强化荟萃分析和重复研究确定了五个新的银屑病易感基因座。
Enhanced meta-analysis and replication studies identify five new psoriasis susceptibility loci.
作者信息
Tsoi Lam C, Spain Sarah L, Ellinghaus Eva, Stuart Philip E, Capon Francesca, Knight Jo, Tejasvi Trilokraj, Kang Hyun M, Allen Michael H, Lambert Sylviane, Stoll Stefan W, Weidinger Stephan, Gudjonsson Johann E, Koks Sulev, Kingo Külli, Esko Tonu, Das Sayantan, Metspalu Andres, Weichenthal Michael, Enerback Charlotta, Krueger Gerald G, Voorhees John J, Chandran Vinod, Rosen Cheryl F, Rahman Proton, Gladman Dafna D, Reis Andre, Nair Rajan P, Franke Andre, Barker Jonathan N W N, Abecasis Goncalo R, Trembath Richard C, Elder James T
机构信息
Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
Division of Genetics and Molecular Medicine, King's College London, London WC2R 2LS, UK.
出版信息
Nat Commun. 2015 May 5;6:7001. doi: 10.1038/ncomms8001.
Psoriasis is a chronic autoimmune disease with complex genetic architecture. Previous genome-wide association studies (GWAS) and a recent meta-analysis using Immunochip data have uncovered 36 susceptibility loci. Here, we extend our previous meta-analysis of European ancestry by refined genotype calling and imputation and by the addition of 5,033 cases and 5,707 controls. The combined analysis, consisting of over 15,000 cases and 27,000 controls, identifies five new psoriasis susceptibility loci at genome-wide significance (P<5 × 10(-8)). The newly identified signals include two that reside in intergenic regions (1q31.1 and 5p13.1) and three residing near PLCL2 (3p24.3), NFKBIZ (3q12.3) and CAMK2G (10q22.2). We further demonstrate that NFKBIZ is a TRAF3IP2-dependent target of IL-17 signalling in human skin keratinocytes, thereby functionally linking two strong candidate genes. These results further integrate the genetics and immunology of psoriasis, suggesting new avenues for functional analysis and improved therapies.
银屑病是一种具有复杂遗传结构的慢性自身免疫性疾病。以往的全基因组关联研究（GWAS）以及最近一项使用免疫芯片数据的荟萃分析已经发现了36个易感位点。在此，我们通过优化基因型分型和填充以及增加5033例病例和5707例对照，扩展了我们之前对欧洲血统人群的荟萃分析。由超过15000例病例和27000例对照组成的联合分析在全基因组显著性水平（P<5×10⁻⁸）下鉴定出五个新的银屑病易感位点。新发现的信号包括两个位于基因间区域的位点（1q31.1和5p13.1）以及三个位于PLCL2（3p24.3）、NFKBIZ（3q12.3）和CAMK2G（10q22.2）附近的位点。我们进一步证明，在人皮肤角质形成细胞中，NFKBIZ是IL-17信号通路依赖TRAF3IP2的靶点，从而在功能上连接了两个强有力的候选基因。这些结果进一步整合了银屑病的遗传学和免疫学，为功能分析和改进治疗方法指明了新的方向。
Zotero 插件