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Sequencing of the MHC region defines HLA-DQA1 as the major independent risk for anti-citrullinated protein antibodies (ACPA)-positive rheumatoid arthritis in Han population

By Jianping Guo, Tao Zhang, Hongzhi Cao, Xiaowei Li, Hao Liang, Mengru Liu, Yundong Zou, Yuanwei Zhang, Xiaolin Sun, Fanlei Hu, Yan Du, Xiaodong Mo, Xu Liu, Yue Yang, Huanjie Yang, Xinyu Wu, Xuewu Zhang, Huijue Jia, Hui Jiang, Yong Hou, Xin Liu, Yin Su, Mingrong Zhang, Huanming Yang, Jian Wang, Liangdan Sun, Liang Liu, Leonid Padyukov, Luhua Lai, Kazuhiko Yamamoto, Xuejun Zhang, Lars Klareskog, Xun Xu, Zhanguo Li

Posted 27 Aug 2018
bioRxiv DOI: 10.1101/400937

The strong genetic contribution of the major histocompatibility complex (MHC) to rheumatoid arthritis (RA) susceptibility has been generally attributed to HLA-DRB1. However, due to the high linkage disequilibrium in the MHC region, it is difficult to define the real or additional independent genetic risks using the conventional HLA genotyping or chip-based microarray technology. By the capture sequencing of entire MHC region for discovery and HLA-typing for validation in 2,773 subjects of Han ancestry, we identified HLA-DQα1:160D as the strongest independent genetic risk for anti-citrullinated protein antibodies (ACPA)-positive RA in Han population (P = 6.16 x 10-36, OR=2.29). Further stepwise conditional analysis revealed that DRβ1:37N has an independent protective effect on ACPA-positive RA (P=5.81 x 10-16, OR=0.49). The DQα1:160 coding allele DQA1*0303 displayed high impact on joint radiographic severity, especially in patients with early disease and smoking (P = 3.02 x 10-5). Interaction analysis by comparative molecular modeling revealed that the negative charge of DQα1:160D stabilizes the dimer of dimers, leading to an increased T cell activation. The electrostatic potential surface analysis indicated that the negative charged DRβ1:37N encoding alleles could bind with epitope P9 arginine, thus may result in a decreased RA susceptibility. In this study, we provide the first evidence that HLA-DQA1, instead of HLA-DRB1, is the strongest and independent genetic risk for ACPA-positive RA in Chinese Han population. Our study also illustrates the value of MHC deep sequencing for fine mapping disease risk variants in the MHC region.

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