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

Jingyuan Xie (), Lili Liu, Nikol Mladkova, Yifu Li, Hong Ren, Weiming Wang, Zhao Cui, Li Lin, Xiaofan Hu, Xialian Yu, Jing Xu, Gang Liu, Yasar Caliskan, Carlo Sidore, Olivia Balderes, Raphael J. Rosen, Monica Bodria, Francesca Zanoni, Jun Y. Zhang, Priya Krithivasan, Karla Mehl, Maddalena Marasa, Atlas Khan, Fatih Ozay, Pietro A. Canetta, Andrew S. Bomback, Gerald B. Appel, Simone Sanna-Cherchi, Matthew G. Sampson, Laura H. Mariani, Agnieszka Perkowska-Ptasinska, Magdalena Durlik, Krzysztof Mucha, Barbara Moszczuk, Bartosz Foroncewicz, Leszek Pączek, Ireneusz Habura, Elisabet Ars, Jose Ballarin, Laila-Yasmin Mani, Bruno Vogt, Savas Ozturk, Abdülmecit Yildiz, Nurhan Seyahi, Hakki Arikan, Mehmet Koc, Taner Basturk, Gonca Karahan, Sebahat Usta Akgul, Mehmet Sukru Sever, Dan Zhang, Domenico Santoro, Mario Bonomini, Francesco Londrino, Loreto Gesualdo, Jana Reiterova, Vladimir Tesar, Claudia Izzi, Silvana Savoldi, Donatella Spotti, Carmelita Marcantoni, Piergiorgio Messa, Marco Galliani, Dario Roccatello, Simona Granata, Gianluigi Zaza, Francesca Lugani, GianMarco Ghiggeri, Isabella Pisani, Landino Allegri, Ben Sprangers, Jin-Ho Park, BeLong Cho, Yon Su Kim, Dong Ki Kim, Hitoshi Suzuki, Antonio Amoroso, Daniel C. Cattran, Fernando C. Fervenza, Antonello Pani, Patrick Hamilton, Shelly Harris, Sanjana Gupta, Chris Cheshire, Stephanie Dufek, Naomi Issler, Ruth J. Pepper, John Connolly, Stephen Powis, Detlef Bockenhauer, Horia C. Stanescu, Neil Ashman, Ruth J. F. Loos, Eimear E. Kenny, Matthias Wuttke, Kai-Uwe Eckardt, Anna Köttgen, Julia M. Hofstra, Marieke J. H. Coenen, Lambertus A. Kiemeney, Shreeram Akilesh, Matthias Kretzler, Lawrence H. Beck, Benedicte Stengel, Hanna Debiec, Pierre Ronco, Jack F. M. Wetzels, Magdalena Zoledziewska, Francesco Cucca, Iuliana Ionita-Laza, Hajeong Lee, Elion Hoxha, Rolf A. K. Stahl, Paul Brenchley, Francesco Scolari, Ming-hui Zhao, Ali G. Gharavi, Robert Kleta (), Nan Chen and Krzysztof Kiryluk ()
Additional contact information
Jingyuan Xie: Shanghai Jiao Tong University School of Medicine
Lili Liu: Columbia University, College of Physicians & Surgeons
Nikol Mladkova: Columbia University, College of Physicians & Surgeons
Yifu Li: Columbia University, College of Physicians & Surgeons
Hong Ren: Shanghai Jiao Tong University School of Medicine
Weiming Wang: Shanghai Jiao Tong University School of Medicine
Zhao Cui: Peking University First Hospital
Li Lin: Shanghai Jiao Tong University School of Medicine
Xiaofan Hu: Shanghai Jiao Tong University School of Medicine
Xialian Yu: Shanghai Jiao Tong University School of Medicine
Jing Xu: Shanghai Jiao Tong University School of Medicine
Gang Liu: Peking University First Hospital
Yasar Caliskan: Istanbul University
Carlo Sidore: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche
Olivia Balderes: Columbia University, College of Physicians & Surgeons
Raphael J. Rosen: Columbia University, College of Physicians & Surgeons
Monica Bodria: Columbia University, College of Physicians & Surgeons
Francesca Zanoni: Columbia University, College of Physicians & Surgeons
Jun Y. Zhang: Columbia University, College of Physicians & Surgeons
Priya Krithivasan: Columbia University, College of Physicians & Surgeons
Karla Mehl: Columbia University, College of Physicians & Surgeons
Maddalena Marasa: Columbia University, College of Physicians & Surgeons
Atlas Khan: Columbia University, College of Physicians & Surgeons
Fatih Ozay: Columbia University, College of Physicians & Surgeons
Pietro A. Canetta: Columbia University, College of Physicians & Surgeons
Andrew S. Bomback: Columbia University, College of Physicians & Surgeons
Gerald B. Appel: Columbia University, College of Physicians & Surgeons
Simone Sanna-Cherchi: Columbia University, College of Physicians & Surgeons
Matthew G. Sampson: University of Michigan School of Medicine
Laura H. Mariani: University of Michigan
Agnieszka Perkowska-Ptasinska: Medical University of Warsaw
Magdalena Durlik: Medical University of Warsaw
Krzysztof Mucha: Medical University of Warsaw
Barbara Moszczuk: Medical University of Warsaw
Bartosz Foroncewicz: Medical University of Warsaw
Leszek Pączek: Medical University of Warsaw
Ireneusz Habura: University Hospital of Karol Marcinkowski in Zielona Góra
Elisabet Ars: Universitat Autònoma de Barcelona, REDINREN, IISCIII
Jose Ballarin: Universitat Autònoma de Barcelona, REDINREN, IISCIII
Laila-Yasmin Mani: Bern University Hospital, University of Bern
Bruno Vogt: Bern University Hospital, University of Bern
Savas Ozturk: Nephrology Clinic, Haseki Training and Research Hospital
Abdülmecit Yildiz: Uludag University Faculty of Medicine
Nurhan Seyahi: Cerrahpasa Medical Faculty, Istanbul University - Cerrahpasa
Hakki Arikan: Marmara University School of Medicine
Mehmet Koc: Marmara University School of Medicine
Taner Basturk: Sisli Hamidiye Etfal Training and Research Hospital
Gonca Karahan: Istanbul University
Sebahat Usta Akgul: Istanbul University
Mehmet Sukru Sever: Istanbul University
Dan Zhang: Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Domenico Santoro: University of Messina
Mario Bonomini: University of Chieti-Pescara, SS. Annunziata Hospital
Francesco Londrino: S. Andrea Hospital
Loreto Gesualdo: University of Bari
Jana Reiterova: 1st Faculty of Medicine and General University Hospital, Charles University
Vladimir Tesar: 1st Faculty of Medicine and General University Hospital, Charles University
Claudia Izzi: Second Division of Nephrology, ASST-Spedali Civili di Brescia Presidio di Montichiari
Silvana Savoldi: Unit of Nephrology and Dialysis ASL TO4
Donatella Spotti: San Raffaele Hospital
Carmelita Marcantoni: Cannizzaro Hospital
Piergiorgio Messa: Nephrology Dialysis and Kidney Transplant Unit, Fundazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Università degli studi di Milano
Marco Galliani: Sandro Pertini Hospital
Dario Roccatello: San Giovanni Bosco Hospital (ERK-net Member) and University of Turin
Simona Granata: University of Verona
Gianluigi Zaza: University of Verona
Francesca Lugani: Division of Nephrology, Dialysis, Transplantation, IRCCS Giannina Gaslini
GianMarco Ghiggeri: Division of Nephrology, Dialysis, Transplantation, IRCCS Giannina Gaslini
Isabella Pisani: University of Parma
Landino Allegri: University of Parma
Ben Sprangers: Laboratory of Molecular Immunology, Rega Institute, KU
Jin-Ho Park: Seoul National University College of Medicine and Seoul National University Hospital
BeLong Cho: Seoul National University College of Medicine and Seoul National University Hospital
Yon Su Kim: Seoul National University College of Medicine
Dong Ki Kim: Seoul National University College of Medicine
Hitoshi Suzuki: Juntendo University Faculty of Medicine
Antonio Amoroso: University of Torino and Immunogenetics and Transplant Biology Service, University Hospital “Città della Salute e della Scienza di Torino”
Daniel C. Cattran: University of Toronto, Toronto General Hospital
Fernando C. Fervenza: Division of Nephrology and Hypertension, Mayo Clinic
Antonello Pani: G. Brotzu Hospital
Patrick Hamilton: Manchester University Hospitals NHS Trust
Shelly Harris: Manchester University Hospitals NHS Trust
Sanjana Gupta: University College London
Chris Cheshire: University College London
Stephanie Dufek: University College London
Naomi Issler: University College London
Ruth J. Pepper: University College London
John Connolly: University College London
Stephen Powis: University College London
Detlef Bockenhauer: University College London
Horia C. Stanescu: University College London
Neil Ashman: Renal Unit, Royal London Hospital, Barts Health, Whitechapel
Ruth J. F. Loos: The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
Eimear E. Kenny: The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
Matthias Wuttke: Faculty of Medicine and Medical Center – University of Freiburg
Kai-Uwe Eckardt: Charité – Universitätsmedizin Berlin
Anna Köttgen: Faculty of Medicine and Medical Center – University of Freiburg
Julia M. Hofstra: Radboud University Medical Center
Marieke J. H. Coenen: Radboud University Medical Centre, Radboud Institute for Health Sciences
Lambertus A. Kiemeney: Radboud University Medical Center
Shreeram Akilesh: University of Washington
Matthias Kretzler: University of Michigan
Lawrence H. Beck: Boston University School of Medicine and Boston Medical Center
Benedicte Stengel: Institut National de la Santé et de la Recherche Médicale, Centre for Research in Epidemiology and Population Health
Hanna Debiec: Sorbonne Université, Pierre and Marie Curie University Paris 06
Pierre Ronco: Sorbonne Université, Pierre and Marie Curie University Paris 06
Jack F. M. Wetzels: Radboud University Medical Center
Magdalena Zoledziewska: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche
Francesco Cucca: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche
Iuliana Ionita-Laza: Columbia University
Hajeong Lee: Seoul National University College of Medicine
Elion Hoxha: University Medical Center Hamburg-Eppendorf
Rolf A. K. Stahl: University Medical Center Hamburg-Eppendorf
Paul Brenchley: University of Manchester
Francesco Scolari: Second Division of Nephrology, ASST-Spedali Civili di Brescia Presidio di Montichiari
Ming-hui Zhao: Peking University First Hospital
Ali G. Gharavi: Columbia University, College of Physicians & Surgeons
Robert Kleta: University College London
Nan Chen: Shanghai Jiao Tong University School of Medicine
Krzysztof Kiryluk: Columbia University, College of Physicians & Surgeons

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15383-w

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