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

J. Xie, L. Liu, N. Mladkova, Y. Li, H. Ren, W. Wang, Z. Cui, L. Lin, X. Hu, X. Yu, J. Xu, G. Liu, Y. Caliskan, C. Sidore, O. Balderes, R.J. Rosen, M. Bodria, F. Zanoni, J.Y. Zhang, P. KrithivasanK. Mehl, M. Marasa, A. Khan, F. Ozay, P.A. Canetta, A.S. Bomback, G.B. Appel, S. Sanna-Cherchi, M.G. Sampson, L.H. Mariani, A. Perkowska-Ptasinska, M. Durlik, K. Mucha, B. Moszczuk, B. Foroncewicz, L. Pączek, I. Habura, E. Ars, J. Ballarin, L.-Y. Mani, B. Vogt, S. Ozturk, A. Yildiz, N. Seyahi, H. Arikan, M. Koc, T. Basturk, G. Karahan, S.U. Akgul, M.S. Sever, D. Zhang, D. Santoro, M. Bonomini, F. Londrino, L. Gesualdo, J. Reiterova, V. Tesar, C. Izzi, S. Savoldi, D. Spotti, C. Marcantoni, P. Messa, M. Galliani, D. Roccatello, S. Granata, G. Zaza, F. Lugani, G.M. Ghiggeri, I. Pisani, L. Allegri, B. Sprangers, J.-H. Park, B.L. Cho, Y.S. Kim, D.K. Kim, H. Suzuki, A. Amoroso, D.C. Cattran, F.C. Fervenza, A. Pani, P. Hamilton, S. Harris, S. Gupta, C. Cheshire, S. Dufek, N. Issler, R.J. Pepper, J. Connolly, S. Powis, D. Bockenhauer, H.C. Stanescu, N. Ashman, R.J.F. Loos, E.E. Kenny, M. Wuttke, K.-U. Eckardt, A. Köttgen, J.M. Hofstra, M.J.H. Coenen, L.A. Kiemeney, S. Akilesh, M. Kretzler, L.H. Beck, B. Stengel, H. Debiec, P. Ronco, J.F.M. Wetzels, M. Zoledziewska, F. Cucca, I. Ionita-Laza, H. Lee, E. Hoxha, R.A.K. Stahl, P. Brenchley, F. Scolari, M.-H. Zhao, A.G. Gharavi, R. Kleta, N. Chen, K. Kiryluk

Research output: Contribution to journalArticlepeer-review

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. © 2020, The Author(s).
Original languageEnglish
Article number1600
JournalNat. Commun.
Volume11
Issue number1
DOIs
Publication statusPublished - 2020

Keywords

  • HLA antigen
  • immunoglobulin enhancer binding protein
  • interferon regulatory factor 4
  • interferon regulatory factor
  • interferon regulatory factor-4
  • NFKB1 protein, human
  • phospholipase A2 receptor
  • PLA2R1 protein, human
  • ancestry
  • antibody
  • cohort analysis
  • detection method
  • genetic analysis
  • membrane
  • testing method
  • allele
  • Article
  • controlled study
  • diagnostic test accuracy study
  • East Asian
  • enzyme linked immunosorbent assay
  • ethnicity
  • European
  • gene
  • gene locus
  • genetic risk
  • genome-wide association study
  • human
  • human tissue
  • major clinical study
  • membranous glomerulonephritis
  • non invasive measurement
  • PLA2R1 gene
  • sensitivity and specificity
  • amino acid sequence
  • Asian continental ancestry group
  • case control study
  • Caucasian
  • genetics
  • immunology
  • meta analysis
  • molecular model
  • single nucleotide polymorphism
  • Alleles
  • Amino Acid Sequence
  • Asian Continental Ancestry Group
  • Case-Control Studies
  • European Continental Ancestry Group
  • Genome-Wide Association Study
  • Glomerulonephritis, Membranous
  • Humans
  • Interferon Regulatory Factors
  • Models, Molecular
  • NF-kappa B p50 Subunit
  • Polymorphism, Single Nucleotide
  • Receptors, Phospholipase A2

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