Methods for treating, diagnosing, and monitoring lupus

Abstract

Methods of identifying, diagnosing, and prognosing lupus, including certain subphenotypes of lupus, are provided, as well as methods of treating lupus, including certain subpopulations of patients. The methods provided are based on a set of alleles associated with systemic lupus erythematosus (SLE) risk loci including BLK, TNIP1, PRDM1, JAZF1, UHRF1BP1, IL1 O, IFIH1, CFB, CEC16A, IL12B and SH2B3 that contribute to SLE risk. Also provided are methods for identifying effective lupus therapeutic agents and predicting responsiveness to lupus therapeutic agents.

1 - 14 . (canceled) 
     
     
         15 . A method for predicting responsiveness of a subject with lupus to a lupus therapeutic agent, the method comprising determining whether the subject comprises a variation in a SLE risk locus, wherein the SLE risk locus is BLK, wherein the variation in the BLK locus occurs at a nucleotide position corresponding to the position of a single nucleotide polymorphism (SNP), wherein the SNP is rs922483 (SEQ ID NO: 13), wherein the variation is thymine at chromosomal location 11389322 on human chromosome 8, wherein the presence of the variation in the BLK locus indicates the responsiveness of the subject to the therapeutic agent. 
     
     
         16 . A method for predicting responsiveness of a subject with lupus to a lupus therapeutic agent, the method comprising determining whether the subject comprises a variation in at least one SLE risk locus as set forth in Table 4, wherein the variation in the at least one locus occurs at a nucleotide position corresponding to the position of a single nucleotide polymorphism (SNP) for the at least one locus as set forth in Table 4, wherein the presence of the variation in the at least one locus indicates the responsiveness of the subject to the therapeutic agent. 
     
     
         17 . The method of  claim 16 , wherein a variation is detected in at least two loci, or at least three loci, or at least four, or at least five loci, or at least ten loci, or at least 13 loci, or at 26 loci. 
     
     
         18 . The method of  claim 16 , wherein the at least one locus is selected from TNIP1, PRDM1, JAZF1, UHRF1BP1, and IL10. 
     
     
         19 . The method of  claim 16 , wherein the variation in the at least one locus comprises a SNP as set forth in Table 4. 
     
     
         20 . A method for predicting responsiveness of a subject with lupus to a lupus therapeutic agent, the method comprising determining whether the subject comprises a variation in at least one SLE risk locus as set forth in Table 6, wherein the variation in the at least one locus occurs at a nucleotide position corresponding to the position of a single nucleotide polymorphism (SNP) for the at least one locus as set forth in Table 6, wherein the presence of the variation in the at least one locus indicates the responsiveness of the subject to the therapeutic agent. 
     
     
         21 . The method of  claim 20 , wherein a variation is detected in at least two loci, or at least three loci, or at least four, or at five loci. 
     
     
         22 . The method of  claim 20 , wherein the at least one locus is selected from IFIH1, CFB, CLEC16A, IL12B, and SH2B3. 
     
     
         23 . The method of  claim 20 , wherein the variation in the at least one locus comprises a SNP as set forth in Table 6. 
     
     
         24 . The method of  claim 15 , comprising determining whether the subject comprises a further variation in at least one SLE risk locus as set forth in Table 4, wherein the further variation in the at least one locus occurs at a nucleotide position corresponding to the position of a SNP for the at least one locus as set forth in Table 4. 
     
     
         25 . The method of  claim 15 , comprising determining whether the subject comprises a further variation in at least one SLE risk locus as set forth in Table 6, wherein the further variation in the at least one locus occurs at a nucleotide position corresponding to the position of a SNP for the at least one locus as set forth in Table 6. 
     
     
         26 . The method of  claim 24 , comprising determining whether the subject comprises a further variation in at least one SLE risk locus as set forth in Table 6, wherein the further variation in the at least one locus occurs at a nucleotide position corresponding to the position of a SNP for the at least one locus as set forth in Table 6. 
     
     
         27 . The method of  claim 16 , comprising determining whether the subject comprises a further variation in at least one SLE risk locus as set forth in Table 6, wherein the further variation in the at least one locus occurs at a nucleotide position corresponding to the position of a SNP for the at least one locus as set forth in Table 6. 
     
     
         28 . A method of diagnosing or prognosing lupus in a subject, the method comprising detecting in a biological sample derived from the subject the presence of a variation in a SLE risk locus, wherein the SLE risk locus is BLK, wherein:
 (a) the biological sample is known to comprise, or is suspected of comprising, nucleic acid comprising a variation in the BLK locus;   (b) the variation occurs at a nucleotide position corresponding to the position of a single nucleotide polymorphism (SNP), wherein the SNP is rs922483 (SEQ ID NO: 13), wherein the variation is thymine at chromosomal location 11389322 on human chromosome 8; and   (c) the presence of the variation in the BLK locus is a diagnosis or prognosis of lupus in the subject.   
     
     
         29 . A method of diagnosing or prognosing lupus in a subject, the method comprising detecting in a biological sample derived from the subject the presence of a variation in at least one SLE risk locus as set forth in Table 4, wherein:
 (a) the biological sample is known to comprise, or is suspected of comprising, nucleic acid comprising a variation in at least one SLE risk locus as set forth in Table 4;   (b) the variation in the at least one locus comprises, or is located at a nucleotide position corresponding to, a SNP as set forth in Table 4; and   (c) the presence of the variation in the at least one locus is a diagnosis or prognosis of lupus in the subject.   
     
     
         30 . The method of  claim 29 , wherein a variation is detected in at least two loci, or at least three loci, or at least four, or at least five loci, or at least ten loci, or at least 13 loci, or at 26 loci. 
     
     
         31 . The method of  claim 29 , wherein the at least one locus is selected from TNIP1, PRDM1, JAZF1, UHRF1BP1, and IL10. 
     
     
         32 . The method of  claim 29 , wherein the variation in the at least one locus comprises a SNP as set forth in Table 4. 
     
     
         33 . A method of diagnosing or prognosing lupus in a subject, the method comprising detecting in a biological sample derived from the subject the presence of a variation in at least one SLE risk locus as set forth in Table 6, wherein:
 (a) the biological sample is known to comprise, or is suspected of comprising, nucleic acid comprising a variation in at least one SLE risk locus as set forth in Table 6;   (b) the variation in the at least one locus comprises, or is located at a nucleotide position corresponding to, a SNP as set forth in Table 6; and   (c) the presence of the variation in the at least one locus is a diagnosis or prognosis of lupus in the subject.   
     
     
         34 . The method of  claim 33 , wherein a variation is detected in at least two loci, or at least three loci, or at least four, or at five loci. 
     
     
         35 . The method of  claim 33 , wherein the at least one locus is selected from IFIH1, CFB, CLEC16A, IL12B, and SH2B3. 
     
     
         36 . The method of  claim 33 , wherein the variation in the at least one locus comprises a SNP as set forth in Table 6. 
     
     
         37 . The method of  claim 28 , wherein:
 (a) the biological sample is known to comprise, or is suspected of comprising, nucleic acid comprising a further variation in at least one SLE risk locus as set forth in Table 4;   (b) the further variation in the at least one locus comprises, or is located at a nucleotide position corresponding to, a SNP as set forth in Table 4; and   (c) the presence of the further variation in the at least one locus is a diagnosis or prognosis of lupus in the subject.   
     
     
         38 . The method of  claim 28 , wherein:
 (a) the biological sample is known to comprise, or is suspected of comprising, nucleic acid comprising a further variation in at least one SLE risk locus as set forth in Table 6;   (b) the further variation in the at least one locus comprises, or is located at a nucleotide position corresponding to, a SNP as set forth in Table 6; and   (c) the presence of the further variation in the at least one locus is a diagnosis or prognosis of lupus in the subject.   
     
     
         39 . The method of  claim 37 , wherein:
 (a) the biological sample is known to comprise, or is suspected of comprising, nucleic acid comprising a further variation in at least one SLE risk locus as set forth in Table 6;   (b) the further variation in the at least one locus comprises, or is located at a nucleotide position corresponding to, a SNP as set forth in Table 6; and   (c) the presence of the further variation in the at least one locus is a diagnosis or prognosis of lupus in the subject.   
     
     
         40 . The method of  claim 29 , wherein:
 (a) the biological sample is known to comprise, or is suspected of comprising, nucleic acid comprising a further variation in at least one SLE risk locus as set forth in Table 6;   (b) the further variation in the at least one locus comprises, or is located at a nucleotide position corresponding to, a SNP as set forth in Table 6; and   (c) the presence of the further variation in the at least one locus is a diagnosis or prognosis of lupus in the subject.   
     
     
         41 . The method of any one of  claims 28 ,  29 , or  33 , wherein the detecting comprises carrying out a process selected from a primer extension assay; an allele-specific primer extension assay; an allele-specific nucleotide incorporation assay; an allele-specific oligonucleotide hybridization assay; a 5′ nuclease assay; an assay employing molecular beacons; and an oligonucleotide ligation assay. 
     
     
         42 . A method of treating a lupus condition in a subject in whom a genetic variation is known to be present at a nucleotide position corresponding to a single nucleotide polymorphism (SNP) in a SLE risk locus, wherein the SNP is rs922483 (SEQ ID NO: 13), the SLE risk locus is BLK, and wherein the variation is thymine at chromosomal location 11389322 on human chromosome 8, the method comprising administering to the subject a therapeutic agent effective to treat the condition. 
     
     
         43 . A method of treating a lupus condition in a subject in whom a genetic variation is known to be present at a nucleotide position corresponding to a single nucleotide polymorphism (SNP) as set forth in Table 4 in at least one SLE risk locus as set forth in Table 4, the method comprising administering to the subject a therapeutic agent effective to treat the condition. 
     
     
         44 . A method of treating a lupus condition in a subject in whom a genetic variation is known to be present at a nucleotide position corresponding to a single nucleotide polymorphism (SNP) as set forth in Table 6 in at least one SLE risk locus as set forth in Table 6, the method comprising administering to the subject a therapeutic agent effective to treat the condition. 
     
     
         45 . A method of treating a subject having a lupus condition, the method comprising administering to the subject a therapeutic agent effective to treat the condition in a subject who has a genetic variation in a SLE risk locus, wherein the SLE risk locus is BLK, wherein the variation in the BLK locus occurs at a nucleotide position corresponding to the position of a single nucleotide polymorphism (SNP), wherein the SNP is rs922483 (SEQ ID NO: 13), and wherein the variation is thymine at chromosomal location 11389322 on human chromosome 8. 
     
     
         46 . A method of treating a subject having a lupus condition, the method comprising administering to the subject a therapeutic agent effective to treat the condition in a subject who has a genetic variation at a nucleotide position corresponding to a single nucleotide polymorphism (SNP) as set forth in Table 4 in at least one SLE risk locus as set forth in Table 4. 
     
     
         47 . The method of  claim 46 , wherein the at least one SLE risk locus is selected from TNIP1, PRDM1, JAZF1, UHRF1BP1, and IL10. 
     
     
         48 . A method of treating a subject having a lupus condition, the method comprising administering to the subject a therapeutic agent effective to treat the condition in a subject who has a genetic variation at a nucleotide position corresponding to a single nucleotide polymorphism (SNP) as set forth in Table 6 in at least one SLE risk locus as set forth in Table 6. 
     
     
         49 . The method of  claim 48 , wherein the at least one SLE risk locus is selected from IFIH1, CFB, CLEC16A, IL12B, and SH2B3. 
     
     
         50 - 62 . (canceled) 
     
     
         63 . A method of diagnosing lupus in a subject, the method comprising detecting in a biological sample obtained from the subject, the presence of a genetic signature indicative of lupus, wherein said genetic signature comprises a set of at least three single nucleotide polymorphisms (SNPs), each SNP occurring in a SLE risk locus as set forth in Table 4 and in Table 6. 
     
     
         64 . The method of  claim 63 , wherein the genetic signature comprises a set of at least four SNPs, or at least five SNPs, or at least seven SNPs, or at least ten SNPs, or at least 15 SNPs, or at least 20 SNPs, or at least 30 SNPs. 
     
     
         65 . The method of  claim 63 , wherein each of the SLE risk loci is selected from TNIP1, PRDM1, JAZF1, UHRF1BP1, IL10, IFIH1, CFB, CLEC16A, IL12B, and SH2B3. 
     
     
         66 . The method of  claim 63 , wherein the genetic signature further comprises a SNP in a SLE risk locus, wherein the SNP is rs922483 (SEQ ID NO: 13) and the SLE risk locus is BLK, wherein the variation is thymine at chromosomal location 11389322 on human chromosome 8. 
     
     
         67 . The method of  claim 63 , wherein the detecting comprises carrying out a process selected from a primer extension assay; an allele-specific primer extension assay; an allele-specific nucleotide incorporation assay; an allele-specific oligonucleotide hybridization assay; a 5′ nuclease assay; an assay employing molecular beacons; and an oligonucleotide ligation assay. 
     
     
         68 . The method of any one of  claim 15 ,  16 , or  20 , wherein the determining comprises carrying out a process selected from a primer extension assay; an allele-specific primer extension assay; an allele-specific nucleotide incorporation assay; an allele-specific oligonucleotide hybridization assay; a 5′ nuclease assay; an assay employing molecular beacons; and an oligonucleotide ligation assay.