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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Gene Expression Omnibus
Helmick, C.G. et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 58, 15–25 (2008).
Pillemer, S.R. et al. Incidence of physician-diagnosed primary Sjögren syndrome in residents of Olmsted County, Minnesota. Mayo Clin. Proc. 76, 593–599 (2001).
Plesivcnik Novljan, M. et al. Incidence of primary Sjögren's syndrome in Slovenia. Ann. Rheum. Dis. 63, 874–876 (2004).
Jonsson, R. et al. The complexity of Sjögren's syndrome: novel aspects on pathogenesis. Immunol. Lett. 141, 1–9 (2011).
Vitali, C. et al. Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann. Rheum. Dis. 61, 554–558 (2002).
Thanou-Stavraki, A. & James, J.A. Primary Sjögren's syndrome: current and prospective therapies. Semin. Arthritis Rheum. 37, 273–292 (2008).
Cobb, B.L., Lessard, C.J., Harley, J.B. & Moser, K.L. Genes and Sjögren's syndrome. Rheum. Dis. Clin. North Am. 34, 847–868 (2008).
Hjelmervik, T.O., Petersen, K., Jonassen, I., Jonsson, R. & Bolstad, A.I. Gene expression profiling of minor salivary glands clearly distinguishes primary Sjögren's syndrome patients from healthy control subjects. Arthritis Rheum. 52, 1534–1544 (2005).
Emamian, E.S. et al. Peripheral blood gene expression profiling in Sjögren's syndrome. Genes Immun. 10, 285–296 (2009).
Ice, J.A. et al. Genetics of Sjögren's syndrome in the genome-wide association era. J. Autoimmun. 39, 57–63 (2012).
Cruz-Tapias, P., Rojas-Villarraga, A., Maier-Moore, S. & Anaya, J.M. HLA and Sjögren's syndrome susceptibility. A meta-analysis of worldwide studies. Autoimmun. Rev. 11, 281–287 (2012).
Korman, B.D. et al. Variant form of STAT4 is associated with primary Sjögren's syndrome. Genes Immun. 9, 267–270 (2008).
Miceli-Richard, C. et al. Association of an IRF5 gene functional polymorphism with Sjögren's syndrome. Arthritis Rheum. 56, 3989–3994 (2007).
Nordmark, G. et al. Association of EBF1, FAM167A(C8orf13)-BLK and TNFSF4 gene variants with primary Sjögren's syndrome. Genes Immun. 12, 100–109 (2011).
Nordmark, G. et al. Additive effects of the major risk alleles of IRF5 and STAT4 in primary Sjögren's syndrome. Genes Immun. 10, 68–76 (2009).
Kang, H.I. et al. Comparison of HLA class II genes in Caucasoid, Chinese, and Japanese patients with primary Sjögren's syndrome. J. Immunol. 150, 3615–3623 (1993).
ENCODE Project Consortium. A user's guide to the encyclopedia of DNA elements (ENCODE). PLoS Biol. 9, e1001046 (2011).
Rossin, E.J. et al. Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology. PLoS Genet. 7, e1001273 (2011).
Frisch, M., Klocke, B., Haltmeier, M. & Frech, K. LitInspector: literature and signal transduction pathway mining in PubMed abstracts. Nucleic Acids Res. 37, W135–W140 (2009).
Nekrep, N. et al. Mutation in a winged-helix DNA-binding motif causes atypical bare lymphocyte syndrome. Nat. Immunol. 3, 1075–1081 (2002).
Meissner, T.B. et al. NLRC5 cooperates with the RFX transcription factor complex to induce MHC class I gene expression. J. Immunol. 188, 4951–4958 (2012).
Loiseau, P. et al. HLA class I and class II are both associated with the genetic predisposition to primary Sjögren syndrome. Hum. Immunol. 62, 725–731 (2001).
Raychaudhuri, S. et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat. Genet. 44, 291–296 (2012).
Savitsky, D., Tamura, T., Yanai, H. & Taniguchi, T. Regulation of immunity and oncogenesis by the IRF transcription factor family. Cancer Immunol. Immunother. 59, 489–510 (2010).
Takaoka, A. et al. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 434, 243–249 (2005).
Sigurdsson, S. et al. Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am. J. Hum. Genet. 76, 528–537 (2005).
Sigurdsson, S. et al. Association of a haplotype in the promoter region of the interferon regulatory factor 5 gene with rheumatoid arthritis. Arthritis Rheum. 56, 2202–2210 (2007).
Stahl, E.A. et al. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat. Genet. 42, 508–514 (2010).
Dideberg, V. et al. An insertion-deletion polymorphism in the interferon regulatory Factor 5 (IRF5) gene confers risk of inflammatory bowel diseases. Hum. Mol. Genet. 16, 3008–3016 (2007).
Liu, X. et al. Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis. Nat. Genet. 42, 658–660 (2010).
Dieudé, P. et al. Association between the IRF5 rs2004640 functional polymorphism and systemic sclerosis: a new perspective for pulmonary fibrosis. Arthritis Rheum. 60, 225–233 (2009).
Radstake, T.R. et al. Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus. Nat. Genet. 42, 426–429 (2010).
Harley, J.B. et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat. Genet. 40, 204–210 (2008).
Graham, R.R. et al. Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus. Proc. Natl. Acad. Sci. USA 104, 6758–6763 (2007).
Miceli-Richard, C. et al. The CGGGG insertion/deletion polymorphism of the IRF5 promoter is a strong risk factor for primary Sjögren's syndrome. Arthritis Rheum. 60, 1991–1997 (2009).
Sigurdsson, S. et al. Comprehensive evaluation of the genetic variants of interferon regulatory factor 5 (IRF5) reveals a novel 5 bp length polymorphism as strong risk factor for systemic lupus erythematosus. Hum. Mol. Genet. 17, 872–881 (2008).
Dawidowicz, K. et al. The interferon regulatory factor 5 gene confers susceptibility to rheumatoid arthritis and influences its erosive phenotype. Ann. Rheum. Dis. 70, 117–121 (2011).
Kristjansdottir, G. et al. Interferon regulatory factor 5 (IRF5) gene variants are associated with multiple sclerosis in three distinct populations. J. Med. Genet. 45, 362–369 (2008).
Kaplan, M.H. STAT4: a critical regulator of inflammation in vivo. Immunol. Res. 31, 231–242 (2005).
Remmers, E.F. et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N. Engl. J. Med. 357, 977–986 (2007).
Rueda, B. et al. The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype. Hum. Mol. Genet. 18, 2071–2077 (2009).
Mells, G.F. et al. Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nat. Genet. 43, 329–332 (2011).
Gestermann, N. et al. STAT4 is a confirmed genetic risk factor for Sjogren's syndrome and could be involved in type 1 interferon pathway signaling. Genes Immun. 11, 432–438 (2010).
Watford, W.T. et al. Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol. Rev. 202, 139–156 (2004).
Xu, M. et al. Regulation of antitumor immune responses by the IL-12 family cytokines, IL-12, IL-23, and IL-27. Clin. Dev. Immunol. 2010, 832454 (2010).
Hirschfield, G.M. et al. Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N. Engl. J. Med. 360, 2544–2555 (2009).
Hunt, K.A. et al. Newly identified genetic risk variants for celiac disease related to the immune response. Nat. Genet. 40, 395–402 (2008).
Lessard, C.J. et al. Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as susceptibility loci for systemic lupus erythematosus in a large-scale multiracial replication study. Am. J. Hum. Genet. 90, 648–660 (2012).
Gottenberg, J.E. et al. Activation of IFN pathways and plasmacytoid dendritic cell recruitment in target organs of primary Sjögren's syndrome. Proc. Natl. Acad. Sci. USA 103, 2770–2775 (2006).
Pérez, P. et al. Gene expression and chromosomal location for susceptibility to Sjögren's syndrome. J. Autoimmun. 33, 99–108 (2009).
Cornall, R.J. & Goodnow, C.C. B cell antigen receptor signalling in the balance of tolerance and immunity. Novartis Found. Symp. 215, 21–30 (1998).
Nemazee, D. & Weigert, M. Revising B cell receptors. J. Exp. Med. 191, 1813–1817 (2000).
Hom, G. et al. Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N. Engl. J. Med. 358, 900–909 (2008).
Simpfendorfer, K.R. et al. The autoimmunity-associated BLK haplotype exhibits cis-regulatory effects on mRNA and protein expression that are prominently observed in B cells early in development. Hum. Mol. Genet. 21, 3918–3925 (2012).
Sawcer, S. et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476, 214–219 (2011).
Hansen, A., Lipsky, P.E. & Dorner, T. B cells in Sjögren's syndrome: indications for disturbed selection and differentiation in ectopic lymphoid tissue. Arthritis Res. Ther. 9, 218 (2007).
Ma, C.S. et al. Early commitment of naive human CD4+ T cells to the T follicular helper (TFH) cell lineage is induced by IL-12. Immunol. Cell Biol. 87, 590–600 (2009).
Adrianto, I. et al. Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus. Nat. Genet. 43, 253–258 (2011).
Uddin, M., Sturge, M., Rahman, P. & Woods, M.O. Autosome-wide copy number variation association analysis for rheumatoid arthritis using the WTCCC high-density SNP genotype data. J. Rheumatol. 38, 797–801 (2011).
Allanore, Y. et al. Genome-wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis. PLoS Genet. 7, e1002091 (2011).
Nair, R.P. et al. Genome-wide scan reveals association of psoriasis with IL-23 and NF-κB pathways. Nat. Genet. 41, 199–204 (2009).
Adrianto, I. et al. Two independent functional risk haplotypes in TNIP1 are associated with systemic lupus erythematosus. Arthritis Rheum. 64, 3695–3705 (2012).
Gateva, V. et al. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat. Genet. 41, 1228–1233 (2009).
Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).
Cortes, A. & Brown, M.A. Promise and pitfalls of the Immunochip. Arthritis Res. Ther. 13, 101 (2011).
Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).
McKeigue, P.M., Carpenter, J.R., Parra, E.J. & Shriver, M.D. Estimation of admixture and detection of linkage in admixed populations by a Bayesian approach: application to African-American populations. Ann. Hum. Genet. 64, 171–186 (2000).
Halder, I., Shriver, M., Thomas, M., Fernandez, J.R. & Frudakis, T. A panel of ancestry informative markers for estimating individual biogeographical ancestry and admixture from four continents: utility and applications. Hum. Mutat. 29, 648–658 (2008).
Willer, C.J., Li, Y. & Abecasis, G.R. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191 (2010).
Cochran, W.G. The combination of estimates from different experiments. Biometrics 10, 101–129 (1954).
Higgins, J.P., Thompson, S.G., Deeks, J.J. & Altman, D.G. Measuring inconsistency in meta-analyses. Br. Med. J. 327, 557–560 (2003).
Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).
Pruim, R.J. et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 2336–2337 (2010).
Frazer, K.A. et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007).
Howie, B.N., Donnelly, P. & Marchini, J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 5, e1000529 (2009).
Via, M., Gignoux, C. & Burchard, E.G. The 1000 Genomes Project: new opportunities for research and social challenges. Genome Med. 2, 3 (2010).
Zheng, X. et al. HIBAG-HLA genotype imputation with attribute bagging. Pharmacogenomics J. published online, doi:10.1038/tpj.2013.18 (28 May 2013).10.1038/tpj.2013.18
Barbosa-Morais, N.L. et al. A re-annotation pipeline for Illumina BeadArrays: improving the interpretation of gene expression data. Nucleic Acids Res. 38, e17 (2010).
Irizarry, R.A. et al. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4, 249–264 (2003).
Johnson, W.E., Li, C. & Rabinovic, A. Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics 8, 118–127 (2007).
Shabalin, A.A. Matrix eQTL: ultra fast eQTL analysis via large matrix operations. Bioinformatics 28, 1353–1358 (2012).
Dozmorov, M.G., Cara, L.R., Giles, C.B. & Wren, J.D. GenomeRunner: automating genome exploration. Bioinformatics 28, 419–420 (2012).
Fujita, P.A. et al. The UCSC Genome Browser database: update 2011. Nucleic Acids Res. 39, D876–D882 (2011).
Quinlan, A.R. & Hall, I.M. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841–842 (2010).
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 developing 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.
The authors declare no competing financial interests.
Further details appear in the Supplementary Note.
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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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