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 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.

Author information

Affiliations

  1. Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.

    • Christopher J Lessard
    • , He Li
    • , Indra Adrianto
    • , John A Ice
    • , Astrid Rasmussen
    • , Kiely M Grundahl
    • , Jennifer A Kelly
    • , Mikhail G Dozmorov
    • , Joel M Guthridge
    • , Adam J Adler
    • , Jacen S Maier-Moore
    • , A Darise Farris
    • , Jonathan D Wren
    • , Patrick M Gaffney
    • , Judith A James
    • , R Hal Scofield
    • , Courtney G Montgomery
    •  & Kathy L Sivils
  2. Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

    • Christopher J Lessard
    • , He Li
    • , Judith A James
    •  & Kathy L Sivils
  3. Université Paris-Sud, Assistance Publique–Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Paris-Sud, Institut National de la Santé et de la Recherche Médicale (INSERM) U1012, Paris, France.

    • Corinne Miceli-Richard
    •  & Xavier Mariette
  4. Rheumatology Department, University Hospital Birmingham, Birmingham, UK.

    • Simon Bowman
  5. Department of Rheumatology, The Queen Elizabeth Hospital, South Australia.

    • Sue Lester
    •  & Maureen Rischmueller
  6. Department of Rheumatology, Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.

    • Per Eriksson
  7. Department of Medical Sciences, Rheumatology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

    • Maija-Leena Eloranta
    • , Lars Rönnblom
    •  & Gunnel Nordmark
  8. Section for Rheumatology, Department of Clinical Science, University of Bergen, Bergen, Norway.

    • Johan G Brun
  9. Department of Rheumatology, Haukeland University Hospital, Bergen, Norway.

    • Johan G Brun
    •  & Roland Jonsson
  10. Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway.

    • Lasse G Gøransson
    • , Erna Harboe
    •  & Roald Omdal
  11. Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

    • Kenneth M Kaufman
    •  & John B Harley
  12. Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA.

    • Kenneth M Kaufman
    •  & John B Harley
  13. Department of Medicine, Karolinska Institutet, Stockholm, Sweden.

    • Marika Kvarnström
    • , Helmi Jazebi
    •  & Marie Wahren-Herlenius
  14. Department of Rheumatology, Örebro University Hospital, Örebro, Sweden.

    • Helmi Jazebi
  15. Department of Medical and Molecular Genetics, King's College London, London, UK.

    • Deborah S Cunninghame Graham
    •  & Timothy J Vyse
  16. United Medical Specialties, St. Paul, Minnesota, USA.

    • Martha E Grandits
  17. School of Dental Medicine, University of Colorado–Denver, Denver, Colorado, USA.

    • Abu N M Nazmul-Hossain
  18. Department of Developmental and Surgical Science, Division of Oral and Maxillofacial Surgery, University of Minnesota School of Dentistry, Minneapolis, Minnesota, USA.

    • Ketan Patel
    •  & Pamela J Hughes
  19. Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

    • Jacen S Maier-Moore
    • , Judith A James
    •  & R Hal Scofield
  20. Department of Oral Medicine, Carolinas Medical Center, Charlotte, North Carolina, USA.

    • Michael T Brennan
  21. Valley Bone and Joint Clinic, Grand Forks, North Dakota, USA.

    • James A Lessard
  22. Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.

    • James Chodosh
  23. Department of Diagnostic and Biological Sciences, Division of Oral and Maxillofacial Pathology, University of Minnesota School of Dentistry, Minneapolis, Minnesota, USA.

    • Rajaram Gopalakrishnan
  24. Hefner Eye Care and Optical Center, Oklahoma City, Oklahoma, USA.

    • Kimberly S Hefner
  25. Department of Oral and Maxillofacial Pathology, University of Oklahoma College of Dentistry, Oklahoma City, Oklahoma, USA.

    • Glen D Houston
    •  & David M Lewis
  26. Department of Ophthalmology and Visual Sciences, Washington University, St. Louis, Missouri, USA.

    • Andrew J W Huang
  27. Oral Diagnosis and Radiology Department, University of Oklahoma College of Dentistry, Oklahoma City, Oklahoma, USA.

    • Lida Radfar
  28. Hard Tissue Research Laboratory, University of Minnesota School of Dentistry, Minneapolis, Minnesota, USA.

    • Michael D Rohrer
  29. Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

    • Donald U Stone
  30. Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

    • Jonathan D Wren
  31. National Institute of Dental and Craniofacial Research, National Institutes of Health (NIH), Bethesda, Maryland, USA.

    • Gabor G Illei
  32. Department of Clinical Immunology and Rheumatology, Hannover Medical School, Hannover, Germany.

    • Torsten Witte
  33. Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway.

    • Roland Jonsson
  34. Department of Rheumatology, The Queen Elizabeth Hospital and Discipline of Medicine, University of Adelaide, South Australia.

    • Maureen Rischmueller
  35. Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.

    • Wan-Fai Ng
  36. Center for Autoimmune Diseases Research (CREA), Universidad del Rosario, Bogotá, Colombia.

    • Juan-Manuel Anaya
  37. Department of Oral Surgery, University of Minnesota School of Dentistry, Minneapolis, Minnesota, USA.

    • Nelson L Rhodus
  38. Division of Rheumatology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.

    • Barbara M Segal
  39. Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma, USA.

    • R Hal Scofield

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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 genotyping. 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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Kathy L Sivils.

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    Supplementary Text and Figures

    Supplementary Note, Supplementary Figures 1–31 and Supplementary Tables 1–16

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DOI

https://doi.org/10.1038/ng.2792

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