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Nat Genet. 2014 Nov;46(11):1187-96. doi: 10.1038/ng.3118. Epub 2014 Oct 12.

Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens.

Author information

  • 1Division of Nephrology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
  • 21] Division of Nephrology, Azienda Ospedaliera Spedali Civili of Brescia, Montichiari Hospital, University of Brescia, Brescia, Italy. [2] Department of Medical and Surgical Specialties, Radiological Sciences, University of Brescia, Brescia, Italy.
  • 31] Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA. [2] Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
  • 41] Division of Nephrology, Azienda Ospedaliera Spedali Civili of Brescia, Montichiari Hospital, University of Brescia, Brescia, Italy. [2] Prenatal Diagnosis Unit, Department of Obstetrics and Gynecology, University of Brescia, Brescia, Italy.
  • 5Division of Nephrology, Azienda Ospedaliera Spedali Civili of Brescia, Spedali Civili Hospital, University of Brescia, Brescia, Italy.
  • 6Renal Division, DMCO (Dipartimento di Medicina, Chirurgia e Odontoiatria), San Paolo Hospital, School of Medicine, University of Milan, Milan, Italy.
  • 71] Immunogenetics and Biology of Transplantation, Città della Salute e della Scienza, University Hospital of Turin, Turin, Italy. [2] Medical Genetics, Department of Medical Sciences, University of Torino, Turin, Italy.
  • 8Nephrology and Dialysis Unit, Ospedali di Cirié e Chivasso, Cirié, Turin, Italy.
  • 9Nephrology, Dialysis and Transplantation Unit, Regina Margheritra Hospital, Turin, Italy.
  • 10Division of Nephrology and Renal Transplantation, Carreggi Hospital, Florence, Italy.
  • 111] Department of Medicine, University of Calgary, Calgary, Alberta, Canada. [2] Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada.
  • 12Division of Nephrology Dialysis and Transplantation, Azienda Ospedaliero Universitaria Policlinico di Modena, Università di Modena e Reggio Emilia, Modena, Italy.
  • 13Division of Nephrology, Dialysis and Transplantation, Giannina Gaslini Institute, Genova, Italy.
  • 141] Division of Nephrology, Azienda Ospedaliero Universitaria, Parma, Italy. [2] Chair of Nephrology, University of Parma, Parma, Italy.
  • 15Division of Nephrology, Dialysis and Renal Transplantation, Riuniti Hospital, Ancona, Italy.
  • 16Division of Nephrology and Dialysis, Gorizia Hospital, Gorizia, Italy.
  • 17Division of Nephrology, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Trieste, Trieste, Italy.
  • 18Nephrology and Dialysis Unit, Humanitas Clinical and Research Center, Milan, Italy.
  • 19Division of Nephrology and Dialysis, Infermi Hospital, Rimini, Italy.
  • 20Division of Nephrology, Cannizzaro Hospital, Catania, Italy.
  • 21Chair of Nephrology, Division of Nephology and Dialysis, University of Messina, Azienda Ospedaliero-Universitaria Policlinico, Messina, Italy.
  • 22Department of Nephrology and Dialysis, G. Brotzu Hospital, Cagliari, Italy.
  • 23Nephrology and Dialysis, Hospital of Viterbo, Viterbo, Italy.
  • 24Division of Nephrology and Dialysis, Sandro Pertini Hospital, Rome, Italy.
  • 25Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
  • 26Section of Nephrology, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
  • 27Department of Nephrology, Second University of Naples, Naples, Italy.
  • 28Unità Operativa di Nefrologia e Dialisi, Ospedale di Acireale, Acireale, Italy.
  • 29Department of Nephrology, 1st Faculty of Medicine and General University Hospital, Charles University, Prague, Czech Republic.
  • 301] Department of Nephrology, RWTH (Rheinisch-Westfälische Technische Hochschule) University of Aachen, Aachen, Germany. [2] Kidney Diseases Research, Bayer Pharma, Wuppertal, Germany.
  • 31Department of Nephrology, RWTH (Rheinisch-Westfälische Technische Hochschule) University of Aachen, Aachen, Germany.
  • 321] Nephrology Center, Medical Faculty, University of Pécs, Pécs, Hungary. [2] Second Department of Internal Medicine, Medical Faculty, University of Pécs, Pécs, Hungary.
  • 33Department of Immunology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland.
  • 34Krysiewicza Children's Hospital, Poznań, Poland.
  • 35Department of Pediatrics and Nephrology, Medical University of Warsaw, Warsaw, Poland.
  • 36Department of Nephrology, Transplantology and Internal Medicine, Poznan Medical University, Poznan, Poland.
  • 37University College London Centre for Nephrology, Royal Free Hospital Pond Street, London, UK.
  • 381] John Walls Renal Unit, University Hospitals of Leicester, Leicester, UK. [2] Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK.
  • 39Department of Nephrology, Dialysis and Renal Transplantation, University North Hospital, Saint Etienne, France.
  • 401] Service de Néphrologie Transplantation Adultes, Hôpital Necker-Enfants Malades, Paris, France. [2] INSERM, Institut Necker-Enfants Malades, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
  • 41Centre National de Génotypage, Commissariat à l'Energie Atomique (CEA), Institut de Génomique, Evry, France.
  • 421] INSERM, Centre for Research in Epidemiology and Population Health, Villejuif, France. [2] University Paris-Sud, Villejuif, France.
  • 43III Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
  • 44Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan.
  • 45Division of Clinical Nephrology and Rheumatology, Niigata University, Niigata, Japan.
  • 46Division of Nephrology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
  • 47Department of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 48Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China.
  • 491] Division of Pediatric Nephrology, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA. [2] Children's Foundation Research Center, Le Bonheur Children's Hospital, Memphis, Tennessee, USA.
  • 50Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
  • 51Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
  • 521] Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA. [2] Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.

Abstract

We performed a genome-wide association study (GWAS) of IgA nephropathy (IgAN), the most common form of glomerulonephritis, with discovery and follow-up in 20,612 individuals of European and East Asian ancestry. We identified six new genome-wide significant associations, four in ITGAM-ITGAX, VAV3 and CARD9 and two new independent signals at HLA-DQB1 and DEFA. We replicated the nine previously reported signals, including known SNPs in the HLA-DQB1 and DEFA loci. The cumulative burden of risk alleles is strongly associated with age at disease onset. Most loci are either directly associated with risk of inflammatory bowel disease (IBD) or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The geospatial distribution of risk alleles is highly suggestive of multi-locus adaptation, and genetic risk correlates strongly with variation in local pathogens, particularly helminth diversity, suggesting a possible role for host-intestinal pathogen interactions in shaping the genetic landscape of IgAN.

PMID:
25305756
[PubMed - indexed for MEDLINE]
PMCID:
PMC4213311
Free PMC Article
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