Session Type: ACR Concurrent Abstract Session
Session Time: 4:30PM-6:00PM
Background/Purpose: Sjögren’s syndrome (SS) is a complex autoimmune disease with both environmental and genetic factors playing important roles in its pathophysiology. The goal of this study was replicate suggestive loci that failed to exceed the genome-wide significance (GWS) threshold of 5x10E-8 in our previously published work. This list included: TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2, and PHIP.
Methods: Our previous study included 1638 SS cases and 6754 population controls typed either on Illumina Omni1 or ImmunoChip arrays. In the current study, we typed an additional 212 SS cases and 2150 population controls on OmniExpress arrays yielding a combined total of 1850 SS cases and 8904 population controls for analysis. The Omni1 data and the ImmunoChip data were imputed using IMPUTE2 with the 1000 Genomes reference panels. Analysis was done using logistic regression accounting for ancestry and gender. and the results were combined using a weighted Z-score method.
Results: Two regions that have not been previously reported were found to exceed the GWS threshold. Association has been previously established with SS to a risk haplotype that spans the TNFAIP3 coding region originally describe in lupus; however, in the current study we identified a novel effect ~230kb 5’ of the TNFAIP3 coding region (rs6933404, Pmeta= 7.79x10E-9, OR= 1.28, 95% CI=1.14-1.44), which was originally describe as a risk effect for rheumatoid arthritis. Association was observed for the haplotype previously established with SS spanning the TNFAIP3 coding region; however, the signal peaks at rs58721818 (P=4.77x10E-4), which is correlated (r2>0.8) with rs7749323, a variant previously described in lupus. Logistic regression analysis adjusting for rs6933404 found that this variant accounted for all association in the TNFAIP3 region. Bioinformatics data provided only limited evidence that rs6933404 might be the true functional/causal variant in this region; however, another variant on this haplotype also surpassing GWS, rs6927172, has been shown to modify 8 transcription factor binding sites, 13 bound proteins in various cell lines by ENCODE, and is located within an enhancer element in CD4+CD25–IL17+ PMA-Ionomycin stimulated Th17 primary cells by the Epigenetics Road Map Project. The second region to surpass the GWS threshold was PRDM1, which peaked at rs526531 (Pmeta= 1.24x10E-8, OR= 1.25, 95% CI=1.12-1.39). Logistic regression adjusting for rs526531 found it accounted for all association in this region. Two additional variants on this haplotype exceeded GWS, but no clear candidate functional/causal variant has emerged based on bioinformatics data. Of the 6 remaining suggestive regions, PTTG1, DGKQ, and FCGR2A continue trending towards GWS.
Conclusion: These data now establish 2 new SS risk haplotypes, TNFAIP3 and PRDM1. TNFAIP3, which codes for the protein A20, is a negative regulator of NF-kB responses. PRDM1, which codes for the protein BLIMP1, is an important transcription factor in regulation of the 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 pathophysiology.
To cite this abstract in AMA style:Lessard CJ, Li H, Ice J, Adrianto I, Rasmussen A, Grundahl K, Kelly JA, Miceli C, Bowman S, Lester S, Brun JG, Goransson LG, Harboe E, Guthridge JM, Kaufman KM, Eriksson P, Eloranta ML, Kvarnström M, Cunninghame-Graham DS, Farris AD, Brennan MT, Chodosh J, Gopalakrishnan R, Huang AJW, Hughes P, Lewis DM, Radfar L, Rohrer MD, Stone DU, Vyse TJ, Gaffney PM, James JA, Harley JB, Omdal R, Wahren-Herlenius M, Illei GG, Witte T, Jonsson R, Rischmueller M, Rönnblom L, Mariette X, Anaya JM, Ng WF, Nordmark G, Montgomery CG, Rhodus NL, Segal BM, Scofield RH, Sivils KL. Identification of Novel Sjogren’s Syndrome Risk Loci in the Regions of TNFAIP3 and PRDM1 [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/identification-of-novel-sjogrens-syndrome-risk-loci-in-the-regions-of-tnfaip3-and-prdm1/. Accessed July 6, 2020.
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