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.

2nd Division of Nephrology ASST Spedali Civili di Brescia Presidio di Montichiari Brescia Italy

3 Department of Medicine University Medical Center Hamburg Eppendorf Hamburg Germany

Arbor Research Collaborative for Health Ann Arbor MI USA

Biomedical Sciences Seoul National University College of Medicine Seoul Korea

Cannizzaro Hospital Catania Italy

Center for Population Genomic Health Icahn School of Medicine at Mount Sinai New York NY USA

Department of Anatomic Pathology University of Washington Seattle USA

Department of Biostatistics Mailman School of Public Health Columbia University New York NY USA

Department of Cinical and Experimental Medicine Unit of Nephrology University of Messina Messina Italy

Department of Epidemiology Biostatistics and HTA Radboud University Medical Center Nijmegen The Netherlands

Department of Family Medicine Seoul National University College of Medicine and Seoul National University Hospital Seoul Korea

Department of Genetics and Genomic Sciences Mount Sinai Health System New York NY USA

Department of Human Genetics Radboud University Medical Centre Radboud Institute for Health Sciences Nijmegen The Netherlands

Department of Immunology Transplantology and Internal Diseases Medical University of Warsaw Warsaw Poland

Department of Medical Biology Istanbul School of Medicine Istanbul University Istanbul Turkey

Department of Medical Sciences University of Torino and Immunogenetics and Transplant Biology Service University Hospital Città della Salute e della Scienza di Torino Turin Italy

Department of Medicine and Surgery University of Parma Parma Italy

Department of Medicine Division of Nephrology Columbia University College of Physicians and Surgeons New York USA

Department of Medicine Renal Section Boston University School of Medicine and Boston Medical Center Boston MA USA

Department of Medicine University of Chieti Pescara SS Annunziata Hospital Chieti Italy

Department of Microbiology and Immunology Laboratory of Molecular Immunology Rega Institute KU Leuven Belgium

Department of Nephrology 1st Faculty of Medicine and General University Hospital Charles University Prague Czech Republic

Department of Nephrology and Dialysis G Brotzu Hospital Cagliari Italy

Department of Nephrology and Hypertension Bern University Hospital University of Bern Bern Switzerland

Department of Nephrology and Hypertension Friedrich Alexander Universität Erlangen Germany

Department of Nephrology and Medical Intensive Care Charité Universitätsmedizin Berlin Berlin Germany

Department of Nephrology Division of Medicine University College London London UK

Department of Nephrology Institute of Nephrology Shanghai Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai China

Department of Nephrology Juntendo University Faculty of Medicine Tokyo Japan

Department of Nephrology Radboud University Medical Center Nijmegen The Netherlands

Department of Nephrology Sisli Hamidiye Etfal Training and Research Hospital Istanbul Turkey

Department of Nephrology Uludag University Faculty of Medicine Bursa Turkey

Department of Nephrology University Hospital of Karol Marcinkowski in Zielona Góra Zielona Góra Poland

Department of Nephrology University Hospitals Leuven Leuven Belgium

Department of Nephrology University of Toronto Toronto General Hospital Toronto ON Canada

Department of Nephrology Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai China

Department of Obstetrics and Gynecology ASST Spedali Civili di Brescia Brescia Italy

Department of Pediatrics Nephrology University of Michigan School of Medicine Ann Arbor MI USA

Department of Transplantology Nephrology and Internal Diseases Medical University of Warsaw Warsaw Poland

Division of Nephrology and Hypertension Mayo Clinic Rochester MN USA

Division of Nephrology Department of Internal Medicine Cerrahpasa Medical Faculty Istanbul University Cerrahpasa Istanbul Turkey

Division of Nephrology Department of Internal Medicine Istanbul School of Medicine Istanbul University Istanbul Turkey

Division of Nephrology Department of Internal Medicine Marmara University School of Medicine Istanbul Turkey

Division of Nephrology Department of Medicine University of Michigan Ann Arbor MI USA

Division of Nephrology Dialysis Transplantation IRCCS Giannina Gaslini Genoa Italy

Faculty of Biology Medicine Health University of Manchester Manchester UK

Institut National de la Santé et de la Recherche Médicale Centre for Research in Epidemiology and Population Health Villejuif France

Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 1155 Paris France

Institute of Biochemistry and Biophysics Polish Academy of Sciences Warsaw Poland

Institute of Genetic Epidemiology Dep of Biometry Epidemiology and Medical Bioinformatics Faculty of Medicine and Medical Center University of Freiburg Freiburg Germany

Institute of Nephrology Peking University Beijing China

Institute on Aging Seoul National University College of Medicine Seoul Korea

Internal Medicine Seoul National University College of Medicine Seoul Korea

Istituto di Ricerca Genetica e Biomedica Consiglio Nazionale delle Ricerche Monserrato Cagliari Italy

Key Laboratory of Renal Disease Ministry of Health of China and Key Laboratory of CKD Prevention and Treatment Ministry of Education of China Beijng China

Kidney Research Institute Seoul National University College of Medicine Seoul Korea

Manchester Institute of Nephrology and Transplantation Manchester University Hospitals NHS Trust Manchester UK

Molecular Biology Laboratory and Nephrology Department Fundació Puigvert Instituto de Investigaciones Biomédicas Sant Pau Universitat Autònoma de Barcelona REDINREN IISCIII Barcelona Spain

Nephrology Clinic Haseki Training and Research Hospital Istanbul Turkey

Nephrology Dialysis and Kidney Transplant Unit Fundazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Università degli studi di Milano Milan Italy

Peking Tsinghua Center for Life Sciences Beijing China

Renal Division Department of Medicine Peking University 1st Hospital Beijing China

Renal Unit Department of Medicine University of Verona Verona Italy

Renal Unit Royal London Hospital Barts Health Whitechapel London UK

S Andrea Hospital La Spezia Italy

San Giovanni Bosco Hospital and University of Turin Turin Italy

San Raffaele Hospital Milan Italy

Sandro Pertini Hospital Rome Italy

Sorbonne Université Pierre and Marie Curie University Paris 06 Paris France

The Charles Bronfman Institute for Personalized Medicine Icahn School of Medicine at Mount Sinai New York NY USA

The Genetics of Obesity and Related Metabolic Traits Program The Icahn School of Medicine at Mount Sinai New York NY USA

The Mindich Child Health and Development Institute Icahn School of Medicine at Mount Sinai New York NY USA

Unit of Nephrology and Dialysis ASL TO4 Cirié Turin Italy

University of Bari Bari Italy

University of Brescia Brescia Italy

University Paris Sud Villejuif France

Komentář v

Nat Rev Nephrol. 2020 Jun;16(6):316. doi: 10.1038/s41581-020-0282-9. PubMed

Zobrazit více v PubMed

Glassock RJ. Diagnosis and natural course of membranous nephropathy. Semin Nephrol. 2003;23:324–332. doi: 10.1016/S0270-9295(03)00049-4. PubMed DOI

Debiec H, et al. Antenatal membranous glomerulonephritis due to anti-neutral endopeptidase antibodies. N. Engl. J. Med. 2002;346:2053–2060. doi: 10.1056/NEJMoa012895. PubMed DOI

Beck LH, Jr., et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N. Engl. J. Med. 2009;361:11–21. doi: 10.1056/NEJMoa0810457. PubMed DOI PMC

Glassock RJ. The pathogenesis of membranous nephropathy: evolution and revolution. Curr. Opin. Nephrol. Hypertens. 2012;21:235–242. doi: 10.1097/MNH.0b013e3283522ea8. PubMed DOI

Tomas NM, et al. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. N. Engl. J. Med. 2014;371:2277–2287. doi: 10.1056/NEJMoa1409354. PubMed DOI PMC

Stanescu HC, et al. Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy. N. Engl. J. Med. 2011;364:616–626. doi: 10.1056/NEJMoa1009742. PubMed DOI

Wunnenburger S, et al. Associations between genetic risk variants for kidney diseases and kidney disease etiology. Sci. Rep. 2017;7:13944. doi: 10.1038/s41598-017-13356-6. PubMed DOI PMC

Gadegbeku CA, et al. Design of the Nephrotic Syndrome Study Network (NEPTUNE) to evaluate primary glomerular nephropathy by a multidisciplinary approach. Kidney Int. 2013;83:749–756. doi: 10.1038/ki.2012.428. PubMed DOI PMC

Cui Z, et al. MHC class II risk alleles and amino acid residues in idiopathic membranous nephropathy. J. Am. Soc. Nephrol. 2017;28:1651–1664. doi: 10.1681/ASN.2016020114. PubMed DOI PMC

Zhou F, et al. Deep sequencing of the MHC region in the Chinese population contributes to studies of complex disease. Nat. Genet. 2016;48:740–746. doi: 10.1038/ng.3576. PubMed DOI

Backenroth D, et al. FUN-LDA: a latent dirichlet allocation model for predicting tissue-specific functional effects of noncoding variation: methods and applications. Am. J. Hum. Genet. 2018;102:920–942. doi: 10.1016/j.ajhg.2018.03.026. PubMed DOI PMC

Consortium GT, et al. Genetic effects on gene expression across human tissues. Nature. 2017;550:204–213. doi: 10.1038/nature24277. PubMed DOI PMC

Gillies CE, et al. An eQTL landscape of kidney tissue in human nephrotic syndrome. Am. J. Hum. Genet. 2018;103:232–244. doi: 10.1016/j.ajhg.2018.07.004. PubMed DOI PMC

Sieber KB, et al. Integrated functional genomic analysis enables annotation of kidney genome-wide association study loci. J. Am. Soc. Nephrol. 2019;30:421–441. doi: 10.1681/ASN.2018030309. PubMed DOI PMC

Westra HJ, et al. Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat. Genet. 2013;45:1238–1243. doi: 10.1038/ng.2756. PubMed DOI PMC

Raj T, et al. Polarization of the effects of autoimmune and neurodegenerative risk alleles in leukocytes. Science. 2014;344:519–523. doi: 10.1126/science.1249547. PubMed DOI PMC

Astle WJ, et al. The allelic landscape of human blood cell trait variation and links to common complex disease. Cell. 2016;167:1415–1429 e19. doi: 10.1016/j.cell.2016.10.042. PubMed DOI PMC

Jostins L, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491:119–124. doi: 10.1038/nature11582. PubMed DOI PMC

Liu JZ, et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat. Genet. 2015;47:979–986. doi: 10.1038/ng.3359. PubMed DOI PMC

Mells GF, et al. Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nat. Genet. 2011;43:329–332. doi: 10.1038/ng.789. PubMed DOI PMC

Cordell HJ, et al. International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways. Nat. Commun. 2015;6:8019. doi: 10.1038/ncomms9019. PubMed DOI PMC

Wu H, et al. Comparative analysis and refinement of human PSC-derived kidney organoid differentiation with single-cell transcriptomics. Cell Stem Cell. 2018;23:869–881.e8. doi: 10.1016/j.stem.2018.10.010. PubMed DOI PMC

Pattaro C, et al. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function. Nat. Commun. 2016;7:10023. doi: 10.1038/ncomms10023. PubMed DOI PMC

Wuttke M, et al. A catalog of genetic loci associated with kidney function from analyses of a million individuals. Nat. Genet. 2019;51:957–972. doi: 10.1038/s41588-019-0407-x. PubMed DOI PMC

Grumont RJ, Gerondakis S. Rel induces interferon regulatory factor 4 (IRF-4) expression in lymphocytes: modulation of interferon-regulated gene expression by rel/nuclear factor kappaB. J. Exp. Med. 2000;191:1281–1292. doi: 10.1084/jem.191.8.1281. PubMed DOI PMC

Saito M, et al. A signaling pathway mediating downregulation of BCL6 in germinal center B cells is blocked by BCL6 gene alterations in B cell lymphoma. Cancer Cell. 2007;12:280–292. doi: 10.1016/j.ccr.2007.08.011. PubMed DOI

Boddicker RL, et al. The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-kappaB positive feedback loop in peripheral T-cell lymphoma. Blood. 2015;125:3118–3127. doi: 10.1182/blood-2014-05-578575. PubMed DOI PMC

Lake BB, et al. A single-nucleus RNA-sequencing pipeline to decipher the molecular anatomy and pathophysiology of human kidneys. Nat. Commun. 2019;10:2832. doi: 10.1038/s41467-019-10861-2. PubMed DOI PMC

Zhao B, et al. The NF-kappaB genomic landscape in lymphoblastoid B cells. Cell Rep. 2014;8:1595–1606. doi: 10.1016/j.celrep.2014.07.037. PubMed DOI PMC

Lee SH, Wray NR, Goddard ME, Visscher PM. Estimating missing heritability for disease from genome-wide association studies. Am. J. Hum. Genet. 2011;88:294–305. doi: 10.1016/j.ajhg.2011.02.002. PubMed DOI PMC

Bobart SA, et al. Noninvasive diagnosis of primary membranous nephropathy using phospholipase A2 receptor antibodies. Kidney Int. 2019;95:429–438. doi: 10.1016/j.kint.2018.10.021. PubMed DOI

Schmid H, et al. Modular activation of nuclear factor-kappaB transcriptional programs in human diabetic nephropathy. Diabetes. 2006;55:2993–3003. doi: 10.2337/db06-0477. PubMed DOI

Atreya I, Atreya R, Neurath MF. NF-kappaB in inflammatory bowel disease. J. Intern. Med. 2008;263:591–596. doi: 10.1111/j.1365-2796.2008.01953.x. PubMed DOI

Schottelius AJ, Baldwin AS., Jr A role for transcription factor NF-kappa B in intestinal inflammation. Int J. Colorectal Dis. 1999;14:18–28. doi: 10.1007/s003840050178. PubMed DOI

Mezzano SA, et al. Tubular NF-kappaB and AP-1 activation in human proteinuric renal disease. Kidney Int. 2001;60:1366–1377. doi: 10.1046/j.1523-1755.2001.00941.x. PubMed DOI

Mudge SJ, Paizis K, Auwardt RB, Thomas RJ, Power DA. Activation of nuclear factor-kappa B by podocytes in the autologous phase of passive Heymann nephritis. Kidney Int. 2001;59:923–931. doi: 10.1046/j.1523-1755.2001.059003923.x. PubMed DOI

Liu S, et al. Urinary messenger RNA of the receptor activator of NF-kappaB could be used to differentiate between minimal change disease and membranous nephropathy. Biomarkers. 2014;19:597–603. doi: 10.3109/1354750X.2014.956148. PubMed DOI

Bonder MJ, et al. Disease variants alter transcription factor levels and methylation of their binding sites. Nat. Genet. 2017;49:131–138. doi: 10.1038/ng.3721. PubMed DOI

Hu X, et al. Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk. Nat. Genet. 2015;47:898–905. doi: 10.1038/ng.3353. PubMed DOI PMC

Raychaudhuri S, et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat. Genet. 2012;44:291–296. doi: 10.1038/ng.1076. PubMed DOI PMC

Xu X, et al. Molecular insights into genome-wide association studies of chronic kidney disease-defining traits. Nat. Commun. 2018;9:4800. doi: 10.1038/s41467-018-07260-4. PubMed DOI PMC

Sekula P, et al. Genetic risk variants for membranous nephropathy: extension of and association with other chronic kidney disease aetiologies. Nephrol. Dial. Transpl. 2017;32:325–332. doi: 10.1093/ndt/gfw001. PubMed DOI PMC

Nevalainen TJ, Graham GG, Scott KF. Antibacterial actions of secreted phospholipases A2. Review. Biochim Biophys. Acta. 2008;1781:1–9. doi: 10.1016/j.bbalip.2007.12.001. PubMed DOI

Morri H, Ozaki M, Watanabe Y. 5’-flanking region surrounding a human cytosolic phospholipase A2 gene. Biochem. Biophys. Res. Commun. 1994;205:6–11. doi: 10.1006/bbrc.1994.2621. PubMed DOI

Devlin B, Roeder K, Bacanu SA. Unbiased methods for population-based association studies. Genet. Epidemiol. 2001;21:273–284. doi: 10.1002/gepi.1034. PubMed DOI

Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010;26:2190–2191. doi: 10.1093/bioinformatics/btq340. PubMed DOI PMC

Wakefield J. Bayes factors for genome-wide association studies: comparison with P-values. Genet. Epidemiol. 2009;33:79–86. doi: 10.1002/gepi.20359. PubMed DOI

Hormozdiari F, Kostem E, Kang EY, Pasaniuc B, Eskin E. Identifying causal variants at loci with multiple signals of association. Genetics. 2014;198:497–508. doi: 10.1534/genetics.114.167908. PubMed DOI PMC

Jia X, et al. Imputing amino acid polymorphisms in human leukocyte antigens. PLoS ONE. 2013;8:e64683. doi: 10.1371/journal.pone.0064683. PubMed DOI PMC

Pillai NE, et al. Predicting HLA alleles from high-resolution SNP data in three Southeast Asian populations. Hum. Mol. Genet. 2014;23:4443–4451. doi: 10.1093/hmg/ddu149. PubMed DOI

Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38:e164. doi: 10.1093/nar/gkq603. PubMed DOI PMC

Ju W, et al. Defining cell-type specificity at the transcriptional level in human disease. Genome Res. 2013;23:1862–1873. doi: 10.1101/gr.155697.113. PubMed DOI PMC

Rinschen MM, et al. A multi-layered quantitative in vivo expression atlas of the podocyte unravels kidney disease candidate genes. Cell Rep. 2018;23:2495–2508. doi: 10.1016/j.celrep.2018.04.059. PubMed DOI PMC

Steyerberg EW, et al. Assessing the performance of prediction models: a framework for traditional and novel measures. Epidemiology. 2010;21:128–138. doi: 10.1097/EDE.0b013e3181c30fb2. PubMed DOI PMC

Levey AS, et al. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann. Intern. Med. 2006;145:247–254. doi: 10.7326/0003-4819-145-4-200608150-00004. PubMed DOI

Yang J, et al. Common SNPs explain a large proportion of the heritability for human height. Nat. Genet. 2010;42:565–569. doi: 10.1038/ng.608. PubMed DOI PMC

Yang J, Lee SH, Goddard ME, Visscher PM. GCTA: a tool for genome-wide complex trait analysis. Am. J. Hum. Genet. 2011;88:76–82. doi: 10.1016/j.ajhg.2010.11.011. PubMed DOI PMC

Autoantibodies in the Diagnosis, Monitoring, and Treatment of Membranous Nephropathy

Zobrazit více v PubMed

ClinicalTrials.gov
NCT01180036