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THU0006 Trans-ethnic meta-analysis of genome-wide association studies identifies GSDMA and PRDM1 as susceptibility genes to systemic sclerosis
  1. C Terao1,
  2. T Kawaguchi2,
  3. P Dieude3,
  4. J Varga4,
  5. M Kuwana5,
  6. M Hudson6,
  7. Y Kawaguchi7,
  8. M Matucci-Cerinic8,
  9. K Ohmura2,
  10. G Riemekasten9,
  11. A Kawasaki10,
  12. P Airo11,
  13. T Horita12,
  14. A Oka13,
  15. E Hachulla14,
  16. H Yoshifuji2,
  17. P Caramaschi15,
  18. N Hunzelmann16,
  19. M Baron6,
  20. T Atsumi12,
  21. P Hassouns17,
  22. A Tochimoto18,
  23. N Ayuzawa19,
  24. H Yanagida19,
  25. H Furukawa10,
  26. S Tohma20,
  27. M Hasegawa21,
  28. M Fujimoto22,
  29. O Ishikawa23,
  30. T Yamamoto24,
  31. D Goto10,
  32. Y Asano25,
  33. M Jinnin26,
  34. H Endo27,
  35. H Takahashi28,
  36. K Takehara29,
  37. S Sato25,
  38. H Ihn26,
  39. S Raychaudhuri1,
  40. K Liao1,
  41. P Gregersen30,
  42. N Tsuchiya10,
  43. V Riccieri31,
  44. I Melchers32,
  45. G Valentini33,
  46. A Cauvet34,
  47. M Martinez35,
  48. T Mimori2,
  49. F Matsuda2,
  50. Y Allanore36
  1. 1Brigham and Women's Hospital, Boston, United States
  2. 2Kyoto University Graduate School of Medicine, Kyoto, Japan
  3. 3Rheumatology Bichat Hospital, Paris, France
  4. 4Northwestern University Feinberg School of Medicine, Chicago, United States
  5. 5Keio University School of Medicine, Tokyo, Japan
  6. 6Jewish General Hospital and Lady Davis Research Institute, Montreal, Canada
  7. 7Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan
  8. 8University of Florence, Firenze, Italy
  9. 9University of Lübeck, Lübeck, Germany
  10. 10University of Tsukuba, Tsukuba, Japan
  11. 11Spedali Civili, Brescia, Italy
  12. 12Hokkaido University Graduate School of Medicine, Sapporo
  13. 13Tokai University, Isehara, Japan
  14. 14Lille University, Lille, France
  15. 15Azienda Ospedaliera Universitaria Integrata, Verona, Italy
  16. 16University of Koln, Koln, Germany
  17. 17Johns Hopkins University, Baltimore, United States
  18. 18Tokyo Women's Medical University, Tokyo
  19. 19Utano National Hospital, Kyoto
  20. 20Sagamihara Hospital, National Hospital Organization, Sagamihara
  21. 21University of Fukui, Fukui
  22. 22Tsukuba, University of Tsukuba
  23. 23Gunma University Graduate School of Medicine, Gunma
  24. 24Fukushima Medical University, Fukushima
  25. 25University of Tokyo Graduate School of Medicine, Tokyo
  26. 26Kumamoto University, Kumamoto
  27. 27Toho University, Tokyo
  28. 28Sapporo Medical University School of Medicine, Sapporo
  29. 29Kanazawa University, Kanazawa, Japan
  30. 30The Feinstein Institute for Medical Research, Manhasset, United States
  31. 31Sapienza University of Rome, Rome, Italy
  32. 32University Medical Center, Freiburg, Germany
  33. 33Second University of Naples, Naples, Italy
  34. 34Paris Descartes University, Paris
  35. 35Batiment B Purpan Hospital, Toulouse
  36. 36Paris Descartes University, Paris, France


Background Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis and composed of two subtypes, limited and diffuse cutaneous forms. Previous genetic studies including genome-wide association studies (GWAS) have identified 12 susceptibility loci satisfying genome-wide significance.

Objectives To expand the list of susceptibility genes and deepen biological insights for SSc.

Methods We performed trans-ethnic meta-analysis of GWAS in the Japanese and European populations, followed by a two-staged replication study comprising a total of 4,436 cases and 14,751 controls. Associations between significant single nuclear polymorphisms (SNPs) and neighboring 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 with immune functions and associated with other autoimmune diseases (p=1.4x10-10 and 6.6x10-10, 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 neighboring genes, and this could explain the association in this locus. We found different HLA association patterns between the two populations or two subtypes. 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.

Disclosure of Interest None declared

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