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 Yang, Huayang Tang, Yan Zhang, Xianfa Tang, Jing Zhang, Liangdan Sun, Jing Yang, Yong Cui, Lu Zhang, Nattiya Hirankarn, Hui Cheng, Hai-Feng Pan, Jinping Gao, Tsz Leung Lee, Yujun Sheng, Chak Sing Lau, Yang Li, Tak Mao Chan, Xianyong Yin, Dingge Ying, Qianjin Lu, Alexander Moon Ho Leung, Xianbo Zuo, Xiang Chen, Kwok Lung Tong, Fusheng Zhou, Qingchun Diao, Niko Kei Chiu Tse, Hongfu Xie, Chi Chiu Mok, Fei Hao, Sik Nin Wong, Bingjun Shi, Ka Wing Lee, Yan Hui, Marco Hok Kung Ho, Bo Liang, Pamela Pui Wah Lee, Hongzhou Cui, Qing Guo, Brian Hon-Yin Chung, Xiongming Pu, Qiji Liu, Xiaoguang Zhang, Change Zhang, Chun Yin Chong, Hong Fang, Raymond Woon Sing Wong, Yonghu Sun, Mo Yin Mok, Xiang-Pei Li, Yingyos Avihingsanon, Zhifang Zhai, Pornpimol Rianthavorn, Thavatchai Deekajorndej, Kanya Suphapeetiporn, Fei Gao, Vorasuk Shotelersuk, Xiaojing Kang, Shirley King Yee Ying, Lijuan Zhang, Wilfred Hing Sang Wong, Dingxian Zhu, Samuel Ka Shun Fung, Fanqin Zeng, Wai Ming Lai, Chun- Ming Wong, Irene Oi Lin Ng, Maria-Mercè Garcia-Barceló, Stacey S. Cherny, Nan Shen, Paul Kwong-Hang Tam, Pak Chung Sham, Dong-Qing Ye, Sen Yang, Xuejun Zhang, Yu Lung Lau  The American Journal of Human Genetics  Volume 92, Issue 1, Pages 41-51 (January 2013) DOI: 10.1016/j.ajhg.2012.11.018 Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 1 Flow Chart of the Experimental Process and SNP Selection Criteria The American Journal of Human Genetics 2013 92, 41-51DOI: (10.1016/j.ajhg.2012.11.018) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 2 Manhattan Plot on the Meta-analysis Results of the Two SLE GWASs on Two Chinese Populations in Hong Kong and Anhui, China Known susceptibility genes are labeled in black, and genes identified in this study are labeled in red. The y axis is the −log10(pmeta) for the autosomal SNPs from the two GWASs. The American Journal of Human Genetics 2013 92, 41-51DOI: (10.1016/j.ajhg.2012.11.018) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 3 Association with SLE across the Five Regions (A–E) Regional association plots show association from meta-analysis (−log10(pmeta)) versus chromosomal position (kb) for all the SNPs in a 500 kb region centered on the newly validated SNP. pmeta values are plotted for all SNPs, shaded white to red by the degree of LD (r2; see insets) with the validated SNP in the respective region (A, rs10845606; B, rs4852234; C, 4948496; D, rs6804441; and E, rs4622329). Local recombination rates (cM/Mb, blue lines) estimated from HapMap CHB and JPT samples are plotted against the secondary y axis, showing recombination hotspots across the region and haplotype blocks in between. Genes in the respective regions are labeled below the plots. Chromosomal regions are as follows: (A) 12p13, (B) 2p13, (C) 10q21, (D) 3q13, and (E) 12q23. The American Journal of Human Genetics 2013 92, 41-51DOI: (10.1016/j.ajhg.2012.11.018) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 4 Forest Plot of Odds Ratios for the SNPs Surpassing Genome-wide Significance of 5 × 10−8 by Joint Analysis The bars are 95% confidence intervals of odds ratios (ORs). The American Journal of Human Genetics 2013 92, 41-51DOI: (10.1016/j.ajhg.2012.11.018) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 5 Potential Roles of the Identified Susceptibility Genes in SLE Etiology Genes labeled in red are the ones identified in this study. Environmental triggers such as UV irradiation cause damage to cells. In affected individuals, genetic variants in DRAM1, ATG5, and CDKN1B (encoding p27kip1) might lead to defects in apoptosis or autophagy and thus increase exposure of nuclear autoantigens to the immune system. Interaction between CD28 and CD80 or CD86 plays a vital role in T cell activation. Upon T cell activation, p27kip1 is phosphorylated and the CDK-cyclin complex is released, allowing cell-cycle progression. Upregulation of p27kip1 is essential for induction of tolerance. p27kip1 also plays a role in dendritic cell apoptosis. Activated autoreactive Th2 cells interact with B cells and induce B cell differentiation and production of autoantibodies. Autoreactive Th1 and Th17 cells can exacerbate this process by secreting proinflammatory cytokines and chemokines, enhancing immune-complex deposition and end-organ damage. Susceptibility genes such as CREBL2, ARID5B, and TET3 are involved in DNA and histone modification and might regulate expression of genes in T and B lymphocytes involved in autoimmunity. The American Journal of Human Genetics 2013 92, 41-51DOI: (10.1016/j.ajhg.2012.11.018) Copyright © 2013 The American Society of Human Genetics Terms and Conditions