HLA class II alleles differing by a single amino acid associate with clinical phenotype and outcome in patients with primary membranous nephropathy.

Abstract

Genome-wide associations and HLA genotyping have revealed associations between HLA alleles and susceptibility to primary membranous nephropathy. However, associations with clinical phenotypes and kidney outcome are poorly defined. We previously identified DRB1*1501 and DRB1*0301 as independent risk alleles for primary membranous nephropathy. Here, we investigated HLA associations with demographic characteristics, anti-phospholipase A2 receptor (PLA2R) antibody, treatment response and kidney outcome after a median follow-up of 52 months in 258 patients. DRB1*0301, but not DRB1*1501, was associated with a significantly higher level of PLA2R antibody (odds ratio 1.58, 95% confidence interval 1.13-2.22). Although DRB1*1502, which differs from DRB1*1501 by a single amino acid, was not a risk allele for primary membranous nephropathy (odds ratio 1.01), it was associated with significantly lower estimated glomerular filtration rates both at baseline (1.79, 1.18-2.72) and at last follow-up (1.72, 1.17-2.53), a significantly worse renal outcome by Kaplan-Meier analysis and a significantly higher risk of end-stage renal disease by Cox regression analysis (hazard ratio 4.52, 1.22-16.74). Nevertheless, the absence of remission remained the only independent risk factor for end-stage renal disease by multivariate analysis. DRB1*1502 was also associated with a significantly higher median PLA2R antibody level [161.4 vs. 36.3 U/mL] and showed interaction with DRB1*0301 for this variable. Thus, HLA genes control PLA2R antibody production and primary membranous nephropathy severity and outcome. Additionally, DRB1*1502 behaves like a modifier gene with a strong predictor value when associated with HLA risk alleles. Other modifier genes need further investigations in larger cohorts.

• Authors: Huai-Yu Wang, Zhao Cui, Li-Jun Xie, Li-Jie Zhang, Zhi-Yong Pei, Fang-Jin Chen, Zhen Qu, Jing Huang, Yi-Miao Zhang, Xin Wang, Fang Wang, Li-Qiang Meng, Xu-Yang Cheng, Gang Liu, Xu-Jie Zhou, Hong Zhang, Hanna Debiec, Pierre Ronco, Ming-Hui Zhao
• Journal: Kidney international (Kidney Int) Vol. 94 Issue 5 Pg. 974-982 (11 2018) ISSN: 1523-1755 [Electronic] United States
• PMID: 30173899 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Autoantibodies
• HLA-DRB1 Chains
• HLA-DRB1*03:01 antigen
• Receptors, Phospholipase A2

Topics

• Adult
• Aged
• Alleles
• Autoantibodies (biosynthesis)
• Female
• Glomerulonephritis, Membranous (genetics, immunology)
• HLA-DRB1 Chains (chemistry, genetics)
• Humans
• Male
• Middle Aged
• Molecular Docking Simulation
• Phenotype
• Proportional Hazards Models
• Receptors, Phospholipase A2 (immunology)