Methods and Compositions For Detecting Autoimmune Disorders

Abstract

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

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  claim 2 , wherein said at least 2 genes comprise genes selected from the group consisting of: (i) OAS3 and HERC5; (ii) ESPTI1 and HERC5; (iii) ESPTI1 and TYKI; and (iv) HERC5 and TYKI. 
     
     
         8 . The method of  claim 2 , 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 genes selected from the group consisting of: (1) IFIT4, OAS1, and MX1; (2) OASL, CHMP5, and ZBP1; (3) IFI44L, OASL, and CIG5; (4) IF144L, CIG5, and ZBP1; (5) EPSTI1, TYKI, and MX1; (6) IFIT4, HERC5, and TYKI; (7) IFIT4, TYKI, and XIAP; (8) IFI44L, OASL, and ZBP1; IFI44L, IFIT4, and OASL; (10) IFI4, OAS1, and IFIT1; (11) EPSTI1, HERC5, and TYKI, (12) IFI44L, EPSTI1, and OASL; (13) IFI44L, EPSTI1, and OAS3; (14) EPSTI1, TYKI, and IFIT1; and (15) G1P2, SAMD9L, and SP110. 
     
     
         10 . The methos of  claim 2 , further comprising the use of a housekeeping gene. 
     
     
         11 . The method of  claim 2 , wherein the normal reference sample comprises a healthy cell or tissue. 
     
     
         12 . A composition comprising polynucleotides capable of specifically hybridizing to at least 2 of the genes listed in Table 1, 2, 3 and/or 4A or complements of said genes. 
     
     
         13 . The composition of  claim 12 , wherein the polynucleotides are provided as an array, a gene chip, or gene set. 
     
     
         14 . The composition of  claim 12  comprising polynucleotides capable of specifically hybridizing to at least 3 genes listed in Table 1, 2, 3 and/or 4A or complements of said genes. 
     
     
         15 . The composition of  claim 14 , wherein said at least 3 genes comprises a 3-gene combination listed in Table 4B. 
     
     
         16 . The composition of  claim 15 , wherein the 3-gene combination comprises genes selected from the group consisting of: (1) IFIT4, OAS1, and MX1; (2) OASL, CHMP5, and ZBP1; (3) IFI44L, OASL, and CIG5; (4) IFI44L, CIG5, and ZBP1; (5) EPSTI1, TYKI, and MX1; (6) IFIT4, HERC5, and TYKI; (7) IFIT4, TYKI, and XIAP; (8) IFI44L, OASL, and ZBP1; (9) IFI44L, IFIT4, and OASL; (10) IFI4, OAS1, and IFIT1; (11) EPSTI1, HERC5, and TYKI; (12) IFI44L, EPSTI1, and OASL; (13) IFI44L, EPSTI1, and OAS3; (14) EPSTI1, TYKI, and IFIT1; or and (15) G1P2, SAMD9L, and SP110. 
     
     
         17 . The composition of  claim 12 , further comprising a housekeeping gene. 
     
     
         18 . A kit comprising the composition of  claim 12 , and instructions for using the composition to detect an autoimmune disorder by determining whether expression of the genes provided is at a level greater than the expression level of the respective genes in a normal reference sample. 
     
     
         19 . The kit of  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 individual probeset to trend of the group of probesets, and calculating the correlation coefficient of each probeset's profile to the mean profile calculated;   (c) determining a scaling factor, wherein the scaling factor is the value required to scale individual probesets to 1;   (d) multiplying the scaling factor by the weighting factor to generate a composite factor   (e) multiplying a normal blood sample's signatures with the composite factor, and 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  claim 20 , 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 , 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  claim 20  wherein the group of probesets comprises at least 2 of those listed in Table 1, 2, and/or 3. 
     
     
         25 . The method of  claim 20 , wherein the group of probesets comprises those listed in Table 1, 2, and/or 3.