Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes-Reference-Cited by-同舟云学术

Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes

Published:2011-09-16 Issue:10 Volume:60 Page:2624-2634
ISSN:0012-1797
Container-title:Diabetes
language:en
Short-container-title:

Author:

Strawbridge Rona J.¹,Dupuis Josée²³,Prokopenko Inga⁴⁵,Barker Adam⁶,Ahlqvist Emma⁷,Rybin Denis⁸,Petrie John R.⁹,Travers Mary E.⁴,Bouatia-Naji Nabila¹⁰¹¹,Dimas Antigone S.⁵¹²,Nica Alexandra¹²¹³,Wheeler Eleanor¹⁴,Chen Han²,Voight Benjamin F.¹⁵¹⁶,Taneera Jalal⁷,Kanoni Stavroula¹³¹⁷,Peden John F.⁵¹⁸,Turrini Fabiola⁷¹⁹,Gustafsson Stefan²⁰,Zabena Carina²¹²²,Almgren Peter⁷,Barker David J.P.²³,Barnes Daniel⁶,Dennison Elaine M.²⁴,Eriksson Johan G.²⁵²⁶²⁷²⁸,Eriksson Per¹,Eury Elodie¹⁰¹¹,Folkersen Lasse²⁹,Fox Caroline S.³³⁰,Frayling Timothy M.³¹,Goel Anuj⁵¹⁸,Gu Harvest F.³²,Horikoshi Momoko⁴⁵,Isomaa Bo²⁷³³,Jackson Anne U.³⁴,Jameson Karen A.²⁴,Kajantie Eero²⁵³⁵,Kerr-Conte Julie¹⁰³⁶,Kuulasmaa Teemu³⁷,Kuusisto Johanna³⁷,Loos Ruth J.F.⁶,Luan Jian'an⁶,Makrilakis Konstantinos³⁸,Manning Alisa K.²,Martínez-Larrad María Teresa²¹²²,Narisu Narisu³⁹,Nastase Mannila Maria¹,Öhrvik John¹,Osmond Clive²⁴,Pascoe Laura⁴⁰,Payne Felicity¹⁴,Sayer Avan A.²⁴,Sennblad Bengt¹,Silveira Angela¹,Stančáková Alena³⁷,Stirrups Kathy¹³,Swift Amy J.³⁹,Syvänen Ann-Christine⁴¹,Tuomi Tiinamaija²⁷⁴²,van 't Hooft Ferdinand M.¹,Walker Mark⁴³,Weedon Michael N.³¹,Xie Weijia³¹,Zethelius Björn⁴⁴,Ongen Halit⁵¹⁸⁴⁵,Mälarstig Anders¹,Hopewell Jemma C.⁴⁶,Saleheen Danish⁴⁷⁴⁸,Chambers John⁴⁹⁵⁰,Parish Sarah⁴⁶,Danesh John⁴⁷,Kooner Jaspal⁵⁰⁵¹,Östenson Claes-Göran³²,Lind Lars⁴¹,Cooper Cyrus C.²⁴,Serrano-Ríos Manuel²¹²²,Ferrannini Ele⁵²,Forsen Tom J.²⁸⁵³,Clarke Robert⁴⁶,Franzosi Maria Grazia⁵⁴,Seedorf Udo⁵⁵,Watkins Hugh⁵¹⁸,Froguel Philippe¹⁰¹¹⁵⁶,Johnson Paul⁴⁵⁷,Deloukas Panos¹³,Collins Francis S.⁵⁸,Laakso Markku³⁷,Dermitzakis Emmanouil T.¹²,Boehnke Michael³⁴,McCarthy Mark I.⁴⁵⁵⁹,Wareham Nicholas J.⁶,Groop Leif⁷,Pattou François¹⁰³⁶,Gloyn Anna L.⁴,Dedoussis George V.¹⁷,Lyssenko Valeriya⁷,Meigs James B.⁶⁰⁶¹,Barroso Inês¹⁴⁶²,Watanabe Richard M.⁶³⁶⁴,Ingelsson Erik²⁰,Langenberg Claudia⁶,Hamsten Anders¹,Florez Jose C.¹⁵¹⁶⁶¹, , , , ,

Affiliation:

1. Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden

2. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts

3. National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, Massachusetts

4. Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, U.K.

5. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.

6. MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, U.K.

7. Department of Clinical Sciences, Diabetes and Endocrinology, University Hospital and Malmö, Lund University, Malmö, Sweden

8. Boston University Data Coordinating Center, Boston, Massachusetts

9. BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, U.K.

10. Université Lille-Nord de France, Lille, France

11. CNRS UMR 8199, Institut Pasteur de Lille, Lille, France

12. Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland

13. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, U.K.

14. Metabolic Disease Group, Wellcome Trust Sanger Institute, Hinxton, Cambridge, U.K.

15. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts

16. Center for Human Genetic Research and Diabetes Research Center (Diabetes Unit), Massachusetts General Hospital, Boston, Massachusetts

17. Department of Dietetics-Nutrition, Harokopio University, Athens, Greece

18. Department of Cardiovascular Medicine, University of Oxford, Oxford, U.K.

19. Department of Medicine, University of Verona, Verona, Italy

20. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

21. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain

22. Fundación Investigación Biomédica del Hospital Clínico San Carlos, Madrid, Spain

23. Heart Research Center, Oregon Health and Science University, Portland, Oregon

24. MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton, U.K.

25. National Institute for Health and Welfare, Helsinki, Finland

26. Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland

27. Folkhälsan Research Centre, Helsinki, Finland

28. Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland

29. Experimental Cardiovascular Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden

30. Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts

31. Institute of Biomedical and Clinical Sciences, Peninsula Medical School, University of Exeter, Exeter, U.K.

32. Endocrinology and Diabetes Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

33. Malmska Municipal Health Care Center and Hospital, Jakobstad, Finland

34. Center for Statistical Genetics, Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan

35. Hospital for Children and Adolescents, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland

36. INSERM UMR 859, Lille, France

37. Department of Medicine, University of Kuopio and Kuopio University Hospital, Kuopio, Finland

38. First Department of Propaedeutic Medicine, Laiko General Hospital, Athens University Medical School, Athens, Greece

39. National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland

40. Institute of Cell and Molecular Biosciences, Newcastle University, Newcastle, U.K.

41. Department of Medical Sciences, Molecular Medicine, Science for Life Laboratory, Uppsala University, Uppsala, Sweden

42. Department of Medicine, Helsinki University Central Hospital, and Research Program of Molecular Medicine, University of Helsinki, Helsinki, Finland

43. Institute of Cellular Medicine, Newcastle University, Newcastle, U.K.

44. Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden

45. Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, U.K.

46. Clinical Trial Service Unit, University of Oxford, Oxford, U.K.

47. Department of Public Health and Primary Care, University of Cambridge, Cambridge, U.K.

48. Center for Non-Communicable Diseases Pakistan, Karachi, Pakistan

49. Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London, U.K.

50. Cardiology, Ealing Hospital NHS Trust, Middlesex, U.K.

51. National Heart and Lung Institute, Imperial College London, London, U.K.

52. Department of Internal Medicine and CNR Institute of Clinical Physiology, University of Pisa School of Medicine, Pisa, Italy

53. Vaasa Health Care Center, Vaasa, Finland

54. Department of Cardiovascular Research, Mario Negri Institute for Pharmacological Research, Milan, Italy

55. Leibniz Institute for Arteriosclerosis Research, University of Münster, Münster, Germany

56. Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London, U.K.

57. DRWF Human Islet Isolation Facility and Oxford Islet Transplant Programme, University of Oxford, Oxford, U.K.

58. National Institutes of Health, Bethesda, Maryland

59. Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, U.K.

60. General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts

61. Department of Medicine, Harvard Medical School, Boston, Massachusetts

62. University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, U.K.

63. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California

64. Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California

Abstract

OBJECTIVE Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10−8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10−4), improved β-cell function (P = 1.1 × 10−5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10−6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

Link

https://journals.org/diabetes/diabetes/article-pdf/60/10/2624/399665/2624.pdf

Reference47 articles.

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