In:
Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 28, No. 5 ( 2017-5), p. 1651-1664
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-DR β 1 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-DR β 1 chain that may confer susceptibility to iMN by presenting T cell epitopes on PLA2R.
Type of Medium:
Online Resource
ISSN:
1046-6673
,
1533-3450
DOI:
10.1681/ASN.2016020114
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2017
detail.hit.zdb_id:
2029124-3
