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

  1. Jose C. Florez15,16,61
  1. 1Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden
  2. 2Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts
  3. 3National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, Massachusetts
  4. 4Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, U.K.
  5. 5Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.
  6. 6MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, U.K.
  7. 7Department of Clinical Sciences, Diabetes and Endocrinology, University Hospital and Malmö, Lund University, Malmö, Sweden
  8. 8Boston University Data Coordinating Center, Boston, Massachusetts
  9. 9BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, U.K.
  10. 10Université Lille-Nord de France, Lille, France
  11. 11CNRS UMR 8199, Institut Pasteur de Lille, Lille, France
  12. 12Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
  13. 13Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, U.K.
  14. 14Metabolic Disease Group, Wellcome Trust Sanger Institute, Hinxton, Cambridge, U.K.
  15. 15Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts
  16. 16Center for Human Genetic Research and Diabetes Research Center (Diabetes Unit), Massachusetts General Hospital, Boston, Massachusetts
  17. 17Department of Dietetics-Nutrition, Harokopio University, Athens, Greece
  18. 18Department of Cardiovascular Medicine, University of Oxford, Oxford, U.K.
  19. 19Department of Medicine, University of Verona, Verona, Italy
  20. 20Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  21. 21CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
  22. 22Fundación Investigación Biomédica del Hospital Clínico San Carlos, Madrid, Spain
  23. 23Heart Research Center, Oregon Health and Science University, Portland, Oregon
  24. 24MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton, U.K.
  25. 25National Institute for Health and Welfare, Helsinki, Finland
  26. 26Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland
  27. 27Folkhälsan Research Centre, Helsinki, Finland
  28. 28Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland
  29. 29Experimental Cardiovascular Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
  30. 30Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  31. 31Institute of Biomedical and Clinical Sciences, Peninsula Medical School, University of Exeter, Exeter, U.K.
  32. 32Endocrinology and Diabetes Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
  33. 33Malmska Municipal Health Care Center and Hospital, Jakobstad, Finland
  34. 34Center for Statistical Genetics, Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan
  35. 35Hospital for Children and Adolescents, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland
  36. 36INSERM UMR 859, Lille, France
  37. 37Department of Medicine, University of Kuopio and Kuopio University Hospital, Kuopio, Finland
  38. 38First Department of Propaedeutic Medicine, Laiko General Hospital, Athens University Medical School, Athens, Greece
  39. 39National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
  40. 40Institute of Cell and Molecular Biosciences, Newcastle University, Newcastle, U.K.
  41. 41Department of Medical Sciences, Molecular Medicine, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
  42. 42Department of Medicine, Helsinki University Central Hospital, and Research Program of Molecular Medicine, University of Helsinki, Helsinki, Finland
  43. 43Institute of Cellular Medicine, Newcastle University, Newcastle, U.K.
  44. 44Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden
  45. 45Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, U.K.
  46. 46Clinical Trial Service Unit, University of Oxford, Oxford, U.K.
  47. 47Department of Public Health and Primary Care, University of Cambridge, Cambridge, U.K.
  48. 48Center for Non-Communicable Diseases Pakistan, Karachi, Pakistan
  49. 49Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London, U.K.
  50. 50Cardiology, Ealing Hospital NHS Trust, Middlesex, U.K.
  51. 51National Heart and Lung Institute, Imperial College London, London, U.K.
  52. 52Department of Internal Medicine and CNR Institute of Clinical Physiology, University of Pisa School of Medicine, Pisa, Italy
  53. 53Vaasa Health Care Center, Vaasa, Finland
  54. 54Department of Cardiovascular Research, Mario Negri Institute for Pharmacological Research, Milan, Italy
  55. 55Leibniz Institute for Arteriosclerosis Research, University of Münster, Münster, Germany
  56. 56Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London, U.K.
  57. 57DRWF Human Islet Isolation Facility and Oxford Islet Transplant Programme, University of Oxford, Oxford, U.K.
  58. 58National Institutes of Health, Bethesda, Maryland
  59. 59Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, U.K.
  60. 60General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts
  61. 61Department of Medicine, Harvard Medical School, Boston, Massachusetts
  62. 62University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, U.K.
  63. 63Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
  64. 64Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California
  1. Corresponding authors: Jose C. Florez, jcflorez{at}; Claudia Langenberg, claudia.langenberg{at}; and Anders Hamsten, anders.hamsten{at}
  1. R.J.S., J.Du., I.P., A.B., and E.A. contributed equally to this work.


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.


  • Received March 23, 2011.
  • Accepted June 29, 2011.

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