Background Sjögren's syndrome (SS) is a complex autoimmune disease with both environmental and genetic factors playing important roles in its etiology.
Objectives The goal of this study was to replicate 8 suggestive loci that failed to exceed the genome-wide significance (GWS) threshold of 5x10E-8 in our previously published work: TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2, and PHIP.
Methods Our previous study included 1638 SS cases and 6754 population controls. In the current study, we genotyped an additional 282 SS cases and 2576 population controls yielding a total of 1920 SS cases and 9330 controls. Analysis was done using logistic regression accounting for ancestry and gender.
Results Two regions exceeded the GWS threshold. Association has been previously established with SS to a risk haplotype spanning the TNFAIP3 coding region described in lupus; however, we identified a novel independent effect ∼230kb 5' of TNFAIP3 (rs6933404 Pmeta=6.85x10E-9, OR=1.28) originally described in rheumatoid arthritis. Association was observed for the haplotype spanning the TNFAIP3 coding region peaking at rs58721818 (P=4.77x10E-4), which is not correlated with rs6933404 (r2=0.02; D'=0.49). Bioinformatics data provided limited support that rs6933404 is the functional variant in this region; however, another variant on this haplotype also surpassing GWS, rs6927172, modifies 8 transcription factor binding sites, and is located within an enhancer element in CD4+CD25–IL17+ PMA-Ionomycin stimulated Th17 primary cells by the Epigenetics Road Map Project. A variant in the region of PRDM1 also surpassed the GWS threshold (rs526531 Pmeta=1.70x10E-8, OR=1.25). Two additional variants on this haplotype exceeded GWS, but no clear candidate functional variant has emerged based on bioinformatics data. Of the 6 remaining suggestive regions, PTTG1, DGKQ, and FCGR2A continue trending towards GWS.
Conclusions These data now establish 2 new SS risk loci, TNFAIP3 and PRDM1. TNFAIP3, which codes for the protein A20, is a negative regulator of NF-kB. PRDM1, which codes for the protein BLIMP1, is a transcription factor that regulates interferon-beta locus and plasma cell differentiation. Additional studies are needed to determine how these association signals function in the human genome and contribute to SS etiology.
Disclosure of Interest None declared