The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis.

ABSTRACT: Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (?rs230540, OR?=?1.25, P?=?3.4?×?10^-12) and IRF4 (?rs9405192, OR?=?1.29, P?=??1.4?×?10^-14), fine-map the PLA2R1 locus (?rs17831251, OR?=?2.25, P?=?4.7?×?10^-103) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR?=?3.81, P?=?2.0?×?10^-49), DQA1*0501 in Europeans (OR?=?2.88, P?=?5.7?×?10^-93), and DRB1*0301 in both ethnicities (OR?=?3.50, P?=?9.2?×?10^-23 and OR?=?3.39, P?=?5.2?×?10^-82, respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20-37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk.

SUBMITTER: Xie J 

PROVIDER: S-EPMC7105485 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature