Leilei Wen 1,2 , Caihong Zhu 2 , Zhengwei Zhu 2 , Chao Yang 1,2 , Xiaodong Zheng 2 , Lu Liu 1,2 , Xianbo Zuo 2 , Yujun Sheng 2 , Huayang Tang 2 , Bo Liang 2 , Yi Zhou 2 , Pan Li 2 , Jun Zhu 2 , Yantao Ding 2 , Gang Chen 2 , Jinping Gao 2 , Lili Tang 1,2 , Yuyan Cheng 1,2 , Jingying Sun 1,2 , Tamilselvi Elango 2 , Anjana Kafle 2 , Ruixing Yu 3 , Ke Xue 3 , Yaohua Zhang 1 , Feng Li 1 , Zhanguo Li 4 , Jianping Guo 4 , Xuan Zhang 5 , Chen Zhou 5 , Yuanjia Tang 6 , Nan Shen 6 , Meng Wang 7 , Xueqing Yu 7 , Shengxiu Liu 2 , Xing Fan 2 , Min Gao 2 , Fengli Xiao 2 , Peiguang Wang 2 , Zaixing Wang 2 , Anping Zhang 2 , Fusheng Zhou 2 , Liangdan Sun 2 , Sen Yang 2 , Jinhua Xu 1 , Xianyong Yin 1,2,8 , Yong Cui 3 , Xuejun Zhang 1,2,3 Show Affiliations »
Abstract
OBJECTIVES: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of considerable genetic predisposition. Genome-wide association studies have identified tens of common variants for SLE. However, the majority of them reside in non-coding sequences. The contributions of coding variants have not yet been systematically evaluated. METHODS: We performed a large-scale exome-wide study in 5004 SLE cases and 8179 healthy controls in a Han Chinese population using a custom exome array, and then genotyped 32 variants with suggestive evidence in an independent cohort of 13 246 samples. We further explored the regulatory effect of one novel non-coding single nucleotide polymorphism (SNP) in ex vivo experiments. RESULTS: We discovered four novel SLE gene regions (LCT, TPCN2, AHNAK2 and TNFRSF13B) encompassing three novel missense variants (XP_016859577.1:p.Asn1639Ser, XP_016859577.1:p.Val219Phe and XP_005267356.1:p.Thr4664Ala) and two non-coding variants (rs10750836 and rs4792801) with genome-wide significance (pmeta <5.00×10-8). These variants are enriched in several chromatin states of primary B cells. The novel intergenic variant rs10750836 exhibited an expression quantitative trait locus effect on the TPCN2 gene in immune cells. Clones containing this novel SNP exhibited gene promoter activity for TPCN2 (P=1.38×10-3) whose expression level was reduced significantly in patients with SLE (P<2.53×10-2) and was suggested to be further modulated by rs10750836 in CD19+ B cells (P=7.57×10-5) in ex vivo experiments. CONCLUSIONS: This study identified three novel coding variants and four new susceptibility gene regions for SLE. The results provide insights into the biological mechanism of SLE. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
OBJECTIVES: Systemic lupus erythematosus (SLE ) is a chronic autoimmune disease of considerable genetic predisposition. Genome-wide association studies have identified tens of common variants for SLE . However, the majority of them reside in non-coding sequences. The contributions of coding variants have not yet been systematically evaluated. METHODS: We performed a large-scale exome-wide study in 5004 SLE cases and 8179 healthy controls in a Han Chinese population using a custom exome array, and then genotyped 32 variants with suggestive evidence in an independent cohort of 13 246 samples. We further explored the regulatory effect of one novel non-coding single nucleotide polymorphism (SNP) in ex vivo experiments. RESULTS: We discovered four novel SLE gene regions (LCT, TPCN2 , AHNAK2 and TNFRSF13B ) encompassing three novel missense variants (XP_016859577.1:p.Asn1639Ser , XP_016859577.1:p.Val219Phe and XP_005267356.1:p.Thr4664Ala ) and two non-coding variants (rs10750836 and rs4792801 ) with genome-wide significance (pmeta <5.00×10-8). These variants are enriched in several chromatin states of primary B cells. The novel intergenic variant rs10750836 exhibited an expression quantitative trait locus effect on the TPCN2 gene in immune cells. Clones containing this novel SNP exhibited gene promoter activity for TPCN2 (P=1.38×10-3) whose expression level was reduced significantly in patients with SLE (P<2.53×10-2) and was suggested to be further modulated by rs10750836 in CD19+ B cells (P=7.57×10-5) in ex vivo experiments. CONCLUSIONS: This study identified three novel coding variants and four new susceptibility gene regions for SLE . The results provide insights into the biological mechanism of SLE . © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
Entities: Disease
Gene
Mutation
Species
Keywords:
autoimmune diseases; gene polymorphism; systemic lupus erythematosus
Mesh： See more »
Year: 2017
PMID： 29233832 DOI： 10.1136/annrheumdis-2017-211823
Source DB: PubMed Journal: Ann Rheum Dis ISSN： 0003-4967 Impact factor: 19.103