The amino acid variants in HLA II molecules explain the major association with adult-onset Still's disease in the Han Chinese population
Jialin Teng, Xia Chen, Jianhua Chen, Ting Zeng, Lin He, Meihang Li, Cainan Luo, Shuang Liu, Tingting Ding, Kuerbanjiang Yimaiti, Xingwang Li, Yonghe Ding, Xiaobing Cheng, Juan Zhou, Junna Ye, Jue Ji, Yutong Su, Hui Shi, Yue Sun, Chengwen Gao, Qiongyi Hu, Huihui Chi, Xuan Yuan, Zhuochao Zhou, Dong Wang, Ke Wang, Feng Dong, Changgui Li, Yuanchao Sun, Yujuan Niu, Xiaolei Xu, Linjie Chen, Jian Xu, Lijun Wu, Zhaowei Zhou, Dun Pan, Haitao Niu, Chengde Yang, Yongyong Shi, Zhiqiang Li, Hong-lei Liu
Abstract
Adult-onset Still's disease (AOSD) is a rare autoinflammatory disease with systemic involvement, and its pathophysiology remains unclear. Genome-wide association studies (GWAS) in the Chinese population have revealed an association between AOSD and the major histocompatibility complex (MHC) locus; however, causal variants in the MHC remain undetermined. In the present study, we identified independent amino-acid polymorphisms in human leukocyte antigen (HLA) molecules that are associated with Han Chinese patients with AOSD by fine-mapping the MHC locus. Through conditional analyses, we identified position 34 in HLA-DQα1 (p = 1.44 × 10−14) and Asn in HLA-DRβ1 position 37 (p = 5.12 × 10−11) as the major determinants for AOSD. Moreover, we identified the associations for three main HLA class II alleles: HLA-DQB1*06:02 (OR = 2.70, p = 3.02 × 10−14), HLA-DRB1*15:01 (OR = 2.44, p = 3.66 × 10−13), and HLA-DQA1*01:02 (OR = 1.97, p = 1.09 × 10−9). This study reveals the relationship between functional variations in the class II HLA region and AOSD, implicating the MHC locus in the pathogenesis of AOSD.