Transethnic meta-analysis identifies GSDMA and PRDM1 as susceptibility genes to systemic sclerosis.
Transethnic meta-analysis identifies GSDMA and PRDM1 as susceptibility genes to systemic sclerosis.
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DOI：
10.1136/annrheumdis-2016-210645
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发表时间：
2017-06
影响因子：
27.4
通讯作者：
Allanore Y
中科院分区：
文献类型：
--
作者：
Terao C;Kawaguchi T;Dieude P;Varga J;Kuwana M;Hudson M;Kawaguchi Y;Matucci-Cerinic M;Ohmura K;Riemekasten G;Kawasaki A;Airo P;Horita T;Oka A;Hachulla E;Yoshifuji H;Caramaschi P;Hunzelmann N;Baron M;Atsumi T;Hassoun P;Torii T;Takahashi M;Tabara Y;Shimizu M;Tochimoto A;Ayuzawa N;Yanagida H;Furukawa H;Tohma S;Hasegawa M;Fujimoto M;Ishikawa O;Yamamoto T;Goto D;Asano Y;Jinnin M;Endo H;Takahashi H;Takehara K;Sato S;Ihn H;Raychaudhuri S;Liao K;Gregersen P;Tsuchiya N;Riccieri V;Melchers I;Valentini G;Cauvet A;Martinez M;Mimori T;Matsuda F;Allanore Y
系统性硬化症（SSc）是一种自身免疫性疾病，其特征是皮肤和系统性纤维化，最终导致器官损伤。包括全基因组关联研究（GWAS）在内的遗传学研究已经确定了12个满足全基因组显著性的易感基因座。跨种族荟萃分析成功地扩大了易感基因的名单，并加深了对其他自身免疫性疾病的生物学见解。我们对日本和欧洲人群的GWAS进行了跨种族荟萃分析，随后进行了一项两阶段重复研究，共包括4436例病例和14751例对照。显着的单核多态性（SNPs）和相邻基因之间的关联进行了评估。用扩展的SSc易感基因列表对活性启动子的代表性组蛋白标记H3 K4 Me 3进行富集分析。我们在两个基因座GSDMA和PRDM 1中发现了两个显著的SNP，这两个基因座都与免疫功能相关，并与其他自身免疫性疾病相关（p分别为1.4×10−10和6.6×10−10）。GSDMA也显示出与有限的皮肤SSc的显着关联。我们还复制了先前报道的基因座的关联，包括非GWAS基因座TNFAIP 3。PRDM 1编码BLIMP 1，一种调节T细胞增殖和浆细胞分化的转录因子。在GSDMA中，最高的SNP是一个错义变异，与邻近基因的基因表达相关，这可以解释该位点的关联。我们发现不同的人类白细胞抗原（HLA）的关联模式之间的两个群体。富集分析提示CD 4-naïve原代T细胞的重要性。GSDMA和PRDM 1与SSc相关联。这些发现为SSc的遗传和生物学基础提供了更深入的了解。
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. 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. 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. GSDMA and PRDM1 are associated with SSc. These findings provide enhanced insight into the genetic and biological basis of SSc.