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Transethnic meta-analysis identifies GSDMA and PRDM1 as susceptibility genes to systemic sclerosis
  1. Chikashi Terao1,2,3,4,5,
  2. Takahisa Kawaguchi1,
  3. Philippe Dieude6,
  4. John Varga7,
  5. Masataka Kuwana8,
  6. Marie Hudson9,
  7. Yasushi Kawaguchi10,
  8. Marco Matucci-Cerinic11,
  9. Koichiro Ohmura12,
  10. Gabriela Riemekasten13,14,
  11. Aya Kawasaki15,
  12. Paolo Airo16,
  13. Tetsuya Horita17,
  14. Akira Oka18,
  15. Eric Hachulla19,
  16. Hajime Yoshifuji12,
  17. Paola Caramaschi20,
  18. Nicolas Hunzelmann21,
  19. Murray Baron9,
  20. Tatsuya Atsumi17,
  21. Paul Hassoun22,
  22. Takeshi Torii23,
  23. Meiko Takahashi1,
  24. Yasuharu Tabara1,
  25. Masakazu Shimizu1,
  26. Akiko Tochimoto10,
  27. Naho Ayuzawa24,
  28. Hidetoshi Yanagida24,
  29. Hiroshi Furukawa15,25,
  30. Shigeto Tohma25,
  31. Minoru Hasegawa26,
  32. Manabu Fujimoto27,
  33. Osamu Ishikawa28,
  34. Toshiyuki Yamamoto29,
  35. Daisuke Goto30,
  36. Yoshihide Asano31,
  37. Masatoshi Jinnin32,
  38. Hirahito Endo33,
  39. Hiroki Takahashi34,
  40. Kazuhiko Takehara35,
  41. Shinichi Sato31,
  42. Hironobu Ihn32,
  43. Soumya Raychaudhuri3,4,5,36,
  44. Katherine Liao3,
  45. Peter Gregersen37,
  46. Naoyuki Tsuchiya15,
  47. Valeria Riccieri38,
  48. Inga Melchers39,
  49. Gabriele Valentini40,
  50. Anne Cauvet41,
  51. Maria Martinez42,
  52. Tsuneyo Mimori12,
  53. Fumihiko Matsuda1,
  54. Yannick Allanore43
  1. 1Department of Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
  2. 2Center for the Promotion of Interdisciplinary Education and Research, Kyoto University Graduate School of Medicine, Kyoto, Japan
  3. 3Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA
  4. 4Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
  5. 5Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA
  6. 6Rheumatology Bichat Hospital, Paris 7 University, Paris, France
  7. 7Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
  8. 8Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
  9. 9Jewish General Hospital and Lady Davis Research Institute, Montreal, Quebec, Canada
  10. 10Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan
  11. 11Division of Rheumatology AOUC, Department of Experimental and Clinical Medicine, Department of Medical & Geriatrics Medicine, University of Florence, Firenze, Italy
  12. 12Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan
  13. 13Clinic for Rheumatology, University of Lübeck, Lübeck, Germany
  14. 14German Lung Center Borstel, Leibniz Institute, Germany
  15. 15Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
  16. 16Rheumatology Unit, Spedali Civili, Brescia, Italy
  17. 17Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
  18. 18The Institute of Medical Science, Tokai University, Isehara, Japan
  19. 19Internal Medicine Department, FHU Immune-Mediated Inflammatory Diseases and Targeted Therapies, Lille University, Lille, France
  20. 20Rheumatology Department, University of Verona, Azienda Ospedaliera Universitaria Integrata, Italy
  21. 21Dermatology Department, University of Koln, Koln, Germany
  22. 22Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
  23. 23Torii Clinic, Kyoto, Japan
  24. 24Department of Rheumatology, National Hospital Organization, Utano National Hospital, Kyoto, Japan
  25. 25Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara, Japan
  26. 26Division of Medicine, Faculty of Medical Sciences, Department of Dermatology, University of Fukui, Fukui, Japan
  27. 27Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
  28. 28Department of Dermatology, Gunma University Graduate School of Medicine, Gunma, Japan
  29. 29Department of Dermatology, Fukushima Medical University, Fukushima, Japan
  30. 30Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
  31. 31Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
  32. 32Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
  33. 33Division of Rheumatology, Department of Internal Medicine, School of Medicine, Toho University, Tokyo, Japan
  34. 34Department of Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan
  35. 35Department of Dermatology, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
  36. 36Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
  37. 37Robert S. Boas Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, Manhasset, New York, USA
  38. 38Sapienza University of Rome, Rome, Italy
  39. 39University Medical Center, Freiburg, Germany
  40. 40Department of Clinical and Experimental Medicine, Rheumatology Section, Second University of Naples, Naples, Italy
  41. 41INSERM U1016/UMR 8104, Cochin Institute, Paris Descartes University, Paris, France
  42. 42INSERM U1220—IRSD—Batiment B Purpan Hospital Toulouse, Paris, France
  43. 43Rheumatology A Department, INSERM U1016/UMR 8104, Cochin Institute, Paris Descartes University, Paris, France
  1. Correspondence to Dr Yannick Allanore, INSERM U1016/UMR 8104, Cochin Institute, Rheumatology A Department, Paris Descartes University, 75014 Paris, France; yannick.allanore{at} or Dr Chikashi Terao, Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Shogoin-Kawahara-cho 54, Sakyo-ku, Kyoto 606-8507, Japan; a0001101{at}


Objectives Systemic sclerosis (SSc) is an autoimmune disease characterised by skin and systemic fibrosis culminating in organ damage. Previous genetic studies including genome-wide association studies (GWAS) have identified 12 susceptibility loci satisfying genome-wide significance. Transethnic meta-analyses have successfully expanded the list of susceptibility genes and deepened biological insights for other autoimmune diseases.

Methods We performed transethnic meta-analysis of GWAS in the Japanese and European populations, followed by a two-staged replication study comprising a total of 4436 cases and 14 751 controls. Associations between significant single nuclear polymorphisms (SNPs) and neighbouring genes were evaluated. Enrichment analysis of H3K4Me3, a representative histone mark for active promoter was conducted with an expanded list of SSc susceptibility genes.

Results We identified two significant SNP in two loci, GSDMA and PRDM1, both of which are related to immune functions and associated with other autoimmune diseases (p=1.4×10−10 and 6.6×10−10, respectively). GSDMA also showed a significant association with limited cutaneous SSc. We also replicated the associations of previously reported loci including a non-GWAS locus, TNFAIP3. PRDM1 encodes BLIMP1, a transcription factor regulating T-cell proliferation and plasma cell differentiation. The top SNP in GSDMA was a missense variant and correlated with gene expression of neighbouring genes, and this could explain the association in this locus. We found different human leukocyte antigen (HLA) association patterns between the two populations. Enrichment analysis suggested the importance of CD4-naïve primary T cell.

Conclusions GSDMA and PRDM1 are associated with SSc. These findings provide enhanced insight into the genetic and biological basis of SSc.

  • Systemic Sclerosis
  • Gene Polymorphism
  • Autoimmune Diseases

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  • Handling editor Tore K Kvien

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  • Contributors Wrote the paper: CT, YA. Performed imputation and analyses: CT, TK, MM Performed the experimental work: CT, AK, AO, MS, AC. Conceived and designed the study: CT, TM, FM, YA. Substantial contribution to acquired samples and creation of data in GWAS: CT, TK, PD, MK, YK, KO, TH, HY, TA, TT, MT, YT, MS, AT, AC, MM, TM, FM, YA. Substantial contribution to acquired samples and creation of data in replication study: CT, PD, JV, MH, MMC, KO, GR, AK, PA, TH, AO, EH, HY, PC, NH, MB, TA, PH, TT, MT, YT, MS, NA, HY, HF, ST, MH, MF, OI, TY, DG, YA, MJ, HE, HT, KT, SS, HI, SR, KL, PG, NT, VR, IM, GV, AC, TM, FM, YA. Contribution to collection of clinical information: CT, PD, JV, MK, MH, YK, MMC, KO, GR, PA, TH, AO, EH, PC, NH, MB, TA, PH, YT, AT, NA, HY, HF, ST, MH, MF, OI, TY, DG, YA, MJ, HE, HT, KT, SS, HI, VR, IM, GV, AC, TM, FM, YA. All authors revised and approved the manuscript to be published.

  • Funding This study was supported by JSPS KAKENHI Grant Number JP16H06251, KANAE foundation for the promotion of medical science, Research Project of Genetic Studies for Intractable Diseases, Nagao Memorial Fund, The Uehara Memorial Foundation, The John Mung Advanced Program, Kyoto University and Associattion des Sclerodermie de France, INSERM, CNRS, ATIP AVENIR Programme, Agence Nationale pour la Recherche (Project ANR-08-GENO-016-1).

  • Competing interests None declared.

  • Ethics approval This study was approved by local ethical committees.

  • Provenance and peer review Not commissioned; externally peer reviewed.