Genetic Risk Variants for Membranous Nephropathy: Extension of and Association with Other Chronic Kidney Disease Aetiologies

Overview

Journal Nephrol Dial Transplant

Publisher Oxford University Press

Specialties General Surgery
Nephrology

Date 2016 Jun 23

PMID 27333618

Citations 30

Authors

Peggy Sekula

Yong Li

Horia C Stanescu

Matthias Wuttke

Arif B Ekici

Detlef Bockenhauer

Gerd Walz

Stephen H Powis

Jan T Kielstein

Paul Brenchley

Kai-Uwe Eckardt

Florian Kronenberg

Robert Kleta

Anna Kottgen

Affiliations

Soon will be listed here.

Abstract

Background: Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. Previous genome-wide association studies (GWAS) of 300 000 genotyped variants identified MN-associated loci at HLA-DQA1 and PLA2R1.

Methods: We used a combined approach of genotype imputation, GWAS, human leucocyte antigen (HLA) imputation and extension to other aetiologies of chronic kidney disease (CKD) to investigate genetic MN risk variants more comprehensively. GWAS using 9 million high-quality imputed genotypes and classical HLA alleles were conducted for 323 MN European-ancestry cases and 345 controls. Additionally, 4960 patients with different CKD aetiologies in the German Chronic Kidney Disease (GCKD) study were genotyped for risk variants at HLA-DQA1 and PLA2R1.

Results: In GWAS, lead variants in known loci [rs9272729, HLA-DQA1, odds ratio (OR) = 7.3 per risk allele, P = 5.9 × 10 and rs17830558, PLA2R1, OR = 2.2, P = 1.9 × 10] were significantly associated with MN. No novel signals emerged in GWAS of X-chromosomal variants or in sex-specific analyses. Classical HLA alleles (DRB1*0301-DQA1*0501-DQB1*0201 haplotype) were associated with MN but provided little additional information beyond rs9272729. Associations were replicated in 137 GCKD patients with MN (HLA-DQA1: P = 6.4 × 10; PLA2R1: P = 5.0 × 10). MN risk increased steeply for patients with high-risk genotype combinations (OR > 79). While genetic variation in PLA2R1 exclusively associated with MN across 19 CKD aetiologies, the HLA-DQA1 risk allele was also associated with lupus nephritis (P = 2.8 × 10), type 1 diabetic nephropathy (P = 6.9 × 10) and focal segmental glomerulosclerosis (P = 5.1 × 10), but not with immunoglobulin A nephropathy.

Conclusions: PLA2R1 and HLA-DQA1 are the predominant risk loci for MN detected by GWAS. While HLA-DQA1 risk variants show an association with other CKD aetiologies, PLA2R1 variants are specific to MN.

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