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Sequencing of the MHC region defines HLA-DQA1 as the major genetic risk for seropositive rheumatoid arthritis in Han Chinese population 期刊论文

编号：

8026c655-3e91-459e-8409-ea9026105df2
作者：

Guo, Jianping^[1,2];Zhang, Tao^[3,4];Cao, Hongzhi^[3,5,6];Li, Xiaowei^[3,4];Liang, Hao^[7,8];Liu, Mengru^[1];Zou, Yundong^[1];Zhang, Yuanwei^[3,4];Wang, Yuxuan^[1];Sun, Xiaolin^[1,2];Hu, Fanlei^[1,2];Du, Yan^[1];Mo, Xiaodong^[3,4];Liu, Xu^[1];Yang, Yue^[1];Yang, Huanjie^[3,4];Wu, Xinyu^[1];Zhang, Xuewu^[1];Jia, Huijue^[3,4];Jiang, Hui^[3,4];Hou, Yong^[3,4];Liu, Xin^[3,4];Su, Yin^[1,2];Zhang, Mingrong^[3,4];Yang, Huanming^[3,9];Wang, Jian^[3,9];Sun, Liangdan^[10,11];Liu, Liang^[12];Padyukov, Leonid^[13];Lai, Luhua^[7,8];Yamamoto, Kazuhiko^[14];Zhang, Xuejun(张学军)^{[10,11,15,16]}Klareskog, Lars^[13];Xu, Xun^[3,4];Li, Zhanguo^[1,2,17,18];
语种：

英文
期刊：

ANNALS OF THE RHEUMATIC DISEASES ISSN：0003-4967 2019 年 78 卷 6 期 (773 - 780) ; JUN
收录：
摘要：

Objective The strong genetic contribution of the major histocompatibility complex (MHC) region to rheumatoid arthritis (RA) has been generally attributed to human leukocyte antigen (HLA)-DRB1. However, due to the high polymorphisms and linkage disequilibrium within MHC, it is difficult to define novel and/or independent genetic risks using conventional HLA genotyping or chip-based microarray technology. This study aimed to identify novel RA risk variants by performing deep sequencing for MHC.
Methods We first conducted target sequencing for the entire MHC region in 357 anticitrullinated protein antibodies (ACPA)-positive patients with RA and 1001 healthy controls, and then performed HLA typing in an independent case-control cohort consisting of 1415 samples for validation. All study subjects were Han Chinese. Genetic associations for RA susceptibility and severity were analysed. Comparative modelling was constructed to predict potential functions for the newly discovered RA association variants.
Results HLA-DQ alpha 1:160D conferred the strongest and independent susceptibility to ACPA-positive RA (p=6.16x10(-36), OR=2.29). DR beta 1:37N had an independent protective effect (p=5.81x10(-16), OR=0.49). As predicted by comparative modelling, the negatively charged DQ alpha 1:160D stabilises the dimer of dimers, thus may lead to an increased T cell activation. The negatively charged DR beta 1:37N encoding alleles preferentially bind with epitope P9 arginine, thus may result in a decreased RA susceptibility.
Conclusions We provide the first evidence that HLA-DQ alpha 1:160D, instead of HLA-DRB1*0405, is the strongest and independent genetic risk for ACPA-positive RA in Han Chinese. Our study also illustrates the value of deep sequencing for fine-mapping disease risk variants in the MHC region.
推荐引用方式
GB/T 7714：

Guo Jianping,Zhang Tao,Cao Hongzhi, et al. Sequencing of the MHC region defines HLA-DQA1 as the major genetic risk for seropositive rheumatoid arthritis in Han Chinese population [J].ANNALS OF THE RHEUMATIC DISEASES,2019,78(6):773-780.
APA：

Guo Jianping,Zhang Tao,Cao Hongzhi,Li Xiaowei,&Li Zhanguo.(2019).Sequencing of the MHC region defines HLA-DQA1 as the major genetic risk for seropositive rheumatoid arthritis in Han Chinese population .ANNALS OF THE RHEUMATIC DISEASES,78(6):773-780.
MLA：

Guo Jianping, et al. "Sequencing of the MHC region defines HLA-DQA1 as the major genetic risk for seropositive rheumatoid arthritis in Han Chinese population" .ANNALS OF THE RHEUMATIC DISEASES 78,6(2019):773-780.
入库时间：

2020/2/8 14:52:56
更新时间：

2020/2/8 14:52:56

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