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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

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... Full description

Journal Title: BioRxiv Aug 27, 2018
Main Author: Guo, Jianping
Other Authors: Zhang, Tao , Cao, Hongzhi , Li, Xiaowei , Liang, Hao , Liu, Mengru , Zou, Yundong , Zhang, Yuanwei , Sun, Xiaolin , Hu, Fanlei , Du, Yan , Mo, Xiaodong , Liu, Xu , Yang, Yue , Yang, Huanjie , Wu, Xinyu , Zhang, Xuewu , Jia, Huijue , Jiang, Hui , Hou, Yong , Liu, Xin , Yin, Su , Zhang, Mingrong , Yang, Huanming , Wang, Jian , Sun, Liangdan , Liu, Liang , Padyukov, Leonid , Lai, Luhua , Yamamoto, Kazuhiko , Zhang, Xuejun , Klareskog, Lars , Xu, Xun , Li, Zhanguo
Format: Electronic Article Electronic Article
Language: English
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ID: DOI: 10.1101/400937
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title: 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
format: Article
creator:
  • Guo, Jianping
  • Zhang, Tao
  • Cao, Hongzhi
  • Li, Xiaowei
  • Liang, Hao
  • Liu, Mengru
  • Zou, Yundong
  • Zhang, Yuanwei
  • Sun, Xiaolin
  • Hu, Fanlei
  • Du, Yan
  • Mo, Xiaodong
  • Liu, Xu
  • Yang, Yue
  • Yang, Huanjie
  • Wu, Xinyu
  • Zhang, Xuewu
  • Jia, Huijue
  • Jiang, Hui
  • Hou, Yong
  • Liu, Xin
  • Yin, Su
  • Zhang, Mingrong
  • Yang, Huanming
  • Wang, Jian
  • Sun, Liangdan
  • Liu, Liang
  • Padyukov, Leonid
  • Lai, Luhua
  • Yamamoto, Kazuhiko
  • Zhang, Xuejun
  • Klareskog, Lars
  • Xu, Xun
  • Li, Zhanguo
subjects:
  • Rheumatoid Arthritis
  • Health Risk Assessment
ispartof: BioRxiv, Aug 27, 2018
description: 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.
language: eng
source: © ProQuest LLC All rights reserved
identifier: DOI: 10.1101/400937
fulltext: fulltext_linktorsrc
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titleSequencing of the MHC region defines HLA-DQA1 as the major independent risk for anti-citrullinated protein antibodies (ACPA)-positive rheumatoid arthritis in Han population
creatorGuo, Jianping ; Zhang, Tao ; Cao, Hongzhi ; Li, Xiaowei ; Liang, Hao ; Liu, Mengru ; Zou, Yundong ; Zhang, Yuanwei ; Sun, Xiaolin ; Hu, Fanlei ; Du, Yan ; Mo, Xiaodong ; Liu, Xu ; Yang, Yue ; Yang, Huanjie ; Wu, Xinyu ; Zhang, Xuewu ; Jia, Huijue ; Jiang, Hui ; Hou, Yong ; Liu, Xin ; Yin, Su ; Zhang, Mingrong ; Yang, Huanming ; Wang, Jian ; Sun, Liangdan ; Liu, Liang ; Padyukov, Leonid ; Lai, Luhua ; Yamamoto, Kazuhiko ; Zhang, Xuejun ; Klareskog, Lars ; Xu, Xun ; Li, Zhanguo
contributorLi, Zhanguo (pacrepositoryorg)
ispartofBioRxiv, Aug 27, 2018
identifierDOI: 10.1101/400937
subjectRheumatoid Arthritis ; Health Risk Assessment
descriptionThe 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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titleSequencing of the MHC region defines HLA-DQA1 as the major independent risk for anti-citrullinated protein antibodies (ACPA)-positive rheumatoid arthritis in Han population
descriptionThe 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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titleSequencing of the MHC region defines HLA-DQA1 as the major independent risk for anti-citrullinated protein antibodies (ACPA)-positive rheumatoid arthritis in Han population
authorGuo, Jianping ; Zhang, Tao ; Cao, Hongzhi ; Li, Xiaowei ; Liang, Hao ; Liu, Mengru ; Zou, Yundong ; Zhang, Yuanwei ; Sun, Xiaolin ; Hu, Fanlei ; Du, Yan ; Mo, Xiaodong ; Liu, Xu ; Yang, Yue ; Yang, Huanjie ; Wu, Xinyu ; Zhang, Xuewu ; Jia, Huijue ; Jiang, Hui ; Hou, Yong ; Liu, Xin ; Yin, Su ; Zhang, Mingrong ; Yang, Huanming ; Wang, Jian ; Sun, Liangdan ; Liu, Liang ; Padyukov, Leonid ; Lai, Luhua ; Yamamoto, Kazuhiko ; Zhang, Xuejun ; Klareskog, Lars ; Xu, Xun ; Li, Zhanguo
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abstractThe 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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doi10.1101/400937
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date2018-08-27