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Genetic risk variants for membranous nephropathy: extension of and association with other chronic kidney disease aetiologies

Sekula, P; Li, Y; Stanescu, HC; Wuttke, M; Ekici, AB; Bockenhauer, D; Walz, G; ... Koettgen, A; + view all (2016) Genetic risk variants for membranous nephropathy: extension of and association with other chronic kidney disease aetiologies. Nephrology Dialysis Transplantation , 32 (2) pp. 325-332. 10.1093/ndt/gfw001. Green open access

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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 × 10−27 and rs17830558, PLA2R1, OR = 2.2, P = 1.9 × 10−8] 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 × 10−24; PLA2R1: P = 5.0 × 10−4). 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 × 10−6), type 1 diabetic nephropathy (P = 6.9 × 10−5) and focal segmental glomerulosclerosis (P = 5.1 × 10−5), 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.

Type: Article
Title: Genetic risk variants for membranous nephropathy: extension of and association with other chronic kidney disease aetiologies
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/ndt/gfw001
Publisher version: http://doi.org/10.1093/ndt/gfw001
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Chronic kidney disease, genome-wide association study, membranous nephropathy
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Renal Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/1501272
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