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

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.