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

Xie J, Liu L, Mladkova N, Li Y, Ren H, Wang W, Cui Z, Lin L, Hu X, Yu X, Xu J, Liu G, Caliskan Y, Sidore C, Balderes O, Rosen RJ, Bodria M, Zanoni F, Zhang JY, Krithivasan P, Mehl K, Marasa M, Khan A, Ozay F, Canetta PA, Bomback AS, Appel GB, Sanna-Cherchi S, Sampson MG, Mariani LH, Perkowska-Ptasinska A, Durlik M, Mucha K, Moszczuk B, Foroncewicz B, Pączek L, Habura I, Ars E, Ballarin J, Mani LY, Vogt B, Ozturk S, Yildiz A, Seyahi N, Arikan H, Koc M, Basturk T, Karahan G, Akgul SU, Sever MS, Zhang D, Santoro D, Bonomini M, Londrino F, Gesualdo L, Reiterova J, Tesar V, Izzi C, Savoldi S, Spotti D, Marcantoni C, Messa P, Galliani M, Roccatello D, Granata S, Zaza G, Lugani F, Ghiggeri GM, Pisani I, Allegri L, Sprangers B, Park JH, Cho BL, Kim YS, Kim DK, Suzuki H, Amoroso A, Cattran DC, Fervenza FC, Pani A, Hamilton P, Harris S, Gupta S, Cheshire C, Dufek S, Issler N, Pepper RJ, Connolly J, Powis S, Bockenhauer D, Stanescu HC, Ashman N, Loos RJ, Kenny EE, Wuttke M, Eckardt KU, Köttgen A, Hofstra JM, Coenen MJ, Kiemeney LA, Akilesh S, Kretzler M, Beck LH, Stengel B, Debiec H, Ronco P, Wetzels JF, Zoledziewska M, Cucca F, Ionita-Laza I, Lee H, Hoxha E, Stahl RA, Brenchley P, Scolari F, Zhao Mh, Gharavi AG, Kleta R, Chen N, Kiryluk K (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Book Volume: 11

Article Number: 1600

Journal Issue: 1

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.

Authors with CRIS profile

Involved external institutions

Columbia University Irving Medical Center (CUIMC) United States (USA) (US) Ospedale San Raffaele (früher: Centro San Raffaele del Monte Tabor Foundation) Italy (IT) Istanbul University / İstanbul Üniversitesi Turkey (TR) Istituto Giannina Gaslini Italy (IT) University College London (UCL) United Kingdom (GB) Rega Institute for Medical Research Belgium (BE) Sandro Pertini Hospital / Ospedale Sandro Pertini Italy (IT) Azienda ospedaliero universitaria San Giovanni Battista Italy (IT) University of Bari Aldo Moro / Università degli Studi di Bari Aldo Moro Italy (IT) University of Parma / Università degli Studi di Parma Italy (IT) Seoul National University (SNU) / 서울대학교 Korea, Republic of (KR) Shanghai Jiao Tong University / 上海交通大学 China (CN) XinHua Hospital / 新华医院 China (CN) İstanbul Eğitim ve Araştırma Hastanesi Turkey (TR) Manchester University NHS Foundation Trust (MFT) United Kingdom (GB) Wrocław Medical University / Uniwersytet Medyczny we Wrocławiu Poland (PL) Mayo Clinic United States (USA) (US) Università degli studi di Milano Italy (IT) Peking University First Hospital / 北大国际医院 China (CN) Juntendo University Japan (JP) University of Michigan United States (USA) (US) Institute of Genetic and Biomedical Research / Istituto di Ricerca Genetica e Biomedica (IRGB CNR) Italy (IT) Ospedale Cannizzaro Italy (IT) Autonomous University of Barcelona (UAB) / Universitat Autònoma de Barcelona Spain (ES) Inselspital, Universitätsspital Bern Switzerland (CH) University of Zielona Góra / Uniwersytet Zielonogórski Poland (PL) Azienda ospedaliera Sant'Andrea Italy (IT) University of Verona / Università degli Studi di Verona Italy (IT) Brotzu Hospital Italy (IT) Univerzita Karlova v Praze / Charles University in Prague Czech Republic (CZ) Marmara University Turkey (TR) University of Turin / Università degli Studi di Torino (UNITO) Italy (IT) İstanbul Haseki Training and Research Hospital Turkey (TR) Uludag University / Uludağ Üniversitesi Turkey (TR) University of Messina / Università degli Studi di Messina Italy (IT) Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia Italy (IT) Istanbul University Cerrahpaşa / İstanbul Üniversitesi Cerrahpaşa (IUC) Turkey (TR) Università degli Studi Gabriele D'Annunzio Italy (IT) Albert-Ludwigs-Universität Freiburg Germany (DE) University of Toronto Canada (CA) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) National Institute for Health and Medical Research / Institut national de la santé et de la recherche médicale (INSERM) France (FR) Icahn School of Medicine at Mount Sinai United States (USA) (US) Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) Netherlands (NL) Sorbonne Université France (FR) Boston Medical Center (BMC) United States (USA) (US) University of Washington United States (USA) (US) University of Manchester United Kingdom (GB) Royal London Hospital / London Infirmary United Kingdom (GB)

How to cite

APA:

Xie, J., Liu, L., Mladkova, N., Li, Y., Ren, H., Wang, W.,... Kiryluk, K. (2020). The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis. Nature Communications, 11(1). https://doi.org/10.1038/s41467-020-15383-w

MLA:

Xie, Jingyuan, et al. "The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis." Nature Communications 11.1 (2020).

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