MHC Class II Risk Alleles and Amino Acid Residues in Idiopathic   Membranous Nephropathy

doi:10.1681/ASN.2016020114

CORC > 北京大学 > 化学与分子工程学院

	MHC Class II Risk Alleles and Amino Acid Residues in Idiopathic Membranous Nephropathy
	Cui, Zhao ; Xie, Li-jun ; Chen, Fang-jin ; Pei, Zhi-yong ; Zhang, Li-jie ; Qu, Zhen ; Huang, Jing ; Gu, Qiu-hua ; Zhang, Yi-miao ; Wang, Xin ; Wang, Fang ; Meng, Li-qiang ; Liu, Gang ; Zhou, Xu-jie ; Zhu, Li ; Lv, Ji-cheng ; Liu, Fan ; Zhang, Hong ; Liao, Yun-hua ; Lai, Lu-hua ; Ronco, Pierre ; Zhao, Ming-hui
刊名	JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
	2017
关键词	MAJOR HISTOCOMPATIBILITY COMPLEX STRONG ASSOCIATION RECEPTOR PROTEIN SUSCEPTIBILITY IDENTIFICATION PEPTIDE EPITOPE A(2) GLOMERULONEPHRITIS
DOI	10.1681/ASN.2016020114
英文摘要	Epitopes of phospholipase A2 receptor (PLA2R), the target antigen in idiopathic membranous nephropathy (iMN), must be presented by the HLA encoded MHC class II molecules to stimulate autoantibody production. A genome wide association study identified risk alleles at HLA and PLA2R loci, with the top variant rs2187668 within HLA-DQA1 showing a risk effect greater than that of the top variant rs4664308 within PLA2R1. How the HLA risk alleles affect epitope presentation by MHC class II molecules in iMN is unknown. Here, we genotyped 261 patients with iMN and 599 healthy controls at the HLA-DRB1, HLA-DQA1, HLA-DQB1, and HLA-DPB1 loci with four-digit resolution and extracted the encoded amino acid sequences from the IMGT/HLA database. We predicted T cell epitopes of PLA2R and constructed MHC-DR molecule-PLA2R peptide-T cell receptor structures using Modeler. We identified DRB11501 (odds ratio, 4.65; 95% confidence interval [95% CI], 3.39 to 6.41; P<0.001) and DRB10301 (odds ratio, 3.96; 95% CI, 2.61 to 6.05; P<0.001) as independent risk alleles for iMN and associated with circulating anti PLA2R antibodies. Strong gene-gene interaction was noted between rs4664308(AA) and HLA-DRB11501/DRB10301. Amino acid positions 13 (P<0.001) and 71 (P<0.001) in the MHC-DR beta 1 chain independently associated with iMN. Structural models showed that arginine13 and alanine71, encoded by DRB11501, and lysine71, encoded by DRB10301, facilitate interactions with T cell epitopes of PLA2R. In conclusion, we identified two risk alleles of HLA class II genes and three amino acid residues on positions 13 and 71 of the MHC-DRP1 chain that may confer susceptibility to iMN by presenting T cell epitopes on PLA2R.; Natural Science Foundation of China [81321064, 81622009, 81330020, 81370801]; National Key Technology RD Program [2013BAI09B14]; European Research Council [ERC-2012-ADG_20120314, 322947]; European Community [2012-305608]; SCI(E); ARTICLE; 5; 1651-1664; 28
语种	英语
内容类型	期刊论文
源URL	[http://ir.pku.edu.cn/handle/20.500.11897/473774]
专题	化学与分子工程学院
推荐引用方式 GB/T 7714	Cui, Zhao,Xie, Li-jun,Chen, Fang-jin,et al. MHC Class II Risk Alleles and Amino Acid Residues in Idiopathic Membranous Nephropathy[J]. JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY,2017.
APA	Cui, Zhao.,Xie, Li-jun.,Chen, Fang-jin.,Pei, Zhi-yong.,Zhang, Li-jie.,...&Zhao, Ming-hui.(2017).MHC Class II Risk Alleles and Amino Acid Residues in Idiopathic Membranous Nephropathy.JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY.
MLA	Cui, Zhao,et al."MHC Class II Risk Alleles and Amino Acid Residues in Idiopathic Membranous Nephropathy".JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY (2017).