BLK polymorphisms are associated with sjogren's syndrome only in patients with anti-SSA antibodies

Abstract

Background/Purpose: Primary Sjögren's syndrome (pSS) shares a number of pathogenic mechanisms with systemic lupus erythematosus (SLE), including an IFN type I signature illustrated by genetic association with STAT4 and IRF5 in both diseases and involvement of B cells. Polymorphisms of genes involved in B-cell function, such as BLK, have been associated with lupus and recently to pSS. Our goal for this study was to determine whether BLK polymorphisms are associated with risk of pSS. Methods: Our study population included 624 pSS patients and 577 control individuals of French Caucasian ancestry. A total of 9 SNPs located within the BLK locus, as well as 48 AIMs (Ancestry Informative Markers), were genotyped among patients and controls. Principal components analysis of the AIM data identified 32 cases and 53 controls with evidence of non-European ancestry and these subjects were removed from subsequent association analyses. Case control association tests were performed among the remaining 592 pSS and 524 controls for the 9 BLK SNPs and tested for independence. Subphenotype analyses were performed to determine whether genetic association results differed substantially according to the presence of anti-SSA auto-antibodies (328 SSA+ and 264 SSA-), systemic manifestations (N=307), cryoglobulinemia (N=60) or lymphoma (N=24). Results: We observed significant evidence of association with pSS for 3 SNPs within the BLK locus. The rs13277113 A allele was the most significantly associated BLK variant with an OR of 1.30 (95% CI 1.06-1.58), p = 9.10-3. Two other BLK SNPs were associated with pSS: the rs12677843 T allele: OR of 1.29 (95% CI 1.06-1.56), p = 9.7.10-3 and the rs2736340 T allele: OR of 1.28 (95% CI 1.05-1.56), p = 1.2.10-2. For these 3 SNPs, there were differences between anti-SSA positive and anti-SSA negative patients suggesting that these associations were restricted to anti-SSA positive patients. Comparison of anti-SSA positive patients to controls revealed 2 additional SNPs associated with anti-SSA positive pSS: the rs922483 T allele: OR of 1.28 (95% CI 1.03-1.60), p = 2.0.10-2 and the rs12549796 T allele: OR of 1.24 (95% CI 1.01-1.53), p = 3.7.10-2. Case-only analyses comparing patients with systemic manifestations, cryoglobulinemia, or lymphoma versus patients without each of these manifestations did not demonstrate significant association. Conditional haplotype analysis suggested that haplotypes comprised of 2 SNPs (rs13277113 and rs1382563) contribute to risk of pSS (p=0.019). Conclusion: We replicated the study from Nordmark et al (1) and found additional BLK SNPs that contribute to the risk of pSS. These results provide an additional example of shared genetic susceptibility to SLE and pSS. BLK is a gene involved in B-cell function and studying functional consequences of these polymorphisms may provide clues to the mechanisms of B cell activation in these 2 autoimmune diseases.