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

Nat Commun. 2020 Mar 30;11(1):1600. doi: 10.1038/s41467-020-15383-w.

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.

Trial registration: ClinicalTrials.gov NCT01180036.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Amino Acid Sequence
  • Asians / genetics
  • Case-Control Studies
  • Genome-Wide Association Study*
  • Glomerulonephritis, Membranous / diagnosis*
  • Glomerulonephritis, Membranous / genetics*
  • Glomerulonephritis, Membranous / immunology
  • Humans
  • Interferon Regulatory Factors / genetics
  • Models, Molecular
  • NF-kappa B p50 Subunit / genetics
  • Polymorphism, Single Nucleotide
  • Receptors, Phospholipase A2 / genetics
  • Whites / genetics

Substances

  • Interferon Regulatory Factors
  • NF-kappa B p50 Subunit
  • NFKB1 protein, human
  • PLA2R1 protein, human
  • Receptors, Phospholipase A2
  • interferon regulatory factor-4

Associated data

  • ClinicalTrials.gov/NCT01180036