AJHG：全基因组关联Meta分析搜寻系统性红斑狼疮易感基因

12月27日，国际著名学术期刊《美国人类遗传学杂志》在线发表了由安徽医科大学张学军教授团队和香港大学刘宇隆教授团队合作完成的研究成果――全基因组关联Meta分析搜寻系统性红斑狼疮易感基因。这是亚洲地区第一项系统性红斑狼疮全基因组关联meta分析的研究成果，为红斑狼疮的预警、临床诊断、发病机制研究及新药研发提供了新的理论依据。

系统性红斑狼疮是一种复杂的自身免疫性疾病，好发于女性，特别是育龄期妇女，可累及全身各个系统和脏器，最终诱发肾衰竭、狼疮性脑病和严重继发感染，甚至可危及生命导致患者死亡，严重危害人类健康。其病因和发病机制尚未明确，多认为与遗传、免疫异常及环境等因素有关。据估计，目前我国红斑狼疮患者 约100多万。

合作双方曾在中国大陆和中国香港汉族人群中分别开展系统性红斑狼疮全基因组关联研究，基于前期研究基础，为进一步发现疾病的易感基因，深入揭示疾病的遗传学发病机制，此次双方合作研究利用两个团队各自拥有的红斑狼疮全基因组关联分析数据进行Meta分析，并在中国大陆、中国香港、中国台湾、泰国曼谷4个亚洲汉族人群中进行大样本验证，发现了5个与系统性红斑狼疮相关的易感基因CDKN1B、TET3、CD80、DRAM1和ARID5B，揭示了细胞周期调节、吞噬及DNA甲基化等机制在红斑狼疮发病中具有重要的作用。该研究不仅发现了红斑狼疮发病机制中的遗传危险因素在不同人种间具有遗传异质性，而且揭示了疾病新的发病通路，为揭示疾病病因和发病机制研究提供了新的科学依据。

据悉，2007年以来，安徽医科大学皮肤病遗传学研究团队利用建立的国际先进水平疾病基因组学研究平台和独特的疾病基因组学研究技术和方法，先后在《自然——遗传》和《新英格兰医学杂志》上陆续发表了银屑病、红斑狼疮、白癜风、异位性皮炎和麻风易感基因的全基因组关联分析系列研究成果以及全基因组外显子测序分析发现汗孔角化症致病基因，并先后获得2010年度中国科学十大进展和2012年度中国高等学校科技十大进展。(生物谷Bioon.com)

doi:10.1016/j.ajhg.2012.11.018
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Meta-Analysis Followed by Replication Identifies Loci in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as Associated with Systemic Lupus Erythematosus in Asians

Wanling Yang1, 29, Huayang Tang2, 29, Yan Zhang1, 29, Xianfa Tang2, 29, Jing Zhang1, 29, Liangdan Sun2, Jing Yang1, Yong Cui2, Lu Zhang1, Nattiya Hirankarn3, Hui Cheng2, Hai-Feng Pan4, Jinping Gao2, Tsz Leung Lee1, Yujun Sheng2, Chak Sing Lau6, Yang Li2, Tak Mao Chan6, Xianyong Yin2, Dingge Ying1, Qianjin Lu7, Alexander Moon Ho Leung10, Xianbo Zuo2, Xiang Chen11, Kwok Lung Tong12, Fusheng Zhou2, Qingchun Diao13, Niko Kei Chiu Tse14, Hongfu Xie11, Chi Chiu Mok5, Fei Hao15, Sik Nin Wong9, Bingjun Shi13, Ka Wing Lee8, Yan Hui16, Marco Hok Kung Ho1, Bo Liang2, Pamela Pui Wah Lee1, Hongzhou Cui2, Qing Guo17, Brian Hon-Yin Chung1, Xiongming Pu18, Qiji Liu19, Xiaoguang Zhang2, Change Zhang2, Chun Yin Chong1, Hong Fang20, Raymond Woon Sing Wong6, Yonghu Sun2, Mo Yin Mok6, Xiang-Pei Li21, Yingyos Avihingsanon22, Zhifang Zhai15, Pornpimol Rianthavorn23, Thavatchai Deekajorndej23, Kanya Suphapeetiporn23, 24, Fei Gao7, Vorasuk Shotelersuk23, 24, Xiaojing Kang18, Shirley King Yee Ying12, Lijuan Zhang16, Wilfred Hing Sang Wong1, Dingxian Zhu20, Samuel Ka Shun Fung12, Fanqin Zeng17, Wai Ming Lai14, Chun-Ming Wong25, Irene Oi Lin Ng25, Maria-Mercè Garcia-Barceló26, Stacey S. Cherny27, Nan Shen28, Paul Kwong-Hang Tam26, Pak Chung Sham27, Dong-Qing Ye4, Sen Yang2, Xuejun Zhang2, , and Yu Lung Lau1, ,

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic involvement and ethnic differences. Susceptibility genes identified so far only explain a small portion of the genetic heritability of SLE, suggesting that many more loci are yet to be uncovered for this disease. In this study, we performed a meta-analysis of genome-wide association studies on SLE in Chinese Han populations and followed up the findings by replication in four additional Asian cohorts with a total of 5,365 cases and 10,054 corresponding controls. We identified genetic variants in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with the disease. These findings point to potential roles of cell-cycle regulation, autophagy, and DNA demethylation in SLE pathogenesis. For the region involving TET3 and that involving CDKN1B, multiple independent SNPs were identified, highlighting a phenomenon that might partially explain the missing heritability of complex diseases.

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