IFIT5 TYKI MXl 0.967584

0AS2 EPSTIl G1P2 0.967581

IFIT4 0AS3 IFITl 0.967551

IFIT5 0AS2 OASl 0.967489

IFIT5 IFI44L OAS3 0.967466

0AS3 IFITl MXl 0.967409

IFIT5 SAMD9L SPI lO 0.967392

IFIT4 PARP9 MXl 0.967359

EPSTIl OASl ZBPl 0.967286

IFIT5 PARP9 RIGE 0.967265

OASl SAMD9L XIAP 0.967252

PARP9 IFITl MXl 0.967202 OASL PARP9 IFITl 0.967188

IFIT4 PARP9 XIAP 0.967184

G1P2 OASl RIGE 0.967087

IFI44L PARP9 XIAP 0.967006

IRF7 HERC5 SPI lO 0.966994

IFIT5 G1P2 HERC5 0.96692

IFI44L IFIT4 SAMD9L 0.966918

EPSTIl G1P2 SPI lO 0.966913

IFIT4 EPSTIl CHMP5 0.966844

OAS2 OASl CHMP5 0.966812

EPSTIl IFI44 PARP9 0.966774

IFIT4 IFI44 IFITl 0.966763

CIG5 SAMD9L CHMP5 0.966661

IFI44L IFIT4 PARP9 0.966617

IFIT5 RIGl SPI lO 0.966575

EPSTIl CIG5 MXl 0.966555

EPSTIl CHMP5 IFITl 0.966528

OAS2 IFITl XIAP 0.966404

MXl XIAP ZBPl 0.966334

HERC5 MXl RIGE 0.966315

IFIT5 OASl RIGE 0.966293

G1P2 PARP9 MXl 0.966277

IFI44L TYKI MXl 0.96627

IFI44 PARP9 ZBPl 0.966234

OASl CIG5 ZBPl 0.966217

IFIT4 G1P2 IFI44 0.966203

IFIT4 MXl SPI lO 0.966196

OAS2 OASl IRF7 0.966139

IFIT4 CHMP5 XIAP 0.966104

IFIT5 IFIT4 SAMD9L 0.966044

RIGl OASL MXl 0.966034

IFIT5 IRF7 PARP9 0.96594

G1P2 IRF7 PARP9 0.965876

OAS2 RIGl IFI44 0.965818

IFI44L G1P2 MXl 0.96579

IRF7 IFITl SPI lO 0.965745

OAS2 EPSTIl SAMD9L 0.965666

CHMP5 MXl XIAP 0.965604

OAS2 PARP9 IFITl 0.965491

EPSTIl OASl IFI44 0.96548

OAS2 IRF7 MXl 0.965404

OASl SAMD9L RIGE 0.965336

IFITl SPI lO XIAP 0.965321

RIGl G1P2 OASL 0.965315 IFI44L OASl MXl 0.965307

G1P2 IRF7 IFI44 0.965102

IFIT5 TYKI IFITl 0.965094

IFI44L G1P2 HERC5 0.965057

IFI44L G1P2 IFITl 0.965022

IFIT5 SPI lO RIGE 0.965009

EPSTIl OASL HERC5 0.964998

OAS2 RIGl IFITl 0.964968

IFI44L IRF7 SAMD9L 0.964937

OAS3 PARP9 SAMD9L 0.964908

IFIT4 IFI44 TYKI 0.964883

PARP9 TYKI SPI lO 0.964876

IFIT5 IFIT4 RIGl 0.964868

EPSTIl 0AS3 TYKI 0.964834

IFI44L IFIT4 RIGl 0.964794

IFITl MXl RIGE 0.96478

OAS2 SAMD9L XIAP 0.964778

IFIT5 IFIT4 OASl 0.964745

OASL PARP9 TYKI 0.96474

OASl SAMD9L TYKI 0.964718

EPSTIl 0AS3 SAMD9L 0.964666

CIG5 PARP9 MXl 0.96462

OAS2 G1P2 XIAP 0.964584

G1P2 TYKI RIGE 0.964575

OASl 0AS3 TYKI 0.964457

SAMD9L CHMP5 ZBPl 0.964434

IFI44L TYKI IFITl 0.964427

G1P2 0AS3 TYKI 0.964415

IFIT4 TYKI RIGE 0.964415

IFIT5 PARP9 IFITl 0.964404

IFI44 HERC5 MXl 0.964284

IFI44L OASl IRF7 0.964253

OASl IRF7 PARP9 0.964194

IFIT5 OASL RIGE 0.964094

IFIT5 PARP9 MXl 0.963954

G1P2 CIG5 ZBPl 0.963938

IFIT5 OASl OASL 0.963852

IRF7 CHMP5 MXl 0.963787

IFIT5 EPSTIl OASl 0.963774

OASl PARP9 XIAP 0.963475

OASl HERC5 RIGE 0.963465

EPSTIl MXl ZBPl 0.963452

EPSTIl OASL MXl 0.963447

IRF7 PARP9 MXl 0.963413 IFI44 TYKI XIAP 0.963301

G1P2 MXl RIGE 0.96322

EPSTIl IFI44 SAMD9L 0.963203

OASl PARP9 SAMD9L 0.963196

IFI44L OASl IFITl 0.963135

IFI44L IRF7 PARP9 0.963058

OASl SAMD9L SPI lO 0.963012

IFIT5 IRF7 SAMD9L 0.963

EPSTIl OASl CHMP5 0.962935

IFIT4 IRF7 CHMP5 0.962925

IFIT4 EPSTIl XIAP 0.96284

CIG5 HERC5 ZBPl 0.962817

PARP9 TYKI ZBPl 0.96278

OASL CIG5 IFITl 0.962747

OASl PARP9 TYKI 0.962615

IFI44L HERC5 TYKI 0.962603

0AS2 EPSTIl IFITl 0.962552

CIG5 PARP9 CHMP5 0.962508

IFI44L RIGl IRF7 0.962495

IFI44L SAMD9L XIAP 0.962462

IFI44L IFI44 RIGE 0.9624

IRF7 HERC5 CHMP5 0.962383

OASL SAMD9L ZBPl 0.962363

0AS2 CIG5 SAMD9L 0.962348

0AS2 RIGl HERC5 0.962318

0AS2 HERC5 XIAP 0.962291

IFIT5 SAMD9L MXl 0.962201

CIG5 IFITl ZBPl 0.962115

HERC5 SPI lO XIAP 0.962086

RIGl IFITl SPI lO 0.962019

0AS2 OASl PARP9 0.962018

RIGl CIG5 CHMP5 0.961991

IFI44 IFITl MXl 0.961953

IFIT5 OASl MXl 0.961952

HERC5 CHMP5 XIAP 0.961934

RIGl HERC5 SPI lO 0.961903

OAS3 SAMD9L XIAP 0.961841

RIGl SAMD9L SPI lO 0.961804

CHMP5 IFITl XIAP 0.961773

G1P2 OAS3 MXl 0.961665 TYKI CHMP5 XIAP 0.961658

TYKI SPI lO ZBPl 0.961568

OAS2 HERC5 PARP9 0.961517

G1P2 IFI44 MXl 0.961483

IFIT4 OASl IFI44 0.961474

IRF7 IFI44 TYKI 0.961401

IFI44L RIGl XIAP 0.961392

SAMD9L SPI lO XIAP 0.961343

PARP9 SAMD9L SPI lO 0.961334

IFIT5 IFI44L OASL 0.961265

OAS2 G1P2 PARP9 0.961245

OASL HERC5 PARP9 0.961238

RIGl MXl ZBPl 0.96122

OAS2 RIGl G1P2 0.961201

IRF7 OAS3 IFITl 0.961186

OAS2 EPSTIl OASl 0.96115

IFI44 SAMD9L SPI lO 0.961138

OASl XIAP ZBPl 0.961114

IFIT4 G1P2 OAS3 0.961085

IFIT5 RIGl XIAP 0.961054

IFIT5 SAMD9L XIAP 0.961053

IFI44 HERC5 IFITl 0.960963

IFIT5 RIGl IRF7 0.96093

IFI44L CHMP5 RIGE 0.960881

IFIT4 OAS3 MXl 0.960838

IFIT5 OAS3 RIGE 0.960806

OAS2 EPSTIl HERC5 0.960756

OAS2 MXl XIAP 0.960748

IFIT4 TYKI CHMP5 0.960741

EPSTIl RIGl IFI44 0.960722

IFIT5 HERC5 TYKI 0.960702

OASL CIG5 HERC5 0.960689

IFI44L SAMD9L MXl 0.960664

IFIT5 IFI44L CIG5 0.960571

IFIT4 EPSTIl IRF7 0.960461

IRF7 MXl SPI lO 0.96046

IFI44L OASl XIAP 0.960455

IFIT5 CHMP5 RIGE 0.960416

IFIT5 IFI44 RIGE 0.960385

IFIT5 RIGl MXl 0.960368

MXl SPI lO XIAP 0.960338

IRF7 OAS3 HERC5 0.960332

IRF7 OAS3 TYKI 0.960205

IFI44 PARP9 SPI lO 0.960125

OASL TYKI ZBPl 0.960125 IRF7 CHMP5 IFITl 0.960021

OAS2 SAMD9L CHMP5 0.959993

G1P2 IFI44 HERC5 0.959978

IFIT4 CHMP5 MXl 0.959927

IFI44 TYKI MXl 0.959842

G1P2 OASL CIG5 0.959832

IFIT4 CIG5 XIAP 0.959816

IFIT4 OASl RIGE 0.959814

OAS2 TYKI ZBPl 0.959811

IRF7 TYKI CHMP5 0.959787

OAS3 IFITl XIAP 0.959775

OAS2 OASl CIG5 0.959672

G1P2 CHMP5 XIAP 0.959471

G1P2 IFI44 IFITl 0.959467

IFI44L PARP9 IFITl 0.959464

G1P2 OASL PARP9 0.959415

IFIT5 HERC5 PARP9 0.959387

OASl OASL IRF7 0.959375

OASl IFI44 SPI lO 0.959304

IFI44 PARP9 XIAP 0.959285

IFIT5 OASl IFITl 0.959283

PARP9 CHMP5 RIGE 0.959251

OAS3 TYKI XIAP 0.959059

IFIT5 IFI44 0AS3 0.959005

IFIT5 0AS3 CHMP5 0.959002

RIGl CHMP5 ZBPl 0.958994

IFIT4 IFITl RIGE 0.958926

EPSTIl PARP9 XIAP 0.958805

RIGl OASl ZBPl 0.958689

OASl IFI44 MXl 0.958663

EPSTIl 0AS3 IFITl 0.958634

IFIT5 G1P2 PARP9 0.95861

0AS2 EPSTIl MXl 0.958508

PARP9 IFITl ZBPl 0.958503

IFIT4 HERC5 CHMP5 0.958451

G1P2 CIG5 SPI lO 0.958403

IFI44L PARP9 MXl 0.958264

OASl CHMP5 SPI lO 0.95826

G1P2 PARP9 SPI lO 0.958153

OASl TYKI RIGE 0.958151

IFIT4 HERC5 RIGE 0.958132

RIGl OASl TYKI 0.958104

IFIT4 IRF7 PARP9 0.958024

IFIT4 EPSTIl PARP9 0.957986

IFIT5 SAMD9L IFITl 0.957766

RIGl IRF7 XIAP 0.957764

CIG5 SPI lO 0.957721 SAMD9L

IFI44L IFI44 0AS3 0.957601

IFIT5 G1P2 TYKI 0.9576

IFI44L HERC5 PARP9 0.957553

RIGl 0AS3 SAMD9L 0.957356

EPSTIl OASl OASL 0.957294

IFIT4 XIAP ZBPl 0.95721

IFI44L SAMD9L IFITl 0.957107

IFI44L G1P2 TYKI 0.957049

OAS2 RIGl MXl 0.957032

IFI44 TYKI IFITl 0.957022

CIG5 PARP9 XIAP 0.957014

IFIT4 IRF7 ZBPl 0.956993

IFI44L G1P2 OASl 0.956925

OASl OASL CIG5 0.956894

IFIT4 IFI44 PARP9 0.95679

EPSTIl 0AS3 HERC5 0.956754

IFIT4 G1P2 RIGE 0.956716

IFIT4 IRF7 CIG5 0.956703

IFIT4 OASl CHMP5 0.956662

IFI44L OASl HERC5 0.956626

G1P2 IRF7 CHMP5 0.956597

IFIT4 IFI44 SAMD9L 0.956274

IFIT5 IFI44L ZBPl 0.956233

IFI44L RIGl MXl 0.956172

IFIT4 CHMP5 IFITl 0.95615

IFIT5 OASl IRF7 0.956078

OASL CIG5 MXl 0.956076

OASL IFITl ZBPl 0.956072

0AS2 G1P2 CIG5 0.956019

0AS2 PARP9 CHMP5 0.956009

G1P2 PARP9 ZBPl 0.955951

0AS2 OASL TYKI 0.955901

OASl IRF7 IFI44 0.955882

IFI44 HERC5 TYKI 0.955752

0AS3 HERC5 XIAP 0.955729

RIGl PARP9 IFITl 0.955722

0AS2 CIG5 IFITl 0.955705

IFIT4 OASL XIAP 0.955698

IFIT4 CIG5 PARP9 0.955687

OASL PARP9 MXl 0.955668

PARP9 IFITl SPI lO 0.955597

IFIT4 EPSTIl RIGl 0.95557

EPSTIl OASl 0AS3 0.955534

0AS2 TYKI SPI lO 0.955523

IFIT4 G1P2 CHMP5 0.955509 OASl IFI44 IFITl 0.955489

IFIT5 IFI44L 0AS2 0.955474

RIGl IFI44 SPI lO 0.955462

IFIT5 G1P2 SAMD9L 0.955415

RIGl MXl SPI lO 0.955384

CIG5 MXl ZBPl 0.955366

IFI44L HERC5 SAMD9L 0.955348

EPSTIl SAMD9L CHMP5 0.955332

RIGl OASl XIAP 0.955331

EPSTIl IRF7 XIAP 0.95532

IFIT5 RIGl IFITl 0.955282

EPSTIl SAMD9L SPI lO 0.955279

EPSTIl G1P2 OAS3 0.955231

OAS2 CIG5 HERC5 0.955226

TYKI CHMP5 MXl 0.955217

IFI44L 0AS3 CHMP5 0.955174

SAMD9L RIGE XIAP 0.955126

OAS3 PARP9 IFITl 0.955055

RIGl PARP9 SAMD9L 0.955049

HERC5 PARP9 ZBPl 0.954901

OAS2 SAMD9L ZBPl 0.954865

EPSTIl IFITl SPI lO 0.954814

IFIT5 OASl SPI lO 0.954676

OASl PARP9 ZBPl 0.954667

SAMD9L CHMP5 SPI lO 0.954657

IFI44L G1P2 SAMD9L 0.954471

IRF7 PARP9 XIAP 0.954463

CIG5 0AS3 SAMD9L 0.95446

OASl IRF7 OAS3 0.954415

HERC5 CHMP5 MXl 0.954364

OASl IFI44 XIAP 0.954344

IRF7 IFI44 SAMD9L 0.954318

OASl OASL XIAP 0.954263

IFI44L OASL IFI44 0.954204

IFI44 SAMD9L XIAP 0.954127

0AS2 PARP9 MXl 0.9541

OASl CHMP5 MXl 0.95402

OAS2 OASL SAMD9L 0.953851 IRF7 IFI44 PARP9 0.953769

OAS2 OASl XIAP 0.953577

IFI44L G1P2 PARP9 0.953542

EPSTIl HERC5 SPI lO 0.953434

IRF7 SAMD9L RIGE 0.953308

EPSTIl PARP9 CHMP5 0.953256

OASl IRF7 CHMP5 0.953118

IFIT5 HERC5 SAMD9L 0.95311

IFIT5 G1P2 OASl 0.953008

IFI44 SAMD9L MXl 0.952969

IFIT5 OASl XIAP 0.952878

IFIT4 MXl RIGE 0.952876

IFI44L RIGl IFITl 0.952657

CIG5 HERC5 SPI lO 0.95255

IFIT4 OASL IRF7 0.952437

IFIT5 PARP9 TYKI 0.952387

OASl OASL PARP9 0.952351

IFIT5 OASL IFI44 0.952334

TYKI CHMP5 IFITl 0.952291

EPSTIl IRF7 PARP9 0.95219

IRF7 CIG5 XIAP 0.952171

IFITl RIGE XIAP 0.952097

CIG5 IFITl SPI lO 0.952015

G1P2 OASL ZBPl 0.951985

EPSTIl RIGl IRF7 0.951946

IFI44L PARP9 TYKI 0.951921

IFI44 PARP9 MXl 0.951919

OAS3 PARP9 TYKI 0.951916

CIG5 0AS3 TYKI 0.951891

G1P2 IFI44 TYKI 0.951838

OAS2 RIGl CHMP5 0.951825

EPSTIl TYKI RIGE 0.951667

RIGl PARP9 TYKI 0.951655

HERC5 PARP9 SPI lO 0.951639

IFIT4 RIGl ZBPl 0.951613

RIGl HERC5 PARP9 0.951503

G1P2 OASl IFI44 0.951439

IRF7 0AS3 MXl 0.951423

IFI44 PARP9 IFITl 0.95141

CHMP5 IFITl MXl 0.951388

EPSTIl MXl SPI lO 0.951254

OAS2 RIGl OASl 0.951245

IFI44L RIGl HERC5 0.951245

IFIT5 CIG5 IFI44 0.951244

TYKI RIGE XIAP 0.951171

EPSTIl RIGE 0.951147 SAMD9L

HERC5 TYKI CHMP5 0.951145

EPSTIl 0AS3 MXl 0.951138

HERC5 CHMP5 IFITl 0.951107

IFI44L CIG5 IFI44 0.951044

IFI44L OASL CHMP5 0.951043

G1P2 SPI lO ZBPl 0.951027

SAMD9L SPI lO ZBPl 0.95089

G1P2 CHMP5 MXl 0.950868

OAS2 OASL IFITl 0.950862

PARP9 CHMP5 ZBPl 0.950852

OAS3 HERC5 PARP9 0.95078

EPSTIl RIGl XIAP 0.950771

OASL TYKI SPI lO 0.950742

IFIT4 RIGl CIG5 0.950667

OASl IRF7 SPI lO 0.950651

OASl CHMP5 IFITl 0.950645

IFIT5 IFI44L EPSTIl 0.950585

IFIT5 OASL CHMP5 0.950564

OASl CHMP5 XIAP 0.950413

0AS3 MXl XIAP 0.950368

OASL HERC5 ZBPl 0.950235

IFI44 HERC5 PARP9 0.950187

OASl IFI44 HERC5 0.95016

RIGl OASl SAMD9L 0.950071

G1P2 HERC5 CHMP5 0.949965

RIGl 0AS3 IFITl 0.9499

IRF7 CIG5 PARP9 0.949776

IFI44L SAMD9L TYKI 0.949773

IFI44 CHMP5 RIGE 0.949687

G1P2 0AS3 XIAP 0.949642

OASl CIG5 SPI lO 0.949578

0AS2 CIG5 MXl 0.949555

IFIT5 OASl HERC5 0.949513

OASl 0AS3 PARP9 0.94951

G1P2 IRF7 OAS3 0.949402

G1P2 CHMP5 IFITl 0.949251

IFIT5 RIGl HERC5 0.948959

IFIT4 RIGl IFI44 0.948886

IFI44L OASl TYKI 0.948871

RIGl IFI44 XIAP 0.94863

IFIT5 PARP9 SAMD9L 0.948596

IFI44 SAMD9L IFITl 0.948585

IFIT4 OASL PARP9 0.948562

IFIT4 EPSTIl ZBPl 0.948539 IFIT5 RIGl G1P2 0.948086

OASl CIG5 0AS3 0.947983

G1P2 IFI44 PARP9 0.947968

IFIT5 IFI44L SPI lO 0.947938

EPSTIl CIG5 PARP9 0.947921

EPSTIl RIGl CHMP5 0.947831

IFIT5 IFI44 ZBPl 0.947787

IFI44L PARP9 SAMD9L 0.947734

G1P2 IFI44 SAMD9L 0.947721

IFI44L OASl PARP9 0.947446

IFI44 HERC5 SAMD9L 0.947347

OAS2 IFITl ZBPl 0.947303

IFIT4 EPSTIl CIG5 0.947143

RIGl G1P2 PARP9 0.947042

IFIT4 RIGl OASL 0.946997

OAS2 G1P2 ZBPl 0.946916

CIG5 0AS3 IFITl 0.946822

G1P2 RIGE XIAP 0.946802

OASl 0AS3 XIAP 0.946769

IFIT5 SAMD9L TYKI 0.946742

RIGl CIG5 XIAP 0.946738

CIG5 SAMD9L RIGE 0.946558

IRF7 IFITl RIGE 0.946462

IFI44L IFI44 ZBPl 0.946452

PARP9 MXl ZBPl 0.946362

IFIT5 0AS2 IFI44 0.946333

EPSTIl G1P2 RIGE 0.946322

HERC5 RIGE XIAP 0.946188

CIG5 MXl SPI lO 0.946153

RIGl SAMD9L RIGE 0.946083

RIGl IRF7 IFI44 0.946068

IRF7 SAMD9L CHMP5 0.946026

G1P2 TYKI CHMP5 0.945962

RIGl 0AS3 HERC5 0.945918

RIGl IRF7 CIG5 0.945803

OASL MXl ZBPl 0.945774

G1P2 OASl CHMP5 0.945734

IFIT4 0AS2 IRF7 0.945691

CIG5 0AS3 HERC5 0.945585

IFIT4 SAMD9L CHMP5 0.945499

IFIT5 CIG5 CHMP5 0.945489 EPSTIl OASl SPI lO 0.945479

IRF7 TYKI RIGE 0.945447

RIGl IFI44 MXl 0.945413

EPSTIl IFITl RIGE 0.945395

IFIT4 0AS2 PARP9 0.945338

IFI44L RIGl G1P2 0.945334

IFI44 0AS3 CHMP5 0.945317

OAS2 OASl ZBPl 0.945291

RIGl 0AS3 TYKI 0.945221

SAMD9L CHMP5 XIAP 0.945205

PARP9 SAMD9L RIGE 0.945185

OAS2 G1P2 OASL 0.944851

PARP9 CHMP5 XIAP 0.944816

IFIT4 EPSTIl OASL 0.944671

IFI44L 0AS2 IFI44 0.944632

IFIT4 PARP9 ZBPl 0.944622

EPSTIl CIG5 XIAP 0.944456

RIGl OASl OASL 0.944438

OASl HERC5 CHMP5 0.94431

IFI44 PARP9 TYKI 0.944208

PARP9 CHMP5 SPI lO 0.944124

IFITl SPI lO ZBPl 0.944046

IFI44L CIG5 CHMP5 0.943778

IFIT5 IFI44L IFIT4 0.943771

PARP9 MXl SPI lO 0.943665

RIGl CHMP5 SPI lO 0.943533

OAS2 OASL HERC5 0.9435

OASl OASL ZBPl 0.9435

IFIT4 0AS2 XIAP 0.943449

MXl RIGE XIAP 0.943426

CIG5 TYKI RIGE 0.943328

EPSTIl IRF7 CIG5 0.943287

IRF7 HERC5 RIGE 0.943132

RIGl PARP9 MXl 0.942814

OAS2 HERC5 ZBPl 0.942715

IFIT4 RIGl PARP9 0.942684

SAMD9L CHMP5 MXl 0.942597

OASL SAMD9L SPI lO 0.942585

G1P2 0AS3 PARP9 0.942554

OASl IFI44 TYKI 0.942437

OASL IFITl SPI lO 0.942318

IFI44L EPSTIl IFI44 0.942267

0AS3 SAMD9L ZBPl 0.942149

OASl PARP9 SPI lO 0.942068

OASl SPI lO XIAP 0.942012

IFI44L RIGl TYKI 0.94201 IFIT5 OASl PARP9 0.94199

G1P2 OASL SPI lO 0.941717

IFI44 SAMD9L TYKI 0.941631

IFIT4 CIG5 ZBPl 0.941466

EPSTIl HERC5 RIGE 0.941431

IFIT5 OASl TYKI 0.941419

IFIT5 EPSTIl IFI44 0.941395

IFI44L OASl SAMD9L 0.941117

OAS2 OASL MXl 0.941065

IFIT5 CHMP5 ZBPl 0.940941

OAS2 G1P2 SPI lO 0.940753

OAS3 PARP9 MXl 0.940695

OASL IFI44 CHMP5 0.940462

PJGl IFI44 IFITl 0.940444

IRF7 XIAP ZBPl 0.940387

IFIT4 0AS3 XIAP 0.940303

OASl TYKI CHMP5 0.940259

HERC5 SPI lO ZBPl 0.940142

G1P2 CIG5 0AS3 0.939919

OASl IFI44 PARP9 0.939836

IFIT4 PARP9 CHMP5 0.9396

RIGl IFI44 HERC5 0.939599

IFIT4 IRF7 0AS3 0.939488

G1P2 IRF7 RIGE 0.939474

IFIT5 IFI44L XIAP 0.939166

EPSTIl OASl RIGE 0.938921

RIGl PARP9 XIAP 0.938797

EPSTIl IRF7 ZBPl 0.938775

IFIT5 0AS2 CHMP5 0.938637

IFIT4 OASL CIG5 0.938552

EPSTIl MXl RIGE 0.938432

IFIT5 IFI44L IRF7 0.938421

OASL PARP9 XIAP 0.938359

IFIT5 IFI44L MXl 0.93825

CIG5 IFITl RIGE 0.938229

EPSTIl RIGl PARP9 0.938162

IFIT5 RIGl TYKI 0.938067

IFI44 PARP9 SAMD9L 0.937964

IRF7 PARP9 CHMP5 0.937956

SAMD9L CHMP5 IFITl 0.937945

IFI44L IFI44 SPI lO 0.937911

0AS3 TYKI ZBPl 0.937748

IFIT4 0AS3 PARP9 0.937712

CIG5 0AS3 MXl 0.937685

IFI44L CHMP5 ZBPl 0.937606

RIGl OASl PARP9 0.937438 OAS2 SAMD9L SPI lO 0.937426

IRF7 MXl RIGE 0.937279

OAS2 OASl OASL 0.937248

RIGl IFITl RIGE 0.93718

OAS2 MXl ZBPl 0.937132

G1P2 SAMD9L CHMP5 0.936982

EPSTIl XIAP ZBPl 0.936697

RIGl G1P2 IFI44 0.936637

OASl CIG5 RIGE 0.936614

OASL IRF7 XIAP 0.936603

PARP9 IFITl RIGE 0.936593

HERC5 SAMD9L CHMP5 0.93654

IFIT4 SPI lO XIAP 0.936501

IFIT4 0AS2 EPSTIl 0.936231

RIGl CIG5 PARP9 0.936225

IFIT4 EPSTIl OAS3 0.936192

IFIT5 IFI44 SPI lO 0.936081

PARP9 CHMP5 IFITl 0.935858

SAMD9L TYKI CHMP5 0.935842

OAS2 IFITl SPI lO 0.935741

OASl IRF7 RIGE 0.935686

OASL 0AS3 SAMD9L 0.935639

CIG5 HERC5 RIGE 0.935444

OASl RIGE XIAP 0.935361

G1P2 CIG5 RIGE 0.935304

IFIT5 IFI44L IFITl 0.935275

PARP9 CHMP5 MXl 0.935232

RIGl 0AS3 MXl 0.935175

IFI44L 0AS2 CHMP5 0.934781

RIGl OASl OAS3 0.934681

OASL HERC5 SPI lO 0.934566

PARP9 TYKI CHMP5 0.934504

0AS3 IFITl ZBPl 0.934375

SAMD9L RIGE ZBPl 0.934283

HERC5 PARP9 CHMP5 0.93411

IFIT5 IFIT4 IFI44 0.934012

EPSTIl OASL PARP9 0.933922

0AS3 TYKI SPI lO 0.933864

CIG5 IFI44 CHMP5 0.933838

MXl SPI lO ZBPl 0.933692

RIGl CHMP5 XIAP 0.933629

OASl IFI44 SAMD9L 0.933607

IFI44L IFIT4 IFI44 0.933553

PARP9 TYKI RIGE 0.933515 IFIT4 IRF7 SPI lO 0.933498

OAS2 EPSTIl PARP9 0.933446

OASl SPI lO ZBPl 0.933405

OAS2 PARP9 XIAP 0.933338

IFIT5 EPSTIl CHMP5 0.933165

EPSTIl OASL XIAP 0.933115

IFIT4 OASL ZBPl 0.933099

EPSTIl PARP9 ZBPl 0.932945

IFI44L EPSTIl CHMP5 0.932873

OASL 0AS3 IFITl 0.932774

PARP9 XIAP ZBPl 0.932749

EPSTIl RIGl CIG5 0.93261

IFIT5 OASl SAMD9L 0.932602

OASL MXl SPI lO 0.932194

IFIT4 0AS2 RIGl 0.932084

RIGl TYKI RIGE 0.932067

RIGl IRF7 ZBPl 0.931911

EPSTIl OASL IRF7 0.931811

RIGl G1P2 OAS3 0.931711

0AS2 IRF7 PARP9 0.931653

IFI44L RIGl OASl 0.931497

G1P2 PARP9 CHMP5 0.931468

IFIT5 RIGl PARP9 0.931134

IFIT5 IFI44L HERC5 0.931073

RIGl IRF7 CHMP5 0.930931

IFIT5 IFI44 XIAP 0.930929

0AS3 SAMD9L SPI lO 0.930851

OASL 0AS3 TYKI 0.930816

IFIT5 IFI44 MXl 0.930811

IRF7 CIG5 ZBPl 0.930782

RIGl IFI44 TYKI 0.930705

IFI44L IFI44 XIAP 0.930504

OASL IRF7 PARP9 0.930323

CIG5 XIAP ZBPl 0.930024

IFIT5 IFI44L G1P2 0.929939

OASl 0AS3 ZBPl 0.92992

IFIT4 RIGl CHMP5 0.929849

0AS2 HERC5 SPI lO 0.929752

CIG5 MXl RIGE 0.929631

RIGl HERC5 RIGE 0.929627

HERC5 PARP9 RIGE 0.929502

IFI44L RIGl SAMD9L 0.929277

0AS3 HERC5 ZBPl 0.929262

IFIT4 PARP9 SPI lO 0.929202

IFI44L IFI44 MXl 0.929036

OASl PARP9 CHMP5 0.928969 IFI44L IRF7 IFI44 0.928905

TYKI RIGE ZBPl 0.928873

IFIT5 IRF7 IFI44 0.928864

IFIT4 0AS2 CIG5 0.928862

G1P2 PARP9 RIGE 0.928789

IFI44L RIGl PARP9 0.928757

IFI44 CHMP5 ZBPl 0.928586

OAS2 0AS3 TYKI 0.928574

OASL CIG5 PARP9 0.928457

IFI44L CHMP5 SPI lO 0.928425

IFIT5 CHMP5 SPI lO 0.92804

OAS2 0AS3 SAMD9L 0.928004

RIGl OASl SPI lO 0.927916

IRF7 PARP9 ZBPl 0.927757

RIGl CHMP5 MXl 0.927685

OASL CIG5 XIAP 0.927452

IFIT5 IFI44 IFITl 0.927301

RIGl G1P2 RIGE 0.927147

OASl PARP9 RIGE 0.926871

CIG5 PARP9 ZBPl 0.926818

0AS2 EPSTIl IRF7 0.926537

0AS3 IFITl SPI lO 0.926516

0AS2 IRF7 XIAP 0.926247

0AS2 MXl SPI lO 0.926135

IFI44L IFI44 IFITl 0.926123

OASl SAMD9L CHMP5 0.925906

0AS2 CIG5 PARP9 0.925828

EPSTIl 0AS3 PARP9 0.925671

G1P2 0AS3 ZBPl 0.925573

IFITl RIGE ZBPl 0.925539

IFIT4 RIGE XIAP 0.925317

0AS2 IFI44 CHMP5 0.925256

RIGl XIAP ZBPl 0.925255

OASL IRF7 CIG5 0.925231

OASL 0AS3 HERC5 0.92508

IFIT5 IFI44L TYKI 0.924932

EPSTIl RIGl ZBPl 0.924695

IFIT5 RIGl SAMD9L 0.924337

0AS2 0AS3 IFITl 0.924255

IFI44L IFI44 HERC5 0.924174

RIGl IRF7 PARP9 0.923945

EPSTIl CIG5 ZBPl 0.923914

0AS2 OASl SPI lO 0.923858

IFIT5 IFI44 HERC5 0.923703

IFIT5 G1P2 IFI44 0.923603

RIGl MXl RIGE 0.923568 IFIT4 CIG5 0AS3 0.92356

IFIT5 IFIT4 CHMP5 0.923303

EPSTIl IFI44 CHMP5 0.923176

IFIT4 RIGl 0AS3 0.923081

RIGl OASL XIAP 0.922837

RIGl CHMP5 IFITl 0.922695

PARP9 MXl RIGE 0.922687

OAS2 SAMD9L RIGE 0.922634

IFIT5 IFI44L PARP9 0.92262

IFIT4 EPSTIl SPI lO 0.922466

IFI44L G1P2 IFI44 0.922343

OAS3 PARP9 XIAP 0.921953

OAS2 EPSTIl XIAP 0.921908

OAS2 TYKI RIGE 0.921747

IFIT4 0AS2 ZBPl 0.921651

RIGl HERC5 CHMP5 0.92161

IFI44L IFIT4 CHMP5 0.921594

EPSTIl IRF7 0AS3 0.921499

RIGl OASL IRF7 0.921365

G1P2 RIGE ZBPl 0.921333

PARP9 SAMD9L CHMP5 0.92129

IFIT5 CHMP5 XIAP 0.921284

OAS3 MXl ZBPl 0.921266

RIGl TYKI CHMP5 0.92113

IFIT4 0AS2 OASL 0.921102

RIGl OASl IFI44 0.921011

OASL SAMD9L RIGE 0.92072

OAS3 HERC5 SPI lO 0.920417

EPSTIl 0AS3 XIAP 0.920342

IFIT5 CHMP5 MXl 0.920248

OASL 0AS3 MXl 0.920206

G1P2 0AS3 SPI lO 0.920122

G1P2 OASL 0AS3 0.920062

IFIT4 CIG5 SPI lO 0.919544

IFI44L CHMP5 XIAP 0.919301

EPSTIl OASL CIG5 0.91928

OASl OASL SPI lO 0.919179

IFIT5 IRF7 CHMP5 0.919067

0AS2 OASl OAS3 0.918994

IFI44L IFI44 TYKI 0.918961

OASl OASL OAS3 0.918852

HERC5 RIGE ZBPl 0.918551

OASL IFITl RIGE 0.91841

IFIT5 RIGl OASl 0.91814

0AS2 IRF7 CIG5 0.918041

IRF7 0AS3 XIAP 0.918037 IFIT5 IFI44 TYKI 0.917786

OASl RIGE ZBPl 0.917732

RIGl G1P2 CHMP5 0.917667

IFI44L IRF7 CHMP5 0.917628

OAS2 IFITl RIGE 0.917465

OAS2 0AS3 HERC5 0.91737

IRF7 0AS3 PARP9 0.917026

IFI44L CHMP5 MXl 0.916997

IFIT4 IRF7 RIGE 0.916887

IFIT4 RIGl SPI lO 0.916864

IFIT5 CHMP5 IFITl 0.916571

OASL TYKI RIGE 0.916429

IFIT4 EPSTIl RIGE 0.916258

EPSTIl RIGl OASL 0.916184

RIGl IFI44 PARP9 0.916107

IFIT5 IFI44L OASl 0.915943

RIGl IFI44 SAMD9L 0.915918

IFI44 CHMP5 SPI lO 0.915791

PARP9 SPI lO XIAP 0.915523

RIGl OASl RIGE 0.915317

OAS2 CIG5 XIAP 0.915027

IFIT5 IFI44L SAMD9L 0.914239

IFI44L CHMP5 IFITl 0.914106

IFIT5 IFI44 PARP9 0.913922

OASl OAS3 SPI lO 0.913805

IFI44L OASl IFI44 0.913685

0AS2 G1P2 OAS3 0.913341

0AS3 MXl SPI lO 0.913024

MXl RIGE ZBPl 0.91295

IFI44L IFI44 PARP9 0.912714

RIGl CIG5 ZBPl 0.912402

IFIT5 HERC5 CHMP5 0.912293

IFIT4 SPI lO ZBPl 0.912203

CIG5 OAS3 PARP9 0.912168

IFIT5 G1P2 CHMP5 0.912138

IFIT4 OAS3 ZBPl 0.912117

IFIT4 IFI44 CHMP5 0.912012

0AS2 RIGl IRF7 0.911984

IRF7 SPI lO XIAP 0.911965

TYKI SPI lO RIGE 0.9118

IFI44L HERC5 CHMP5 0.911777

0AS2 OAS3 MXl 0.91137

0AS2 G1P2 RIGE 0.911317

IFIT4 PARP9 RIGE 0.911158

IFI44 CHMP5 XIAP 0.910766

0AS2 EPSTIl CIG5 0.910517

OASL IRF7 ZBPl 0.910488 OASL XIAP ZBPl 0.909994

IFI44L TYKI CHMP5 0.909904

EPSTIl PARP9 SPI lO 0.909711

IFI44 CHMP5 MXl 0.909689

IFIT5 TYKI CHMP5 0.90968

G1P2 OASL RIGE 0.90961

IFI44L G1P2 CHMP5 0.909576

IFIT5 OASl IFI44 0.909388

IFIT4 CIG5 RIGE 0.908925

OAS2 OASl RIGE 0.908806

OAS2 HERC5 RIGE 0.908751

OASL HERC5 RIGE 0.908541

CIG5 PARP9 SPI lO 0.908525

EPSTIl OASL ZBPl 0.908429

RIGl OASl CHMP5 0.90836

IFI44L IFI44 SAMD9L 0.907964

IRF7 IFI44 CHMP5 0.907863

CIG5 0AS3 XIAP 0.907513

IRF7 CIG5 OAS3 0.907333

IFIT4 OASL OAS3 0.906832

RIGl OASL CIG5 0.90659

SAMD9L SPI lO RIGE 0.906569

EPSTIl SPI lO XIAP 0.906534

IFIT5 IFI44 SAMD9L 0.90643

EPSTIl CIG5 OAS3 0.906354

IFI44 CHMP5 IFITl 0.906304

OASL MXl RIGE 0.906245

IRF7 PARP9 SPI lO 0.906101

EPSTIl IRF7 SPI lO 0.906008

IFIT4 OASL SPI lO 0.905978

0AS2 MXl RIGE 0.90518

CIG5 SPI lO XIAP 0.90499

IFITl SPI lO RIGE 0.904324

IFI44 HERC5 CHMP5 0.904282

RIGl OASL PARP9 0.904259

0AS3 SAMD9L RIGE 0.904065

IFI44L OASl CHMP5 0.903581

IRF7 CIG5 SPI lO 0.903302

G1P2 IFI44 CHMP5 0.903298

G1P2 SPI lO RIGE 0.903287

0AS2 EPSTIl RIGl 0.903249

OASL PARP9 ZBPl 0.902995

0AS2 OASL PARP9 0.902848

IFI44 TYKI CHMP5 0.902228

OASl OASL RIGE 0.901099

0AS2 IRF7 ZBPl 0.900596 OAS2 RIGl PARP9 0.900166

OAS3 IFITl RIGE 0.900065

OASL CIG5 ZBPl 0.899594

EPSTIl RIGE XIAP 0.899556

IFIT5 OASl CHMP5 0.89953

OAS2 RIGl XIAP 0.899013

IFIT5 PARP9 CHMP5 0.898064

OAS2 OASL IRF7 0.898064

OAS3 TYKI RIGE 0.897749

OAS2 EPSTIl ZBPl 0.897534

IFIT4 RIGl RIGE 0.897168

EPSTIl RIGl OAS3 0.896978

OAS2 PARP9 ZBPl 0.896335

IFIT4 RIGE ZBPl 0.896273

OASl IFI44 CHMP5 0.896108

IFIT5 IFI44L RIGl 0.895894

IFI44L PARP9 CHMP5 0.895497

IFIT4 0AS2 OAS3 0.895401

OAS2 EPSTIl OASL 0.895303

OAS2 OASL XIAP 0.895129

HERC5 SPI lO RIGE 0.894807

EPSTIl CIG5 SPI lO 0.894768

IFIT4 0AS2 SPI lO 0.894337

IRF7 RIGE XIAP 0.8943

RIGl SAMD9L CHMP5 0.89381

IFI44L SAMD9L CHMP5 0.893745

PARP9 RIGE XIAP 0.89358

OAS2 XIAP ZBPl 0.893376

EPSTIl IRF7 RIGE 0.893012

EPSTIl PARP9 RIGE 0.892978

IFIT5 SAMD9L CHMP5 0.892943

RIGl PARP9 ZBPl 0.892935

CIG5 RIGE XIAP 0.892719

IFIT4 0AS3 SPI lO 0.891861

MXl SPI lO RIGE 0.891301

OAS3 HERC5 RIGE 0.891101

RIGl IRF7 OAS3 0.890525

OAS2 RIGl CIG5 0.890495

EPSTIl OAS3 ZBPl 0.890069

OASl OAS3 RIGE 0.89006

IFI44L RIGl IFI44 0.88778

IFIT5 IFI44L IFI44 0.88776

RIGl OAS3 XIAP 0.887549

IFI44 PARP9 CHMP5 0.887524

G1P2 OAS3 RIGE 0.887416

EPSTIl CIG5 RIGE 0.887118 OAS2 CIG5 ZBPl 0.886902

OASl SPI lO RIGE 0.88684

CIG5 PARP9 RIGE 0.886773

OAS2 OASL CIG5 0.886112

IFI44 SAMD9L CHMP5 0.885956

IFIT4 OASL RIGE 0.885918

IFIT5 RIGl IFI44 0.885817

IRF7 CIG5 RIGE 0.885643

IRF7 0AS3 ZBPl 0.885583

OAS3 MXl RIGE 0.885561

EPSTIl OASL OAS3 0.883489

IRF7 SPI lO ZBPl 0.883248

OAS3 XIAP ZBPl 0.883087

RIGl PARP9 CHMP5 0.882158

IFIT4 0AS2 RIGE 0.881223

SPI lO XIAP ZBPl 0.881076

OASL 0AS3 PARP9 0.880696

OAS3 PARP9 ZBPl 0.880421

RIGl IRF7 SPI lO 0.880086

EPSTIl SPI lO ZBPl 0.879636

RIGl OASL ZBPl 0.879626

IRF7 PARP9 RIGE 0.87949

OASL OAS3 XIAP 0.879447

RIGl SPI lO XIAP 0.879006

OASL IRF7 OAS3 0.878692

RIGl OAS3 PARP9 0.878538

OASL SPI lO XIAP 0.876723

OASL PARP9 SPI lO 0.875724

RIGl CIG5 OAS3 0.875511

CIG5 OAS3 ZBPl 0.875241

OASL IRF7 SPI lO 0.874351

PARP9 SPI lO ZBPl 0.873999

0AS2 OAS3 PARP9 0.873713

CIG5 SPI lO ZBPl 0.873581

IFIT5 IFI44L CHMP5 0.873435

EPSTIl OASL SPI lO 0.872477

0AS2 EPSTIl OAS3 0.872405

0AS2 PARP9 SPI lO 0.87155

EPSTIl RIGl SPI lO 0.871342

OASL CIG5 OAS3 0.870785

RIGl CIG5 SPI lO 0.869263

EPSTIl RIGE ZBPl 0.868804

IFIT4 OAS3 RIGE 0.868713

OASL CIG5 SPI lO 0.867945

IFI44L IFI44 CHMP5 0.867675

0AS2 IRF7 OAS3 0.867456

IFIT5 IFI44 CHMP5 0.867157

RIGE XIAP ZBPl 0.866861 IFI44L RIGl CHMP5 0.864815

OAS2 IRF7 SPI lO 0.863904

IFIT5 RIGl CHMP5 0.863765

OAS2 0AS3 XIAP 0.862892

OAS2 OASL ZBPl 0.862277

EPSTIl 0AS3 SPI lO 0.861466

IRF7 RIGE ZBPl 0.861372

OAS3 PARP9 SPI lO 0.861136

EPSTIl RIGl RIGE 0.860936

IFIT4 SPI lO RIGE 0.860801

RIGl RIGE XIAP 0.860302

OAS2 EPSTIl SPI lO 0.860174

CIG5 RIGE ZBPl 0.859596

OAS2 SPI lO XIAP 0.858564

EPSTIl OASL RIGE 0.857914

OAS2 RIGl OASL 0.857565

OASL RIGE XIAP 0.857553

OAS2 CIG5 OAS3 0.857493

IRF7 OAS3 SPI lO 0.857288

OAS3 SPI lO XIAP 0.856743

RIGl IFI44 CHMP5 0.855689

OAS2 RIGl ZBPl 0.85545

RIGl PARP9 SPI lO 0.855367

OAS2 CIG5 SPI lO 0.854157

OAS2 EPSTIl RIGE 0.852592

PARP9 RIGE ZBPl 0.852095

OASL CIG5 RIGE 0.850683

RIGl CIG5 RIGE 0.850622

OASL IRF7 RIGE 0.849649

CIG5 OAS3 SPI lO 0.849016

0AS2 RIGE XIAP 0.848472

OASL PARP9 RIGE 0.847797

RIGl IRF7 RIGE 0.847049

0AS2 PARP9 RIGE 0.84672

0AS2 IRF7 RIGE 0.844908

OASL OAS3 ZBPl 0.843861

0AS2 CIG5 RIGE 0.84326

EPSTIl OAS3 RIGE 0.843087

OASL SPI lO ZBPl 0.840384

0AS3 RIGE XIAP 0.835809

RIGl OAS3 ZBPl 0.835232

CIG5 OAS3 RIGE 0.830689

IRF7 OAS3 RIGE 0.830055

RIGl OASL OAS3 0.829875

0AS3 PARP9 RIGE 0.829849

RIGl PARP9 RIGE 0.827293

RIGl SPI lO ZBPl 0.827103

0AS2 OAS3 ZBPl 0.825923

0AS2 OASL OAS3 0.825647 EPSTIl SPIlO RIGE 0.824627

SPIlO RIGE XIAP 0.823548

OASL RIGE ZBPl 0.821675

OAS2 SPIlO ZBPl 0.821066

OAS2 OASL SPIlO 0.820454

CIG5 SPIlO RIGE 0.819918

PJGl OASL SPIlO 0.818533

OAS3 SPIlO ZBPl 0.814438

IRF7 SPIlO RIGE 0.814248

PARP9 SPIlO RIGE 0.812561

OAS2 RIGE ZBPl 0.810229

OASL OAS3 SPIlO 0.809037

RIGl RIGE ZBPl 0.806619

OAS2 OASL RIGE 0.804693

OAS2 RIGl OAS3 0.803515

OAS3 RIGE ZBPl 0.79653

RIGl OASL RIGE 0.79316

OASL OAS3 RIGE 0.789533

OAS2 OAS3 SPIlO 0.789077

OAS2 RIGl SPIlO 0.78802

RIGl OAS3 SPIlO 0.785883

SPIlO RIGE ZBPl 0.781728

OAS2 RIGl RIGE 0.777652

OAS2 OAS3 RIGE 0.7757

OASL SPIlO RIGE 0.772656

RIGl OAS3 RIGE 0.761256

OAS2 SPIlO RIGE 0.75784

OAS3 SPIlO RIGE 0.7529

RIGl SPIlO RIGE 0.725531

Table 4B. All possible 3-gene combinations of a selected group of 24 genes, indicated with their respective Pearson correlation values.

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. 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 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.

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 any of the preceding claims, wherein said at least 2 genes comprise (i) OAS3 and HERC5; or (ii) ESPTIl and HERC5; or (iii) ESPTIl and TYKI; or HERC5 and TYKI.

8. The method of any of the preceding claims, 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, OASl, and MXl; or (2) OASL, CHMP5, and ZBPl; or (3) IFI44L, OASL, and CIG5; or (4) IFI44L, CIG5, and ZBPl; or (5) EPSTIl, TYKI, and MXl; or (6) IFIT4,

HERC5, and TYKI; or (7) IFIT4, TYKI, and XIAP; or (8) IFI44L, OASL, and ZBPl; or (9) IFI44L, IFIT4, and OASL; or (10) IFI4, OASl, and IFITl; or (11) EPSTIl, HERC5, and TYKI; or (12) IFI44L, EPSTIl, and OASL; or (13) IFI44L, EPSTIl, and OAS3; or (14) EPSTIl, TYKI, and IFITl; or (15) G1P2, SAMD9L, and SPI lO.

10. The method of any of the preceding claims, further comprising the use of a housekeeping gene.

11. The method of any of the preceding claims, 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 or 13 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, OASl, and MXl; or (2) OASL, CHMP5, and ZBPl; or (3) IFI44L, OASL, and

CIG5; or (4) IFI44L, CIG5, and ZBPl; or (5) EPSTIl, TYKI, and MXl; or (6) IFIT4, HERC5, and TYKI; or (7) IFIT4, TYKI, and XIAP; or (8) IFI44L, OASL, and ZBPl; or (9) IFI44L, IFIT4, and OASL; or (10) IFI4, OASl, and IFITl; or (11) EPSTIl, HERC5, and TYKI; or (12) IFI44L, EPSTIl, and OASL; or (13) IFI44L, EPSTIl, and OAS3; or (14) EPSTIl, TYKI, and IFITl; or (15) G1P2, SAMD9L, and SPI lO.

17. The composition of any of claims 12-16, further comprising a housekeeping gene.

18. A kit comprising the composition of any of claims 12-17, 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. 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 invidual 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 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.

21. The method of claim 20, wherein 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.

22. The method of the claim 20 or 21, wherein 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.

23. The method of claim 20, 21 or 22, wherein 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.

24. The method of any of claims 20-23, wherein the group of probesets comprises at least 2 of those listed in Table 1, 2, and/or 3.

25. The method of any of claims 20-24, wherein the group of probesets comprises those listed in Table 1, 2, and/or 3.