PMID- 30936065 OWN - NLM STAT- MEDLINE DCOM- 20200129 LR - 20221207 IS - 1468-2060 (Electronic) IS - 0003-4967 (Linking) VI - 78 IP - 6 DP - 2019 Jun TI - Sequencing of the MHC region defines HLA-DQA1 as the major genetic risk for seropositive rheumatoid arthritis in Han Chinese population. PG - 773-780 LID - 10.1136/annrheumdis-2018-214725 [doi] AB - 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-DQalpha1:160D conferred the strongest and independent susceptibility to ACPA-positive RA (p=6.16x10(-36), OR=2.29). DRbeta1:37N had an independent protective effect (p=5.81x10(-16), OR=0.49). As predicted by comparative modelling, the negatively charged DQalpha1:160D stabilises the dimer of dimers, thus may lead to an increased T cell activation. The negatively charged DRbeta1:37N encoding alleles preferentially bind with epitope P9 arginine, thus may result in a decreased RA susceptibility. CONCLUSIONS: We provide the first evidence that HLA-DQalpha1:160D, 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. CI - (c) Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ. FAU - Guo, Jianping AU - Guo J AUID- ORCID: 0000-0002-5031-3510 AD - Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China jianping.guo@bjmu.edu.cn ayzxj@vip.sina.com lars.klareskog@ki.se xuxun@genomics.cn zli99@bjmu.edu.cn. AD - Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China. FAU - Zhang, Tao AU - Zhang T AD - Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China. AD - China National GeneBank-Shenzhen, BGI-Shenzhen, Shenzhen, China. FAU - Cao, Hongzhi AU - Cao H AD - Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China. AD - Shenzhen Digital Life Institute, Shenzhen, China. AD - iCarbonX, Shenzhen, China. FAU - Li, Xiaowei AU - Li X AD - Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China. AD - China National GeneBank-Shenzhen, BGI-Shenzhen, Shenzhen, China. FAU - Liang, Hao AU - Liang H AD - BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Peking-Tsinghua Center for Life Sciences at College of Chemistry and Molecular Engineering, and Center for Quantitative Biology, Peking University, Beijing, China. FAU - Liu, Mengru AU - Liu M AD - Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China. FAU - Zou, Yundong AU - Zou Y AD - Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China. FAU - Zhang, Yuanwei AU - Zhang Y AD - Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China. AD - China National GeneBank-Shenzhen, BGI-Shenzhen, Shenzhen, China. FAU - Wang, Yuxuan AU - Wang Y AD - Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China. FAU - Sun, Xiaolin AU - Sun X AD - Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China. AD - Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China. FAU - Hu, Fanlei AU - Hu F AD - Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China. AD - Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China. FAU - Du, Yan AU - Du Y AD - Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China. FAU - Mo, Xiaodong AU - Mo X AD - Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China. AD - China National GeneBank-Shenzhen, BGI-Shenzhen, Shenzhen, China. FAU - Liu, Xu AU - Liu X AD - Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China. FAU - Yang, Yue AU - Yang Y AD - Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China. FAU - Yang, Huanjie AU - Yang H AD - Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China. AD - China National GeneBank-Shenzhen, BGI-Shenzhen, Shenzhen, China. FAU - Wu, Xinyu AU - Wu X AD - Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China. FAU - Zhang, Xuewu AU - Zhang X AD - Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China. FAU - Jia, Huijue AU - Jia H AD - Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China. AD - China National GeneBank-Shenzhen, BGI-Shenzhen, Shenzhen, China. FAU - Jiang, Hui AU - Jiang H AD - Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China. AD - China National GeneBank-Shenzhen, BGI-Shenzhen, Shenzhen, China. FAU - Hou, Yong AU - Hou Y AD - Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China. AD - China National GeneBank-Shenzhen, BGI-Shenzhen, Shenzhen, China. FAU - Liu, Xin AU - Liu X AD - Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China. AD - China National GeneBank-Shenzhen, BGI-Shenzhen, Shenzhen, China. FAU - Su, Yin AU - Su Y AD - Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China. AD - Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China. FAU - Zhang, Mingrong AU - Zhang M AD - Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China. AD - China National GeneBank-Shenzhen, BGI-Shenzhen, Shenzhen, China. FAU - Yang, Huanming AU - Yang H AD - Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China. AD - James D Watson Institute of Genome Sciences, Hangzhou, China. FAU - Wang, Jian AU - Wang J AD - Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China. AD - James D Watson Institute of Genome Sciences, Hangzhou, China. FAU - Sun, Liangdan AU - Sun L AD - Institute of Dermatology and Department of Dermatology, No 1 Hospital of Anhui Medical University, Hefei, China. FAU - Liu, Liang AU - Liu L AD - State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, China. FAU - Padyukov, Leonid AU - Padyukov L AD - Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. FAU - Lai, Luhua AU - Lai L AD - BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Peking-Tsinghua Center for Life Sciences at College of Chemistry and Molecular Engineering, and Center for Quantitative Biology, Peking University, Beijing, China. FAU - Yamamoto, Kazuhiko AU - Yamamoto K AUID- ORCID: 0000-0001-9037-3625 AD - Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. FAU - Zhang, Xuejun AU - Zhang X AD - Institute of Dermatology and Department of Dermatology, No 1 Hospital of Anhui Medical University, Hefei, China jianping.guo@bjmu.edu.cn ayzxj@vip.sina.com lars.klareskog@ki.se xuxun@genomics.cn zli99@bjmu.edu.cn. AD - Institute of Dermatology and Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China. FAU - Klareskog, Lars AU - Klareskog L AD - Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden jianping.guo@bjmu.edu.cn ayzxj@vip.sina.com lars.klareskog@ki.se xuxun@genomics.cn zli99@bjmu.edu.cn. FAU - Xu, Xun AU - Xu X AD - Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China jianping.guo@bjmu.edu.cn ayzxj@vip.sina.com lars.klareskog@ki.se xuxun@genomics.cn zli99@bjmu.edu.cn. AD - China National GeneBank-Shenzhen, BGI-Shenzhen, Shenzhen, China. FAU - Li, Zhanguo AU - Li Z AD - Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China jianping.guo@bjmu.edu.cn ayzxj@vip.sina.com lars.klareskog@ki.se xuxun@genomics.cn zli99@bjmu.edu.cn. AD - Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China. AD - Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China. AD - State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190401 PL - England TA - Ann Rheum Dis JT - Annals of the rheumatic diseases JID - 0372355 RN - 0 (Anti-Citrullinated Protein Antibodies) RN - 0 (HLA-DQ alpha-Chains) RN - 0 (HLA-DQA1 antigen) RN - 0 (HLA-DRB1 Chains) SB - IM CIN - Ann Rheum Dis. 2022 Mar;81(3):e38. PMID: 32024650 EIN - Ann Rheum Dis. 2020 Jun;79(6):e76. PMID: 32312771 CIN - Ann Rheum Dis. 2022 Mar;81(3):e39. PMID: 32371386 MH - Adult MH - Aged MH - Anti-Citrullinated Protein Antibodies/immunology MH - Arthritis, Rheumatoid/*genetics/immunology MH - Asian People/genetics MH - Case-Control Studies MH - Female MH - Genetic Predisposition to Disease MH - HLA-DQ alpha-Chains/*genetics MH - HLA-DRB1 Chains/genetics MH - High-Throughput Nucleotide Sequencing/methods MH - Histocompatibility Testing/methods MH - Humans MH - Lymphocyte Activation/genetics MH - Male MH - Middle Aged MH - T-Lymphocytes/immunology OTO - NOTNLM OT - ant-ccp OT - gene polymorphism OT - rheumatoid arthritis COIS- Competing interests: None declared. EDAT- 2019/04/03 06:00 MHDA- 2020/01/30 06:00 CRDT- 2019/04/03 06:00 PHST- 2018/11/08 00:00 [received] PHST- 2019/03/06 00:00 [revised] PHST- 2019/03/09 00:00 [accepted] PHST- 2019/04/03 06:00 [pubmed] PHST- 2020/01/30 06:00 [medline] PHST- 2019/04/03 06:00 [entrez] AID - annrheumdis-2018-214725 [pii] AID - 10.1136/annrheumdis-2018-214725 [doi] PST - ppublish SO - Ann Rheum Dis. 2019 Jun;78(6):773-780. doi: 10.1136/annrheumdis-2018-214725. Epub 2019 Apr 1.