Fall T, Hägg S, Ploner A, Mägi R, Fischer K, Draisma HH, Sarin AP, Benyamin B, Ladenvall C, Åkerlund M, Kals M, Esko T, Nelson CP, Kaakinen M, Huikari V, Mangino M, Meirhaeghe A, Kristiansson K, Nuotio ML, Kobl M, Grallert H, Dehghan A, Kuningas M, de Vries PS, de Bruijn RF, Willems SM, Heikkilä K, Silventoinen K, Pietiläinen KH, Legry V, Giedraitis V, Goumidi L, Syvänen AC, Strauch K, Koenig W, Lichtner P, Herder C, Palotie A, Menni C, Uitterlinden AG, Kuulasmaa K, Havulinna AS, Moreno LA, Gonzalez-Gross M, Evans A, Tregouet DA, Yarnell JW, Virtamo J, Ferrières J, Veronesi G, Perola M, Arveiler D, Brambilla P, Lind L, Kaprio J, Hofman A, Stricker BH, van Duijn CM, Ikram MA, Franco OH, Cottel D, Dallongeville J, Hall AS, Jula A, Tobin MD, Penninx BW, Peters A, Gieger C, Samani NJ, Montgomery GW, Whitfield JB, Martin NG, Groop L, Spector TD, Magnusson PK, Amouyel P, Boomsma DI, Nilsson PM, Järvelin MR, Lyssenko V, Metspalu A, Strachan DP, Salomaa V, Ripatti S, Pedersen NL, Prokopenko I, McCarthy MI, Ingelsson E, ENGAGE Consortium
Diabetes 64 (5) 1841-1852 [2015-05-00; online 2015-02-23]
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.