Mendelian Randomization Studies Do Not Support a Causal Role for Reduced Circulating Adiponectin Levels in Insulin Resistance and Type 2 Diabetes

  1. Timothy M. Frayling1
  1. 1Genetics of Complex Traits, University of Exeter Medical School, Exeter, U.K.
  2. 2Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria
  3. 3MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge, U.K.
  4. 4Department of Epidemiology, Biostatistics and Occupational Health, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada
  5. 5Department of Medicine, Université de Sherbrooke, Sherbrooke, Quebec, Canada
  6. 6General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts
  7. 7Quantitative Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina
  8. 8University of Eastern Finland, Kuopio, Finland
  9. 9School of Health Sciences, Jackson State University, Jackson, Mississippi
  10. 10Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland
  11. 11Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland
  12. 12Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
  13. 13Department of Genetics, University of North Carolina, Chapel Hill, North Carolina
  14. 14Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
  15. 15Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota
  16. 16Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan
  17. 17Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
  18. 18Baylor College of Medicine and Methodist DeBakey Heart and Vascular Center, Houston, Texas
  19. 19Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
  20. 20Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
  21. 21School of Nursing, University of Pittsburgh, Pittsburgh, Pennsylvania
  22. 22Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts
  23. 23Genetics of Diabetes, University of Exeter Medical School, Exeter, U.K.
  24. 24Department of Clinical Physiology, Tampere University Hospital and University of Tampere School of Medicine, Tampere, Finland
  25. 25First Department of Internal Medicine, St. Johann Spital, Paracelsus Private Medical University Salzburg, Salzburg, Austria
  26. 26Section on Genetics and Epidemiology, Joslin Diabetes Center, Boston, Massachusetts
  27. 27Department of Medicine, Stanford University School of Medicine, Stanford, California
  28. 28Cardiovascular Institute, Stanford University School of Medicine, Stanford, California
  29. 29Department of Internal Medicine, University of Pisa, Pisa, Italy
  30. 30Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark
  31. 31Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
  32. 32Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York
  33. 33Division of Endocrinology, Diabetology, Nephrology, Vascular Medicine and Clinical Chemistry, Department of Internal Medicine, University of Tübingen, Tübingen, Germany
  34. 34Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.
  35. 35Steno Diabetes Center, Gentofte, Denmark
  36. 36Hagedorn Research Institute, Copenhagen, Denmark
  37. 37Institute of Biomedical Science, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
  38. 38Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark
  39. 39Department of Molecular and Clinical Medicine, The Lundberg Laboratory for Diabetes Research, Sahlgrenska Academy, Gothenburg, Sweden
  40. 40Department of Preventive Medicine, Mount Sinai School of Medicine, The Charles Bronfman Institute for Personalized Medicine, Institute of Child Health and Development, New York, New York
  41. 41Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K.
  42. 42Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Oxford, U.K.
  43. 43Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, U.K.
  44. 44Boston University School of Medicine, Boston, Massachusetts
  45. 45Framingham Heart Study, Framingham, Massachusetts
  46. 46Twin Research and Genetic Epidemiology, King’s College London, London, U.K.
  47. 47Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland
  48. 48King Abdulaziz University, Jeddah, Saudi Arabia
  49. 49Red RECAVA Grupo RD06/0014/0015, Hospital Universitario La Paz, Madrid, Spain
  50. 50Centre for Vascular Prevention, Danube-University Krems, Krems, Austria
  51. 51Department of Medicine, Turku University Hospital, Turku, Finland
  52. 52Department of Medicine, University of Turku, Turku, Finland
  53. 53The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, U.K.
  54. 54University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge, U.K.
  55. 55Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota
  56. 56Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle, U.K.
  57. 57Research Centre of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
  58. 58Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands
  59. 59Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
  60. 60Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
  61. 61Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, Georgia
  62. 62Department of Community Health and Preventive Medicine, Morehouse School of Medicine, Atlanta, Georgia
  63. 63Quantitative Sciences, GlaxoSmithKline, Upper Merion, Pennsylvania
  64. 64Department of Social Medicine, University of Bristol, Bristol, U.K.
  65. 65Department of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montreal, Canada.
  1. Corresponding author: Timothy M. Frayling, tim.frayling{at}pms.ac.uk.

Abstract

Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic variants at the ADIPOQ gene as instruments to calculate a regression slope between adiponectin levels and metabolic traits (up to 31,000 individuals) and a combination of instrumental variables and summary statistics–based genetic risk scores to test the associations with gold-standard measures of insulin sensitivity (2,969 individuals) and type 2 diabetes (15,960 case subjects and 64,731 control subjects). In conventional regression analyses, a 1-SD decrease in adiponectin levels was correlated with a 0.31-SD (95% CI 0.26–0.35) increase in fasting insulin, a 0.34-SD (0.30–0.38) decrease in insulin sensitivity, and a type 2 diabetes odds ratio (OR) of 1.75 (1.47–2.13). The instrumental variable analysis revealed no evidence of a causal association between genetically lower circulating adiponectin and higher fasting insulin (0.02 SD; 95% CI −0.07 to 0.11; N = 29,771), nominal evidence of a causal relationship with lower insulin sensitivity (−0.20 SD; 95% CI −0.38 to −0.02; N = 1,860), and no evidence of a relationship with type 2 diabetes (OR 0.94; 95% CI 0.75–1.19; N = 2,777 case subjects and 13,011 control subjects). Using the ADIPOQ summary statistics genetic risk scores, we found no evidence of an association between adiponectin-lowering alleles and insulin sensitivity (effect per weighted adiponectin-lowering allele: −0.03 SD; 95% CI −0.07 to 0.01; N = 2,969) or type 2 diabetes (OR per weighted adiponectin-lowering allele: 0.99; 95% CI 0.95–1.04; 15,960 case subjects vs. 64,731 control subjects). These results do not provide any consistent evidence that interventions aimed at increasing adiponectin levels will improve insulin sensitivity or risk of type 2 diabetes.

Footnotes

  • Received January 28, 2013.
  • Accepted June 25, 2013.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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  1. Diabetes vol. 62 no. 10 3589-3598
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