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Diabetes. 2016 Mar;65(3):803-17. doi: 10.2337/db15-1313. Epub 2015 Dec 2.

Genome-wide Association Studies Identify Genetic Loci Associated With Albuminuria in Diabetes.

Teumer A1, Tin A2, Sorice R3, Gorski M4, Yeo NC5, Chu AY6, Li M2, Li Y7, Mijatovic V8, Ko YA9, Taliun D10, Luciani A11, Chen MH12, Yang Q13, Foster MC14, Olden M15, Hiraki LT16, Tayo BO17, Fuchsberger C10, Dieffenbach AK18, Shuldiner AR19, Smith AV20, Zappa AM21, Lupo A22, Kollerits B23, Ponte B24, Stengel B25, Krämer BK26, Paulweber B27, Mitchell BD19, Hayward C28, Helmer C29, Meisinger C30, Gieger C31, Shaffer CM32, Müller C33, Langenberg C34, Ackermann D35, Siscovick D36; DCCT/EDIC, Boerwinkle E37, Kronenberg F23, Ehret GB38, Homuth G39, Waeber G40, Navis G41, Gambaro G42, Malerba G8, Eiriksdottir G43, Li G36, Wichmann HE44, Grallert H45, Wallaschofski H46, Völzke H47, Brenner H48, Kramer H17, Mateo Leach I49, Rudan I50, Hillege HL51, Beckmann JS52, Lambert JC53, Luan J34, Zhao JH34, Chalmers J54, Coresh J55, Denny JC32, Butterbach K48, Launer LJ56, Ferrucci L57, Kedenko L27, Haun M23, Metzger M25, Woodward M58, Hoffman MJ5, Nauck M59, Waldenberger M30, Pruijm M60, Bochud M61, Rheinberger M62, Verweij N49, Wareham NJ34, Endlich N63, Soranzo N64, Polasek O65, van der Harst P51, Pramstaller PP10, Vollenweider P40, Wild PS66, Gansevoort RT51, Rettig R67, Biffar R68, Carroll RJ32, Katz R69, Loos RJ70, Hwang SJ71, Coassin S23, Bergmann S72, Rosas SE73, Stracke S74, Harris TB56, Corre T72, Zeller T33, Illig T75, Aspelund T20, Tanaka T57, Lendeckel U76, Völker U77, Gudnason V20, Chouraki V53, Koenig W78, Kutalik Z79, O'Connell JR19, Parsa A19, Heid IM80, Paterson AD81, de Boer IH69, Devuyst O11, Lazar J82, Endlich K63, Susztak K9, Tremblay J83, Hamet P83, Jacob HJ5, Böger CA62, Fox CS84, Pattaro C85, Köttgen A86.

Author information

1
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany German Center for Cardiovascular Research (DZHK), partner site Greifswald, Greifswald, Germany anna.koettgen@uniklinik-freiburg.de ateumer@uni-greifswald.de foxca@nhlbi.nih.gov cristian.pattaro@eurac.edu.
2
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
3
Institute of Genetics and Biophysics, "Adriano-Buzzati Traverso," Consiglio Nazionale delle Ricerche, Naples, Italy.
4
Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany Department of Nephrology, University Hospital Regensburg, Regensburg, Germany.
5
Department of Physiology, Medical College of Wisconsin, Milwaukee, WI.
6
Preventive Medicine, Brigham and Women's Hospital, Boston, MA National Heart, Lung, and Blood Institute's Framingham Heart Study and the Center for Population Studies, Framingham, MA.
7
Renal Division, Medical Center, University of Freiburg, Freiburg, Germany.
8
Department of Life and Reproduction Sciences, University of Verona, Verona, Italy.
9
Renal-Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA.
10
Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC), affiliated to the University of Lübeck, Bolzano, Italy.
11
Institute of Physiology, Mechanisms of Inherited Kidney Disorders Group, University of Zürich, Zürich, Switzerland.
12
Department of Neurology, Boston University School of Medicine, Boston, MA Department of Biostatistics, Boston University School of Public Health, Boston, MA.
13
Department of Biostatistics, Boston University School of Public Health, Boston, MA.
14
Tufts Medical Center, Boston, MA.
15
Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany Department of Epidemiology and Preventive Medicine, Regensburg University Medical Center, Regensburg, Germany.
16
Genetics and Genome Biology Program, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.
17
Loyola University Chicago, Maywood, IL.
18
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany German Cancer Consortium (DKTK), Heidelberg, Germany.
19
Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.
20
Icelandic Heart Association, Kópavogur, Iceland Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
21
Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI.
22
Renal Unit, Department of Medicine, University of Verona, Verona, Italy.
23
Division of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria.
24
Nephrology Division, Department of Specialties of Internal Medicine, Geneva University Hospitals, Geneva, Switzerland.
25
INSERM U-1018, Centre de recherche en épidémiologie et santé des populations (CESP) Team 5, Villejuif, France UMRS 1018, Centre de recherche en épidémiologie et santé des populations (CESP) Team 5, Univ Paris Sud, Univ Versailles, St. Quentin, France.
26
Fifth Department of Medicine, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany.
27
First Department of Internal Medicine, Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria.
28
Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland, U.K.
29
INSERM U897, Bordeaux University, Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Bordeaux, France.
30
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
31
Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
32
Vanderbilt University School of Medicine, Nashville, TN.
33
University Heart Center Hamburg, Hamburg, Germany German Center for Cardiovascular Research (DZHK e.V.), partner site Hamburg, Lübeck, Kiel, Germany.
34
Medical Research Council Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, U.K.
35
University Clinic for Nephrology, Hypertension and Clinical Pharmacology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.
36
Cardiovascular Health Research Unit, Departments of Epidemiology and Medicine, University of Washington, Seattle, WA.
37
Human Genetics Center, University of Texas Health Science Center, Houston, TX.
38
Cardiology, Department of Specialties of Internal Medicine, Geneva University Hospitals, Geneva, Switzerland.
39
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
40
Department of Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland.
41
Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
42
Division of Nephrology, Department of Internal Medicine and Medical Specialties, Columbus-Gemelli University Hospital, Catholic University, Rome, Italy.
43
Icelandic Heart Association, Kópavogur, Iceland.
44
Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany Institute of Medical Statistics and Epidemiology, Technical University Munich, Munich, Germany.
45
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany German Center for Diabetes Research (DZD), Neuherberg, Germany.
46
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
47
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany German Center for Cardiovascular Research (DZHK), partner site Greifswald, Greifswald, Germany.
48
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
49
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
50
Centre for Population Health Sciences, University of Edinburgh, Edinburgh, Scotland, U.K.
51
Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
52
Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland Swiss Institute of Bioinformatics, Lausanne, Switzerland.
53
INSERM UMR 1167 "Risk factors and molecular determinants of aging-related diseases," Institut Pasteur de Lille, Lille, France.
54
The George Institute for Global Health, University of Sydney, Camperdown, New South Wales, Australia.
55
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD Welch Center for Prevention, Epidemiology and Clinical Research, Baltimore, MD.
56
Laboratory of Epidemiology and Population Sciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD.
57
Clinical Research Branch, National Institute on Aging, Baltimore, MD.
58
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD The George Institute for Global Health, University of Sydney, Camperdown, New South Wales, Australia The George Institute for Global Health, Nuffield Department of Population Health, University of Oxford, Oxford, U.K.
59
German Center for Cardiovascular Research (DZHK), partner site Greifswald, Greifswald, Germany Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
60
Service of Nephrology, Lausanne University Hospital, Lausanne, Switzerland.
61
University Institute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Épalinges, Switzerland.
62
Department of Nephrology, University Hospital Regensburg, Regensburg, Germany.
63
Institute of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany.
64
Human Genetics, Wellcome Trust Sanger Institute, Hinxton, U.K. Department of Haematology, University of Cambridge, Cambridge, U.K.
65
Croatian Centre for Global Health, Faculty of Medicine, University of Split, Split, Croatia.
66
Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg, University Mainz, Mainz, Germany Preventive Cardiology and Preventive Medicine, Department of Medicine 2, University Medical Center of the Johannes Gutenberg, University Mainz, Mainz, Germany German Center for Cardiovascular Research (DZHK), Mainz, Germany.
67
Institute of Physiology, University Medicine Greifswald, Greifswald, Germany.
68
Clinic for Prosthetic Dentistry, Gerostomatology and Material Science, University Medicine Greifswald, Greifswald, Germany.
69
Kidney Research Institute, Department of Medicine, University of Washington, Seattle, WA.
70
Medical Research Council Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, U.K. Genetics of Obesity and Related Metabolic Traits Program, The Charles Bronfman Institute for Personalized Medicine, The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, NY.
71
National Heart, Lung, and Blood Institute's Framingham Heart Study and the Center for Population Studies, Framingham, MA.
72
Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
73
Kidney and Hypertension Section, Joslin Diabetes Center and Harvard Medical School, Boston, MA.
74
Clinic for Internal Medicine A, University Medicine Greifswald, Greifswald, Germany.
75
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany Institute for Human Genetics, Hannover Medical School, Hannover, Germany Hannover Unified Biobank, Hannover Medical School, Hannover, Germany.
76
Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Greifswald, Germany.
77
German Center for Cardiovascular Research (DZHK), partner site Greifswald, Greifswald, Germany Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
78
Abteilung Innere II, Universitätsklinikum Ulm, Ulm, Germany Deutsches Herzzentrum München, Technische Universität München, Munich, Germany German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany.
79
Swiss Institute of Bioinformatics, Lausanne, Switzerland Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland University Institute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
80
Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
81
Genetics and Genome Biology Program, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
82
Department of Dermatology, Medical College of Wisconsin, Milwaukee, WI.
83
Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), University of Montreal, CHUM Research Center, Technopìle Angus, Montreal, Quebec, Canada.
84
National Heart, Lung, and Blood Institute's Framingham Heart Study and the Center for Population Studies, Framingham, MA Division of Endocrinology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA anna.koettgen@uniklinik-freiburg.de ateumer@uni-greifswald.de foxca@nhlbi.nih.gov cristian.pattaro@eurac.edu.
85
Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC), affiliated to the University of Lübeck, Bolzano, Italy anna.koettgen@uniklinik-freiburg.de ateumer@uni-greifswald.de foxca@nhlbi.nih.gov cristian.pattaro@eurac.edu.
86
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD Renal Division, Medical Center, University of Freiburg, Freiburg, Germany anna.koettgen@uniklinik-freiburg.de ateumer@uni-greifswald.de foxca@nhlbi.nih.gov cristian.pattaro@eurac.edu.

Abstract

Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (P = 2.4 × 10(-10)). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. Single nucleotide polymorphisms at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in the average UACR per minor allele was 21% for HS6ST1 (P = 6.3 × 10(-7)) and 13% for RAB38/CTSC (P = 5.8 × 10(-7)). Experiments using streptozotocin-induced diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout versus control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared with control subjects. The loci identified here confirm known pathways and highlight novel pathways influencing albuminuria.

PMID:
26631737
PMCID:
PMC4764151
[Available on 2017-03-01]
DOI:
10.2337/db15-1313
[Indexed for MEDLINE]
Free PMC Article

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