TY - JOUR T1 - Transethnic meta-analysis identifies <em>GSDMA</em> and <em>PRDM1</em> as susceptibility genes to systemic sclerosis JF - Annals of the Rheumatic Diseases JO - Ann Rheum Dis SP - 1150 LP - 1158 DO - 10.1136/annrheumdis-2016-210645 VL - 76 IS - 6 AU - Chikashi Terao AU - Takahisa Kawaguchi AU - Philippe Dieude AU - John Varga AU - Masataka Kuwana AU - Marie Hudson AU - Yasushi Kawaguchi AU - Marco Matucci-Cerinic AU - Koichiro Ohmura AU - Gabriela Riemekasten AU - Aya Kawasaki AU - Paolo Airo AU - Tetsuya Horita AU - Akira Oka AU - Eric Hachulla AU - Hajime Yoshifuji AU - Paola Caramaschi AU - Nicolas Hunzelmann AU - Murray Baron AU - Tatsuya Atsumi AU - Paul Hassoun AU - Takeshi Torii AU - Meiko Takahashi AU - Yasuharu Tabara AU - Masakazu Shimizu AU - Akiko Tochimoto AU - Naho Ayuzawa AU - Hidetoshi Yanagida AU - Hiroshi Furukawa AU - Shigeto Tohma AU - Minoru Hasegawa AU - Manabu Fujimoto AU - Osamu Ishikawa AU - Toshiyuki Yamamoto AU - Daisuke Goto AU - Yoshihide Asano AU - Masatoshi Jinnin AU - Hirahito Endo AU - Hiroki Takahashi AU - Kazuhiko Takehara AU - Shinichi Sato AU - Hironobu Ihn AU - Soumya Raychaudhuri AU - Katherine Liao AU - Peter Gregersen AU - Naoyuki Tsuchiya AU - Valeria Riccieri AU - Inga Melchers AU - Gabriele Valentini AU - Anne Cauvet AU - Maria Martinez AU - Tsuneyo Mimori AU - Fumihiko Matsuda AU - Yannick Allanore Y1 - 2017/06/01 UR - http://ard.bmj.com/content/76/6/1150.abstract N2 - 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. ER -