Genome-Wide Association Study of Diabetic Kidney Disease... : Journal of the American Society of Nephrology (original) (raw)

Clinical Research

Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen

Salem, Rany M.1; Todd, Jennifer N.2,3,4; Sandholm, Niina5,6,7; Cole, Joanne B.2,3,4; Chen, Wei-Min8; Andrews, Darrell9; Pezzolesi, Marcus G.10; McKeigue, Paul M.11; Hiraki, Linda T.12; Qiu, Chengxiang13; Nair, Viji14; Di Liao, Chen12; Cao, Jing Jing12; Valo, Erkka5,6,7; Onengut-Gumuscu, Suna8; Smiles, Adam M.15; McGurnaghan, Stuart J.16; Haukka, Jani K.5,6,7; Harjutsalo, Valma5,6,7,17; Brennan, Eoin P.9; van Zuydam, Natalie18,19; Ahlqvist, Emma20; Doyle, Ross9; Ahluwalia, Tarunveer S.21; Lajer, Maria21; Hughes, Maria F.9; Park, Jihwan13; Skupien, Jan15; Spiliopoulou, Athina11; Liu, Andrew22; Menon, Rajasree14,23; Boustany-Kari, Carine M.24; Kang, Hyun M.23,25; Nelson, Robert G.26; Klein, Ronald27; Klein, Barbara E.27; Lee, Kristine E.27; Gao, Xiaoyu28; Mauer, Michael29; Maestroni, Silvia30; Caramori, Maria Luiza29; de Boer, Ian H.31; Miller, Rachel G.32; Guo, Jingchuan32; Boright, Andrew P.12; Tregouet, David33,34; Gyorgy, Beata33,34; Snell-Bergeon, Janet K.35; Maahs, David M.36; Bull, Shelley B.37; Canty, Angelo J.38; Palmer, Colin N.A.39; Stechemesser, Lars40; Paulweber, Bernhard40; Weitgasser, Raimund40,41; Sokolovska, Jelizaveta42; Rovīte, Vita43; Pīrāgs, Valdis42,44; Prakapiene, Edita45; Radzeviciene, Lina46; Verkauskiene, Rasa46; Panduru, Nicolae Mircea6,47; Groop, Leif C.20,48; McCarthy, Mark I.18,19,49,50; Gu, Harvest F.51,52; Möllsten, Anna53; Falhammar, Henrik54,55; Brismar, Kerstin54,55; Martin, Finian9; Rossing, Peter21,56; Costacou, Tina32; Zerbini, Gianpaolo30; Marre, Michel57,58,59,60; Hadjadj, Samy61,62,63; McKnight, Amy J.64; Forsblom, Carol5,6,7; McKay, Gareth64; Godson, Catherine9; Maxwell, A. Peter64; Kretzler, Matthias14,23; Susztak, Katalin13; Colhoun, Helen M.16; Krolewski, Andrzej15; Paterson, Andrew D.12; Groop, Per-Henrik5,6,7,65; Rich, Stephen S.8; Hirschhorn, Joel N.2,3; Florez, Jose C.3,4,66,67; SUMMIT Consortium, DCCT/EDIC Research Group, GENIE Consortium

1Department of Family Medicine and Public Health, University of California San Diego, La Jolla, California;

2Division of Endocrinology, Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts;

3Programs in Metabolism and Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts;

4Center for Genomic Medicine and

66Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts;

5Folkhälsan Research Center, Folkhälsan Institute of Genetics, Helsinki, Finland;

6Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland;

7Research Program for Clinical and Molecular Metabolism, Faculty of Medicine and

48Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland;

8Center for Public Health Genomics, School of Medicine, University of Virginia, Charlottesville, Virginia;

9Diabetes Complications Research Centre, Conway Institute, School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland;

10Division of Nephrology and Hypertension, Diabetes and Metabolism Center, University of Utah, Salt Lake City, Utah;

11Usher Institute of Population Health Sciences and Informatics and

16Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom;

12The Hospital for Sick Children, Toronto, Ontario, Canada;

13Departments of Medicine and Genetics, University of Pennsylvania, Philadelphia, Pennsylvania;

14Division of Nephrology, Department of Internal Medicine and

23Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan;

15Joslin Diabetes Center, Boston, Massachusetts;

17The Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland;

18Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK;

19Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK;

20Department of Genomics, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden;

21Steno Diabetes Center Copenhagen, Gentofte, Denmark;

22Department of Biostatistics and

25Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, Michigan;

24Cardiometabolic Diseases Research, Boehringer Ingelheim, Ridgefield, Connecticut;

26Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona;

27University of Wisconsin-Madison, Madison, Wisconsin;

28The George Washington University, Washington, DC;

29University of Minnesota, Minneapolis, Minnesota;

30Complications of Diabetes Unit, Division of Immunology, Transplantation and Infectious Diseases, Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milano, Italy;

31University of Washington, Seattle, Washington;

32University of Pittsburgh Public Health, Pittsburgh, Pennsylvania;

33INSERM UMR_S 1166, Sorbonne Université, UPMC Univ Paris 06, Paris, France;

34ICAN Institute for Cardiometabolism and Nutrition, Paris, France;

35University of Colorado School of Medicine, Aurora, Colorado;

36Department of Pediatrics-Endocrinology, Stanford University, Stanford, California;

37The Lunenfeld-Tanenbaum Research Institute, University of Toronto, Toronto, Ontario, Canada;

38Department of Mathematics and Statistics, McMaster University, Hamilton, Ontario, Canada;

39Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK;

40First Department of Medicine, Paracelsus Medical University, Salzburg, Austria;

41Department of Medicine, Diakonissen-Wehrle Hospital, Salzburg, Austria;

42University of Latvia, Riga, Latvia;

44Pauls Stradins University Hospital, Riga, Latvia;

43Latvian Biomedical Research and Study Centre, Riga, Latvia;

45Medical Academy and

46Institute of Endocrinology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania;

472nd Clinical Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania;

49Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK;

50Genentech, 1 DNA Way, South San Francisco, California;

51Department of Clinical Science, Intervention and Technology and

55Department of Endocrinology, Diabetes and Metabolism, Karolinska University Hospital, Stockholm, Sweden;

52School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China;

53Division of Pediatrics, Department of Clinical Sciences, Umeå University, Umeå, Sweden;

54Department of Molecular Medicine and Surgery, Rolf Luft Center for Diabetes Research and Endocrinology, Karolinska Institutet, Stockholm, Sweden;

56University of Copenhagen, Copenhagen, Denmark;

57Department of Diabetology, Endocrinology and Nutrition, Bichat Hospital, DHU FIRE, Assistance Publique–Hôpitaux de Paris, Paris, France;

58UFR de Médecine, Paris Diderot University, Sorbonne Paris Cité, Paris, France;

59INSERM UMRS 1138, Cordeliers Research Center, Paris, France;

60Fondation Ophtalmologique Adolphe de Rothschild, Paris, France;

61Department of Endocrinology and Diabetology, Centre Hospitalier Universitaire de Poitiers, Poitiers, France;

62INSERM CIC 1402, Poitiers, France;

63L’institut du thorax, INSERM, CNRS, CHU Nantes, Nantes, France;

64Centre for Public Health, Queens University of Belfast, Northern Ireland, UK;

65Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia; and

67Department of Medicine, Harvard Medical School, Boston, Massachusetts

R.M.S., J.N.T., N.S., and J.B.C. contributed equally to this work.

Lead author: Jose C. Florez..

Correspondence: Dr. Jose C. Florez, Simches Research Building - CPZN 5.250, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts, 02114. Email: [email protected]

Abstract

Significance Statement

Although studies show that diabetic kidney disease has a heritable component, searches for the genetic determinants of this complication of diabetes have had limited success. In this study, a new international genomics consortium, the JDRF funded Diabetic Nephropathy Collaborative Research Initiative, assembled nearly 20,000 samples from participants with type 1 diabetes, with and without kidney disease. The authors found 16 new diabetic kidney disease–associated loci at genome-wide significance. The strongest signal centers on a protective missense coding variant at COL4A3, a gene that encodes a component of the glomerular basement membrane that, when mutated, causes the progressive inherited nephropathy Alport syndrome. These GWAS-identified risk loci may provide insights into the pathogenesis of diabetic kidney disease and help identify potential biologic targets for prevention and treatment.

Background

Although diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown.

Methods

To identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function.

Results

Our GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in COL4A3 are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width; protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition (BMP7) or renal biology (COLEC11 and DDR1).

Conclusions

The 16 diabetic kidney disease–associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.

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