Qin Song1, Yao Lei2,3, Li Shao1, Weiyang Li2, Qingsheng Kong2, Zhiming Lin4, Xiao Qin2, Wei Wei2, Fei Hou2, Jian Li1, Xianghua Guo1, Yujing Mao1, Yujie Cao3, Zhongyi Liu3, Lichuan Zheng3, Rui Liang3, Yuping Jiang1, Yan Liu1, Lili Zhang1, Jing Yang3, Yu Lung Lau3, Yan Zhang5, Bo Ban6,7, Yong-Fei Wang3,8, Wanling Yang3. 1. Department of Rheumatology, Lupus Research Institute, Affiliated Hospital, Jining Medical University, Shandong, China. 2. Collaborative Innovation Center for Birth Defect Research and Transformation of Shandong Province, Jining Medical University, Shandong, China. 3. Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. 4. Department of Rheumatology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China. 5. Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China. 6. Department of Endocrinology, Affiliated Hospital of Jining Medical University, Jining Medical University, Shandong, China. 7. Chinese Research Center for Behavior Medicine in Growth and Development, Shandong, China. 8. Shenzhen Futian hospital for rheumatic diseases, Shenzhen, China.
Abstract
OBJECTIVES: To identify novel genetic loci associated with systemic lupus erythematosus (SLE) and to evaluate potential genetic differences between ethnic Chinese and European populations in SLE susceptibility. METHODS: A new genome-wide association study (GWAS) was conducted from Jining, North China, on 1,506 individuals (512 SLE cases and 994 matched healthy controls). The association results were meta-analyzed with existing data on Chinese populations from Hong Kong, Guangzhou and Central China, as well as GWAS results from four cohorts of European ancestry. A total of 26 774 individuals (9,310 SLE cases and 17 464 controls) were included in this study. RESULTS: Meta-analysis on four Chinese cohorts identifies KLF2 as a novel locus associated with SLE (rs2362475;OR = 0.85, P = 2.00E-09). KLF2 is likely an Asian-specific locus as no evidence of association was detected in the four European cohorts (OR = 0.98, p = 0.58), with evidence of heterogeneity (p = 0.0019) between the two ancestral groups. Meta-analyses of results from both Chinese and Europeans identify STAB2 (rs10082873; OR = 0.89, P = 4.08E-08) and DOT1L (rs4807205; OR = 1.12, P = 8.17E-09) as trans-ancestral association loci, surpassing the genome-wide significance. CONCLUSIONS: We identified three loci associated with SLE, with KLF2 a likely Chinese-specific locus, highlighting the importance of studying diverse populations in SLE genetics. We hypothesize that DOT1L and KLF2 are plausible SLE treatment targets, with inhibitors of DOT1L and inducers of KLF2 already available clinically.
OBJECTIVES: To identify novel genetic loci associated with systemic lupus erythematosus (SLE) and to evaluate potential genetic differences between ethnic Chinese and European populations in SLE susceptibility. METHODS: A new genome-wide association study (GWAS) was conducted from Jining, North China, on 1,506 individuals (512 SLE cases and 994 matched healthy controls). The association results were meta-analyzed with existing data on Chinese populations from Hong Kong, Guangzhou and Central China, as well as GWAS results from four cohorts of European ancestry. A total of 26 774 individuals (9,310 SLE cases and 17 464 controls) were included in this study. RESULTS: Meta-analysis on four Chinese cohorts identifies KLF2 as a novel locus associated with SLE (rs2362475;OR = 0.85, P = 2.00E-09). KLF2 is likely an Asian-specific locus as no evidence of association was detected in the four European cohorts (OR = 0.98, p = 0.58), with evidence of heterogeneity (p = 0.0019) between the two ancestral groups. Meta-analyses of results from both Chinese and Europeans identify STAB2 (rs10082873; OR = 0.89, P = 4.08E-08) and DOT1L (rs4807205; OR = 1.12, P = 8.17E-09) as trans-ancestral association loci, surpassing the genome-wide significance. CONCLUSIONS: We identified three loci associated with SLE, with KLF2 a likely Chinese-specific locus, highlighting the importance of studying diverse populations in SLE genetics. We hypothesize that DOT1L and KLF2 are plausible SLE treatment targets, with inhibitors of DOT1L and inducers of KLF2 already available clinically.