Genetics/Genomes/Proteomics/Metabolomics

Age- and Sex-Specific Causal Effects of Adiposity on Cardiovascular Risk Factors

  1. Tove Fall1,
  2. Sara Hägg1,2,
  3. Alexander Ploner2,
  4. Reedik Mägi3,
  5. Krista Fischer3,
  6. Harmen H.M. Draisma4,5,
  7. Antti-Pekka Sarin6,7,
  8. Beben Benyamin8,9,
  9. Claes Ladenvall10,
  10. Mikael Åkerlund10,
  11. Mart Kals3,11,
  12. Tõnu Esko3,12,13,14,
  13. Christopher P. Nelson15,16,
  14. Marika Kaakinen17,
  15. Ville Huikari18,
  16. Massimo Mangino19,
  17. Aline Meirhaeghe20,
  18. Kati Kristiansson21,
  19. Marja-Liisa Nuotio21,
  20. Michael Kobl22,
  21. Harald Grallert23,24,25,
  22. Abbas Dehghan26,
  23. Maris Kuningas26,27,
  24. Paul S. de Vries26,
  25. Renée F.A.G. de Bruijn26,28,
  26. Sara M. Willems26,
  27. Kauko Heikkilä29,
  28. Karri Silventoinen30,
  29. Kirsi H. Pietiläinen6,31,32,
  30. Vanessa Legry20,
  31. Vilmantas Giedraitis33,
  32. Louisa Goumidi20,
  33. Ann-Christine Syvänen34,
  34. Konstantin Strauch22,35,
  35. Wolfgang Koenig36,
  36. Peter Lichtner37,
  37. Christian Herder38,39,
  38. Aarno Palotie6,7,14,
  39. Cristina Menni19,
  40. André G. Uitterlinden26,40,
  41. Kari Kuulasmaa21,
  42. Aki S. Havulinna21,
  43. Luis A. Moreno41,
  44. Marcela Gonzalez-Gross42,
  45. Alun Evans43,
  46. David-Alexandre Tregouet44,45,46,
  47. John W.G. Yarnell43,
  48. Jarmo Virtamo21,
  49. Jean Ferrières47,
  50. Giovanni Veronesi48,
  51. Markus Perola21,
  52. Dominique Arveiler49,
  53. Paolo Brambilla50,
  54. Lars Lind34,
  55. Jaakko Kaprio6,29,51,
  56. Albert Hofman26,
  57. Bruno H. Stricker26,27,40,
  58. Cornelia M. van Duijn26,
  59. M. Arfan Ikram26,28,
  60. Oscar H. Franco26,
  61. Dominique Cottel20,
  62. Jean Dallongeville20,
  63. Alistair S. Hall52,
  64. Antti Jula53,
  65. Martin D. Tobin54,
  66. Brenda W. Penninx5,55,
  67. Annette Peters24,
  68. Christian Gieger22,23,24,
  69. Nilesh J. Samani15,16,
  70. Grant W. Montgomery9,
  71. John B. Whitfield9,
  72. Nicholas G. Martin9,
  73. Leif Groop6,10,
  74. Tim D. Spector19,
  75. Patrik K. Magnusson2,
  76. Philippe Amouyel20,
  77. Dorret I. Boomsma4,5,
  78. Peter M. Nilsson56,
  79. Marjo-Riitta Järvelin17,57,58,59,
  80. Valeriya Lyssenko10,60,
  81. Andres Metspalu3,
  82. David P. Strachan61,
  83. Veikko Salomaa21,
  84. Samuli Ripatti6,7,29,62,
  85. Nancy L. Pedersen2,
  86. Inga Prokopenko62,63,64,
  87. Mark I. McCarthy62,64,65 and
  88. Erik Ingelsson1,62⇑
  89. on behalf of the ENGAGE Consortium
  1. 1Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
  2. 2Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  3. 3Estonian Genome Center, University of Tartu, Tartu, Estonia
  4. 4Department of Biological Psychology, VU University Amsterdam, Amsterdam, the Netherlands
  5. 5The EMGO Institute for Health and Care Research, Amsterdam, the Netherlands
  6. 6Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
  7. 7Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland
  8. 8Queensland Brain Institute, University of Queensland, St. Lucia, Queensland, Australia
  9. 9QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  10. 10Department of Clinical Sciences, Diabetes and Endocrinology, Skåne University Hospital, Lund University, Malmö, Sweden
  11. 11Institute of Mathematical Statistics, University of Tartu, Tartu, Estonia
  12. 12Division of Endocrinology, Children's Hospital Boston, Boston, MA
  13. 13Department of Genetics, Harvard Medical School, Boston, MA
  14. 14The Broad Institute, Massachusetts Institute of Technology/Harvard University, Cambridge, MA
  15. 15Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, National Institute for Health Research, Leicester, U.K.
  16. 16Department of Cardiovascular Sciences, University of Leicester, BHF Cardiovascular Research Centre, Glenfield Hospital, Leicester, U.K.
  17. 17Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland
  18. 18Institute of Health Sciences, University of Oulu, Oulu, Finland
  19. 19Department of Twin Research and Genetic Epidemiology, King's College London, London, U.K.
  20. 20INSERM, U744, Institut Pasteur de Lille, Université Lille Nord de France, UDSL, France
  21. 21Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland
  22. 22Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
  23. 23Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
  24. 24Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
  25. 25German Center for Diabetes Research, Neuherberg, Germany
  26. 26Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands
  27. 27Inspectorate for Health Care, the Hague, the Netherlands
  28. 28Department of Neurology, Erasmus Medical Center, Rotterdam, the Netherlands
  29. 29Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland
  30. 30Department of Social Research, University of Helsinki, Helsinki, Finland
  31. 31Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki Finland
  32. 32Department of Medicine, Division of Endocrinology, Helsinki University Central Hospital, Finland
  33. 33Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden
  34. 34Department of Medical Sciences, Uppsala University, Uppsala, Sweden
  35. 35Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany
  36. 36Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Ulm, Germany
  37. 37Institut für Humangenetik, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
  38. 38Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
  39. 39German Center for Diabetes Research, partner Düsseldorf, Germany
  40. 40Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherland
  41. 41Growth, Exercise, Nutrition and Development Research Group, Department of Physiatry and Nursery, Faculty of Health Sciences, University of Zaragoza, Spain
  42. 42ImFine Research Group, Departamento de Salud y Rendimiento Humano, Facultad de Ciencias de la Actividad Física y del Deporte, Universidad Politécnica de Madrid, Madrid, Spain
  43. 43Centre for Public Health, the Queen's University of Belfast, Belfast, Northern Ireland, U.K.
  44. 44Team Genomics & Pathophysiology of Cardiovascular Diseases, Sorbonne Universités, Université Pierre et Marie Curie of Paris 06, UMRS 1166, Paris, France
  45. 45Team Genomics & Pathophysiology of Cardiovascular Diseases, INSERM, UMRS 1166, Paris, France
  46. 46Institute for Cardiometabolism and Nutrition, Paris, France
  47. 47Department of Cardiology, Toulouse University School of Medicine, Rangueil Hospital, Toulouse, France
  48. 48Research Center on Epidemiology and Preventive Medicine, Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy
  49. 49Department of Epidemiology and Public Health, University of Strasbourg and University Hospital of Strasbourg, Strasbourg, France
  50. 50Department of Experimental Medicine, University of Milano-Bicocca, Monza, Italy
  51. 51National Institute for Health and Welfare, Helsinki, Finland
  52. 52Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, U.K.
  53. 53Population Studies Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare, Turku, Finland
  54. 54Department of Health Sciences and Genetics, University of Leicester, Leicester, U.K.
  55. 55Department of Psychiatry, VU University Medical Center, Amsterdam, the Netherlands
  56. 56Department of Clinical Sciences, Lund University, Malmö, Sweden
  57. 57Department of Children, Young People and Families, National Institute for Health and Welfare, Oulu, Finland
  58. 58Department of Epidemiology and Biostatistics, Medical Research Council Health Protection Agency, Centre for Environment & Health, School of Public Health, Imperial College London, U.K.
  59. 59Unit of Primary Care, Oulu University Hospital, Oulu, Finland
  60. 60Steno Diabetes Center, Gentofte, Denmark
  61. 61St. George's, University of London, London, U.K.
  62. 62Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.
  63. 63Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, U.K.
  64. 64Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K.
  65. 65Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Oxford, U.K.
  1. Corresponding author: Erik Ingelsson, erik.ingelsson{at}medsci.uu.se.

  1. T.V. and S.H. contributed equally to this work.

Diabetes 2015 May; 64(5): 1841-1852. https://doi.org/10.2337/db14-0988

Abstract

Observational studies have reported different effects of adiposity on cardiovascular risk factors across age and sex. Since cardiovascular risk factors are enriched in obese individuals, it has not been easy to dissect the effects of adiposity from those of other risk factors. We used a Mendelian randomization approach, applying a set of 32 genetic markers to estimate the causal effect of adiposity on blood pressure, glycemic indices, circulating lipid levels, and markers of inflammation and liver disease in up to 67,553 individuals. All analyses were stratified by age (cutoff 55 years of age) and sex. The genetic score was associated with BMI in both nonstratified analysis (P = 2.8 × 10−107) and stratified analyses (all P < 3.3 × 10−30). We found evidence of a causal effect of adiposity on blood pressure, fasting levels of insulin, C-reactive protein, interleukin-6, HDL cholesterol, and triglycerides in a nonstratified analysis and in the <55-year stratum. Further, we found evidence of a smaller causal effect on total cholesterol (P for difference = 0.015) in the ≥55-year stratum than in the <55-year stratum, a finding that could be explained by biology, survival bias, or differential medication. In conclusion, this study extends previous knowledge of the effects of adiposity by providing sex- and age-specific causal estimates on cardiovascular risk factors.

Footnotes

  • Received June 26, 2014.
  • Accepted November 30, 2014.
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Age- and Sex-Specific Causal Effects of Adiposity on Cardiovascular Risk Factors
Tove Fall, Sara Hägg, Alexander Ploner, Reedik Mägi, Krista Fischer, Harmen H.M. Draisma, Antti-Pekka Sarin, Beben Benyamin, Claes Ladenvall, Mikael Åkerlund, Mart Kals, Tõnu Esko, Christopher P. Nelson, Marika Kaakinen, Ville Huikari, Massimo Mangino, Aline Meirhaeghe, Kati Kristiansson, Marja-Liisa Nuotio, Michael Kobl, Harald Grallert, Abbas Dehghan, Maris Kuningas, Paul S. de Vries, Renée F.A.G. de Bruijn, Sara M. Willems, Kauko Heikkilä, Karri Silventoinen, Kirsi H. Pietiläinen, Vanessa Legry, Vilmantas Giedraitis, Louisa Goumidi, Ann-Christine Syvänen, Konstantin Strauch, Wolfgang Koenig, Peter Lichtner, Christian Herder, Aarno Palotie, Cristina Menni, André G. Uitterlinden, Kari Kuulasmaa, Aki S. Havulinna, Luis A. Moreno, Marcela Gonzalez-Gross, Alun Evans, David-Alexandre Tregouet, John W.G. Yarnell, Jarmo Virtamo, Jean Ferrières, Giovanni Veronesi, Markus Perola, Dominique Arveiler, Paolo Brambilla, Lars Lind, Jaakko Kaprio, Albert Hofman, Bruno H. Stricker, Cornelia M. van Duijn, M. Arfan Ikram, Oscar H. Franco, Dominique Cottel, Jean Dallongeville, Alistair S. Hall, Antti Jula, Martin D. Tobin, Brenda W. Penninx, Annette Peters, Christian Gieger, Nilesh J. Samani, Grant W. Montgomery, John B. Whitfield, Nicholas G. Martin, Leif Groop, Tim D. Spector, Patrik K. Magnusson, Philippe Amouyel, Dorret I. Boomsma, Peter M. Nilsson, Marjo-Riitta Järvelin, Valeriya Lyssenko, Andres Metspalu, David P. Strachan, Veikko Salomaa, Samuli Ripatti, Nancy L. Pedersen, Inga Prokopenko, Mark I. McCarthy, Erik Ingelsson
Diabetes May 2015, 64 (5) 1841-1852; DOI: 10.2337/db14-0988
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