Abstract
Sjögren's syndrome is a common autoimmune disease (affecting ∼0.7% of European Americans) that typically presents as keratoconjunctivitis sicca and xerostomia. Here we report results of a large-scale association study of Sjögren's syndrome. In addition to strong association within the human leukocyte antigen (HLA) region at 6p21 (Pmeta = 7.65 × 10−114), we establish associations with IRF5-TNPO3 (Pmeta = 2.73 × 10−19), STAT4 (Pmeta = 6.80 × 10−15), IL12A (Pmeta = 1.17 × 10−10), FAM167A-BLK (Pmeta = 4.97 × 10−10), DDX6-CXCR5 (Pmeta = 1.10 × 10−8) and TNIP1 (Pmeta = 3.30 × 10−8). We also observed suggestive associations (Pmeta < 5 × 10−5) with variants in 29 other regions, including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2 and PHIP, among others. These results highlight the importance of genes that are involved in both innate and adaptive immunity in Sjögren's syndrome.
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Acknowledgements
We are grateful to all the individuals with Sjögren's syndrome and those serving as healthy controls who participated in this study. We thank the following individuals for their help in the collection and ascertainment of the samples used in this study: E. Rothrock, J. Harris, S. Johnson, S. Cioli, N. Weber, D. Williams, W. Daniels, C. Pritchett-Frazee, K. Crouch, L. Battiest, J. Rodgers, J. Robertson, T. Nguyen, A. Crosbie, E. James, C. Meyer, A. McElroy, E. Emamian, J. Ermer, K. Rohlf, J. Leon, A. Petersen, D. Hartle, J. Novizke, W. Ortman, C. Espy, B. Cobb, G. Kristjansdottir, M. Eidsheim, J. Benessiano, Centre de Ressources Biologiques, Hôpital Bichat, Paris, and the SNP&SEQ Technology Platform, Uppsala, Sweden. We also thank S. Glenn and J. Ning for their ongoing assistance in develo** and maintaining the computational infrastructure used to perform this study.
We thank the following funding agencies for their support: this publication was made possible by grants P50 AR0608040 (K.L.S., C.J.L., R.H.S. and A.D.F.), 5R01 DE015223 (K.L.S. and J.B.H.), 5RC2 AR058959 (P.M.G.), 5P01 AR049084-10 (J.B.H.), 5P30 AR053483 (J.A.J. and J.M.G.), 5U19 AI082714 (K.L.S., J.A.J. and C.J.L.), 1R01 DE018209-02 (K.L.S. and J.B.H.), 5R01 DE018209 (K.L.S.), 8P20 GM103456 (P.M.G., C.J.L., J.D.W. and I.A.), P20 GM103636 (M.G.D. and J.D.W.), 5R37 AI024717-25 (J.B.H.), 5P01 AI083194-03 (K.L.S. and J.B.H.), 7S10 RR027190-02 (J.B.H.), 1U01 AI101934 (J.A.J. and J.M.G.), 1RC1 AR058554 (J.A.J. and J.M.G.) and 5P30 GM103510 (J.A.J. and J.M.G.) from the NIH. The contents are the sole responsibility of the authors and do not necessarily represent the official views of the NIH. Additional funding was obtained from Intramural Research Program of the National Institute of Dental and Craniofacial Research (G.G.I.), US Department of Veterans Affairs IMMA 9 (J.B.H.), US Department of Defense PR094002 (J.B.H.), American College of Rheumatology Research and Education Foundation/Abbott Health Professional Graduate Student Preceptorship Award 2009 (C.J.L. and K.L.S.), Oklahoma Medical Research Foundation (C.J.L. and K.L.S.), Sjögren's Syndrome Foundation (K.L.S.), Phileona Foundation (K.L.S.), the French ministry of health (PHRC 2006-AOM06133) and the French ministry of research (ANR-2010-BLAN-1133) (X.M. and C.M.-R.), The Strategic Research Program at Helse Bergen, Western Norway Regional Health Authority (L.G.G., J.G.B. and R.J.), The Broegelmann Foundation (J.G.B. and R.J.), Norwegian Foundation for Health and Rehabilitation (E.H.), KFO 250 TP03, WI 1031/6-1 (T.W.), KFO 250, Z1 (T.W.), Medical Research Council, UK G0800629 (W.-F.N. and S.B.), Northumberland, Tyne and Wear Comprehensive Local Research Network (CLRN) (W.-F.N.), The Swedish Research Council (M.W.-H. and L. Rönnblom), The King Gustaf the V-th 80-year Foundation (M.W.-H.), Knut and Alice Wallenberg Foundation (L. Rönnblom) and The Swedish Rheumatism Association (M.W.-H., G.N., L. Rönnblom and P.E.). This study made use of genotypes available through dbGAP, with acknowledgments provided in the Supplementary Note.
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C.J.L., K.M.G., J.A.K., C.G.M., J.B.H. and K.L.S. were responsible for the study design. C.J.L., J.A.I., A.R., K.M.G., C.M.-R., S.B., S.L., J.G.B., L.G.G., E.H., J.M.G., D.S.C.G., M.E.G., A.N.M.N.-H., K.P., J.S.M.-M., A.D.F., M.-L.E., J.A.L., J.C., R.G., K.S.H., G.D.H., M.T.B., A.J.W.H., P.J.H., D.M.L., L. Radfar, M.D.R., D.U.S., T.J.V., P.M.G., J.A.J., R.O., M.W.-H., M.K., H.J., G.G.I., T.W., R.J., M.R., G.N., P.E., W.-F.N., X.M., J.-M.A., L. Rönnblom, N.L.R., B.M.S., R.H.S., J.B.H. and K.L.S. assisted in the collection and characterization of the Sjögren's syndrome cases and healthy controls. K.M.K., A.J.A. and P.M.G. performed the genoty**. C.J.L., H.L., I.A. and J.A.I. performed all analyses and imputation under the guidance of C.G.M. and K.L.S. M.G.D. and J.D.W. performed the enrichment analysis. C.J.L., H.L., I.A., J.A.I., J.A.K., C.G.M. and K.L.S. prepared the manuscript, and all authors approved the final draft.
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Lessard, C., Li, H., Adrianto, I. et al. Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren's syndrome. Nat Genet 45, 1284–1292 (2013). https://doi.org/10.1038/ng.2792
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DOI: https://doi.org/10.1038/ng.2792
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