title: MHC Class II Risk Alleles and Amino Acid Residues in Idiopathic Membranous Nephropathy.
abstract: 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 DRB1*1501 (odds ratio, 4.65; 95% confidence interval [95% CI], 3.39 to 6.41;P<0.001) and DRB1*0301 (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-DRB1*1501/DRB1*0301. Amino acid positions 13 (P<0.001) and 71 (P<0.001) in the MHC-DRβ1 chain independently associated with iMN. Structural models showed that arginine13 and alanine71, encoded by DRB1*1501, and lysine71, encoded by DRB1*0301, 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-DRβ1 chain that may confer susceptibility to iMN by presenting T cell epitopes on PLA2R.
authors.affiliation: Renal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Cui
authors.affiliation: Renal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.|Renal Division, Department of Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China.
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Xie
authors.affiliation: State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering and Center for Theoretical Biology, Peking University, Beijing, China.
authors.forename: Fang-Jin
authors.initials: FJ
authors.lastname: Chen
authors.affiliation: Beijing Computing Center, Beijing, China.
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Pei
authors.affiliation: Beijing Computing Center, Beijing, China.
authors.forename: Li-Jie
authors.initials: LJ
authors.lastname: Zhang
authors.affiliation: Renal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Qu
authors.affiliation: Renal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.affiliation: Renal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.
authors.forename: Qiu-Hua
authors.initials: QH
authors.lastname: Gu
authors.affiliation: Renal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.
authors.forename: Yi-Miao
authors.initials: YM
authors.lastname: Zhang
authors.affiliation: Renal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Renal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Renal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.
authors.forename: Li-Qiang
authors.initials: LQ
authors.lastname: Meng
authors.affiliation: Renal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Renal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.
authors.forename: Xu-Jie
authors.initials: XJ
authors.lastname: Zhou
authors.affiliation: Renal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Renal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.
authors.forename: Ji-Cheng
authors.initials: JC
authors.lastname: Lv
authors.affiliation: Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomic, Chinese Academy of Science, Beijing, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Liu
authors.affiliation: Renal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Renal Division, Department of Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China.
authors.forename: Yun-Hua
authors.initials: YH
authors.lastname: Liao
authors.affiliation: State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering and Center for Theoretical Biology, Peking University, Beijing, China.
authors.forename: Lu-Hua
authors.initials: LH
authors.lastname: Lai
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie Univ Paris 06, Paris, France.|Institut National de la Santé et la Recherche Médicale, Unité Mixte de Recherche 1155, Paris, France.|Assistance Publique-Hôpitaux de Paris, Service de Néphrologie et Dialyses, Hôpital Tenon, Paris, France; and.
authors.forename: Pierre
authors.initials: P
authors.lastname: Ronco
authors.affiliation: Renal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China; mhzhao@bjmu.edu.cn.|Peking-Tsinghua Center for Life Sciences, Beijing, China.
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Zhao
mesh_terms: D000483:Alleles; D000596:Amino Acids / Q000502:physiology*; D005802:Genes, MHC Class II / Q000502:physiology*; D015433:Glomerulonephritis, Membranous / Q000235:genetics* / Q000276:immunology*; D006684:HLA-DR Antigens / Q000502:physiology; D006801:Humans; D054507:Receptors, Phospholipase A2 / Q000502:physiology; D012307:Risk Factors
chemical_list: D000596:Amino Acids; D006684:HLA-DR Antigens; D054507:Receptors, Phospholipase A2
keywords: gene expression; immunology; membranous nephropathy