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

Author:

Teumer Alexander12,Tin Adrienne3,Sorice Rossella4,Gorski Mathias56,Yeo Nan Cher7,Chu Audrey Y.89,Li Man3,Li Yong10,Mijatovic Vladan11,Ko Yi-An12,Taliun Daniel13,Luciani Alessandro14,Chen Ming-Huei1516,Yang Qiong16,Foster Meredith C.17,Olden Matthias518,Hiraki Linda T.19,Tayo Bamidele O.20,Fuchsberger Christian13,Dieffenbach Aida Karina2122,Shuldiner Alan R.23,Smith Albert V.2425,Zappa Allison M.26,Lupo Antonio27,Kollerits Barbara28,Ponte Belen29,Stengel Bénédicte3031,Krämer Bernhard K.32,Paulweber Bernhard33,Mitchell Braxton D.23,Hayward Caroline34,Helmer Catherine35,Meisinger Christa36,Gieger Christian37,Shaffer Christian M.38,Müller Christian3940,Langenberg Claudia41,Ackermann Daniel42,Siscovick David43,Boerwinkle Eric44,Kronenberg Florian28,Ehret Georg B.45,Homuth Georg46,Waeber Gerard47,Navis Gerjan48,Gambaro Giovanni49,Malerba Giovanni11,Eiriksdottir Gudny24,Li Guo43,Wichmann H. Erich505152,Grallert Harald365354,Wallaschofski Henri55,Völzke Henry12,Brenner Herrmann21,Kramer Holly20,Leach I. Mateo56,Rudan Igor57,Hillege Hans L.58,Beckmann Jacques S.5960,Lambert Jean Charles61,Luan Jian'an41,Zhao Jing Hua41,Chalmers John62,Coresh Josef363,Denny Joshua C.38,Butterbach Katja21,Launer Lenore J.64,Ferrucci Luigi65,Kedenko Lyudmyla33,Haun Margot28,Metzger Marie3031,Woodward Mark36266,Hoffman Matthew J.7,Nauck Matthias255,Waldenberger Melanie36,Pruijm Menno67,Bochud Murielle68,Rheinberger Myriam6,Verweij Niek56,Wareham Nicholas J.41,Endlich Nicole69,Soranzo Nicole7071,Polasek Ozren72,van der Harst Pim58,Pramstaller Peter Paul13,Vollenweider Peter47,Wild Philipp S.737475,Gansevoort Ron T.58,Rettig Rainer76,Biffar Reiner77,Carroll Robert J.38,Katz Ronit78,Loos Ruth J.F.4179,Hwang Shih-Jen9,Coassin Stefan28,Bergmann Sven80,Rosas Sylvia E.81,Stracke Sylvia82,Harris Tamara B.64,Corre Tanguy80,Zeller Tanja3940,Illig Thomas368384,Aspelund Thor2425,Tanaka Toshiko65,Lendeckel Uwe85,Völker Uwe246,Gudnason Vilmundur2425,Chouraki Vincent61,Koenig Wolfgang868788,Kutalik Zoltan608089,O'Connell Jeffrey R.23,Parsa Afshin23,Heid Iris M.537,Paterson Andrew D.1990,de Boer Ian H.78,Devuyst Olivier14,Lazar Jozef91,Endlich Karlhans69,Susztak Katalin12,Tremblay Johanne92,Hamet Pavel92,Jacob Howard J.7,Böger Carsten A.6,Fox Caroline S.993,Pattaro Cristian13,Köttgen Anna310,

Affiliation:

1. Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany

2. German Center for Cardiovascular Research (DZHK), partner site Greifswald, Greifswald, Germany

3. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD

4. Institute of Genetics and Biophysics, “Adriano-Buzzati Traverso,” Consiglio Nazionale delle Ricerche, Naples, Italy

5. Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany

6. Department of Nephrology, University Hospital Regensburg, Regensburg, Germany

7. Department of Physiology, Medical College of Wisconsin, Milwaukee, WI

8. Preventive Medicine, Brigham and Women's Hospital, Boston, MA

9. National Heart, Lung, and Blood Institute's Framingham Heart Study and the Center for Population Studies, Framingham, MA

10. Renal Division, Medical Center, University of Freiburg, Freiburg, Germany

11. Department of Life and Reproduction Sciences, University of Verona, Verona, Italy

12. Renal-Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA

13. Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC), affiliated to the University of Lübeck, Bolzano, Italy

14. Institute of Physiology, Mechanisms of Inherited Kidney Disorders Group, University of Zürich, Zürich, Switzerland

15. Department of Neurology, Boston University School of Medicine, Boston, MA

16. Department of Biostatistics, Boston University School of Public Health, Boston, MA

17. Tufts Medical Center, Boston, MA

18. Department of Epidemiology and Preventive Medicine, Regensburg University Medical Center, Regensburg, Germany

19. Genetics and Genome Biology Program, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada

20. Loyola University Chicago, Maywood, IL

21. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany

22. German Cancer Consortium (DKTK), Heidelberg, Germany

23. Department of Medicine, University of Maryland School of Medicine, Baltimore, MD

24. Icelandic Heart Association, Kópavogur, Iceland

25. Faculty of Medicine, University of Iceland, Reykjavik, Iceland

26. Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI

27. Renal Unit, Department of Medicine, University of Verona, Verona, Italy

28. Division of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria

29. Nephrology Division, Department of Specialties of Internal Medicine, Geneva University Hospitals, Geneva, Switzerland

30. INSERM U-1018, Centre de recherche en épidémiologie et santé des populations (CESP) Team 5, Villejuif, France

31. UMRS 1018, Centre de recherche en épidémiologie et santé des populations (CESP) Team 5, Univ Paris Sud, Univ Versailles, St. Quentin, France

32. Fifth Department of Medicine, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany

33. First Department of Internal Medicine, Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria

34. Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland, U.K.

35. INSERM U897, Bordeaux University, Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Bordeaux, France

36. Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

37. Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

38. Vanderbilt University School of Medicine, Nashville, TN

39. University Heart Center Hamburg, Hamburg, Germany

40. German Center for Cardiovascular Research (DZHK e.V.), partner site Hamburg, Lübeck, Kiel, Germany

41. Medical Research Council Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, U.K.

42. University Clinic for Nephrology, Hypertension and Clinical Pharmacology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland

43. Cardiovascular Health Research Unit, Departments of Epidemiology and Medicine, University of Washington, Seattle, WA

44. Human Genetics Center, University of Texas Health Science Center, Houston, TX

45. Cardiology, Department of Specialties of Internal Medicine, Geneva University Hospitals, Geneva, Switzerland

46. Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany

47. Department of Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland

48. Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

49. Division of Nephrology, Department of Internal Medicine and Medical Specialties, Columbus-Gemelli University Hospital, Catholic University, Rome, Italy

50. Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

51. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany

52. Institute of Medical Statistics and Epidemiology, Technical University Munich, Munich, Germany

53. Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

54. German Center for Diabetes Research (DZD), Neuherberg, Germany

55. Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany

56. Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

57. Centre for Population Health Sciences, University of Edinburgh, Edinburgh, Scotland, U.K.

58. Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

59. Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland

60. Swiss Institute of Bioinformatics, Lausanne, Switzerland

61. INSERM UMR 1167 “Risk factors and molecular determinants of aging-related diseases,” Institut Pasteur de Lille, Lille, France.

62. The George Institute for Global Health, University of Sydney, Camperdown, New South Wales, Australia

63. Welch Center for Prevention, Epidemiology and Clinical Research, Baltimore, MD

64. Laboratory of Epidemiology and Population Sciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD

65. Clinical Research Branch, National Institute on Aging, Baltimore, MD

66. The George Institute for Global Health, Nuffield Department of Population Health, University of Oxford, Oxford, U.K.

67. Service of Nephrology, Lausanne University Hospital, Lausanne, Switzerland

68. University Institute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Épalinges, Switzerland

69. Institute of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany

70. Human Genetics, Wellcome Trust Sanger Institute, Hinxton, U.K.

71. Department of Haematology, University of Cambridge, Cambridge, U.K.

72. Croatian Centre for Global Health, Faculty of Medicine, University of Split, Split, Croatia

73. Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg, University Mainz, Mainz, Germany

74. Preventive Cardiology and Preventive Medicine, Department of Medicine 2, University Medical Center of the Johannes Gutenberg, University Mainz, Mainz, Germany

75. German Center for Cardiovascular Research (DZHK), Mainz, Germany

76. Institute of Physiology, University Medicine Greifswald, Greifswald, Germany

77. Clinic for Prosthetic Dentistry, Gerostomatology and Material Science, University Medicine Greifswald, Greifswald, Germany

78. Kidney Research Institute, Department of Medicine, University of Washington, Seattle, WA

79. 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

80. Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland

81. Kidney and Hypertension Section, Joslin Diabetes Center and Harvard Medical School, Boston, MA

82. Clinic for Internal Medicine A, University Medicine Greifswald, Greifswald, Germany

83. Institute for Human Genetics, Hannover Medical School, Hannover, Germany

84. Hannover Unified Biobank, Hannover Medical School, Hannover, Germany

85. Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Greifswald, Germany

86. Abteilung Innere II, Universitätsklinikum Ulm, Ulm, Germany

87. Deutsches Herzzentrum München, Technische Universität München, Munich, Germany

88. German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany

89. University Institute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland

90. Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada

91. Department of Dermatology, Medical College of Wisconsin, Milwaukee, WI

92. Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), University of Montreal, CHUM Research Center, Technopìle Angus, Montreal, Quebec, Canada.

93. Division of Endocrinology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA

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.

Funder

National Institutes of Health

NIH

German Research Foundation

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

Reference42 articles.

1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl 2013;3:1–150

2. Plantinga LC, Crews DC, Coresh J, et al. Prevalence of chronic kidney disease in US adults with undiagnosed diabetes or prediabetes. Clin J Am Soc Nephrol 2010;5:673–682

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