A Genome-Wide Association Study of IVGTT-Based Measures of First-Phase Insulin Secretion Refines the Underlying Physiology of Type 2 Diabetes Variants-Reference-Cited by-同舟云学术

A Genome-Wide Association Study of IVGTT-Based Measures of First-Phase Insulin Secretion Refines the Underlying Physiology of Type 2 Diabetes Variants

Published:2017-05-10 Issue:8 Volume:66 Page:2296-2309
ISSN:0012-1797
Container-title:Diabetes
language:en
Short-container-title:

Author:

Wood Andrew R.¹,Jonsson Anna²,Jackson Anne U.³,Wang Nan⁴⁵,van Leewen Nienke⁶,Palmer Nicholette D.⁷,Kobes Sayuko⁸,Deelen Joris⁹,Boquete-Vilarino Lorena¹,Paananen Jussi¹⁰,Stančáková Alena¹⁰^ORCID,Boomsma Dorret I.¹¹,de Geus Eco J.C.¹¹,Eekhoff Elisabeth M.W.¹²,Fritsche Andreas¹³¹⁴¹⁵^ORCID,Kramer Mark¹²,Nijpels Giel¹⁶,Simonis-Bik Annemarie¹²,van Haeften Timon W.¹⁷,Mahajan Anubha¹⁸,Boehnke Michael³,Bergman Richard N.¹⁹^ORCID,Tuomilehto Jaakko²⁰²¹²²²³,Collins Francis S.²⁴,Mohlke Karen L.²⁵^ORCID,Banasik Karina²¹⁸²⁶,Groves Christopher J.²⁷,McCarthy Mark I.¹⁸²⁷²⁸,Pearson Ewan R.²⁹,Natali Andrea³⁰,Mari Andrea³¹,Buchanan Thomas A.⁴⁵³²,Taylor Kent D.³³³⁴,Xiang Anny H.³⁵,Gjesing Anette P.²,Grarup Niels²,Eiberg Hans³⁶,Pedersen Oluf²,Chen Yii-Derr³³,Laakso Markku³⁷,Norris Jill M.³⁸,Smith Ulf³⁹,Wagenknecht Lynne E.⁴⁰,Baier Leslie⁸,Bowden Donald W.⁷,Hansen Torben²,Walker Mark⁴¹,Watanabe Richard M.⁴⁵³²,‘t Hart Leen M.⁶⁴²⁴³,Hanson Robert L.⁸,Frayling Timothy M.¹^ORCID,

Affiliation:

1. Genetics of Complex Traits, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter, U.K.

2. Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

3. Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI

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

5. Diabetes & Obesity Research Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA

6. Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands

7. Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC

8. Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ

9. Max Planck Institute for Biology of Ageing, Cologne, Germany

10. Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland

11. Department of Biological Psychology, VU University, Amsterdam, the Netherlands

12. Diabetes Center, Internal Medicine Unit, VU University Medical Center, Amsterdam, the Netherlands

13. Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine IV, University of Tübingen, Tübingen, Germany

14. Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich, University of Tübingen, Tübingen, Germany

15. German Center for Diabetes Research (DZD e.V.), Tübingen, Germany

16. EMGO+ Institute for Health and Care Research, VU University Medical Center, Department of General Practice, Amsterdam, the Netherlands

17. Department of Internal Medicine, Utrecht University Medical Center, Utrecht, the Netherlands

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

19. Diabetes & Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA

20. Department of Health, National Institute for Health and Welfare, Helsinki, Finland

21. Dasman Diabetes Institute, Dasman, Kuwait

22. Department of Clinical Neurosciences and Preventive Medicine, Danube University Krems, Krems, Austria

23. Saudi Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia

24. Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD

25. Department of Genetics, University of North Carolina, Chapel Hill, NC

26. Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark

27. Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, U.K.

28. Oxford Biomedical Research Centre, National Institute for Health Research, Churchill Hospital, Oxford, U.K.

29. School of Medicine, University of Dundee, Dundee, U.K.

30. Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

31. Institute of Neuroscience, National Research Council, Padova, Italy

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

33. Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA

34. Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA

35. Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA

36. Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark

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

38. Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, CO

39. Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

40. Wake Forest School of Medicine, Winston-Salem, NC

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

42. Section of Molecular Epidemiology, Leiden University Medical Center, Leiden, the Netherlands

43. Department of Epidemiology and Biostatistics, EMGO+ Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands

Abstract

Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed the largest genome-wide association study of first-phase insulin secretion, as measured by intravenous glucose tolerance tests, using up to 5,567 individuals without diabetes from 10 studies. We aimed to refine the mechanisms of 178 known associations between common variants and glycemic traits and identify new loci. Thirty type 2 diabetes or fasting glucose–raising alleles were associated with a measure of first-phase insulin secretion at P < 0.05 and provided new evidence, or the strongest evidence yet, that insulin secretion, intrinsic to the islet cells, is a key mechanism underlying the associations at the HNF1A, IGF2BP2, KCNQ1, HNF1B, VPS13C/C2CD4A, FAF1, PTPRD, AP3S2, KCNK16, MAEA, LPP, WFS1, and TMPRSS6 loci. The fasting glucose–raising allele near PDX1, a known key insulin transcription factor, was strongly associated with lower first-phase insulin secretion but has no evidence for an effect on type 2 diabetes risk. The diabetes risk allele at TCF7L2 was associated with a stronger effect on peak insulin response than on C-peptide–based insulin secretion rate, suggesting a possible additional role in hepatic insulin clearance or insulin processing. In summary, our study provides further insight into the mechanisms by which common genetic variation influences type 2 diabetes risk and glycemic traits.

Funder

European Research Council

National Institute of Diabetes and Digestive and Kidney Diseases

European Union's Seventh Framework Programme

Netherlands Organisation for Health Research and Development

Biobanking and BioMolecular resources Research Infrastructure–The Netherlands

Netherlands Organisation for Scientific Research

European Union

National Institutes of Health

Publisher

American Diabetes Association

Subject