Abstract 17003: Increased Body Mass Index and Increased Risk of Ischemic Heart Disease: Using Genomewide Association Results to Estimate Causal Effects With Mendelian Randomization
Background: The relationship between body mass index (BMI) and ischaemic heart disease (IHD) is one of clinical importance, yet one only explored by observational analyses. The recent Prospective Cohorts study investigating the association of BMI with health outcomes in >900,000 individuals demonstrates this, however fails to make causal estimates. An accepted approach to the assertion of causality in epidemiological relationships is Mendelian randomisation.
Methods and Results: In three large studies (The Copenhagen General Population Study (CGPS) n=55495[4020 IHD cases], The Copenhagen City Heart Study (CCHS) n=10461[2004 IHD cases] and the Copenhagen Ischaemic Heart Disease Study (CIHS) n=15810[5270 IHD cases]), we have used genotypes born of genomewide association study and reliably associated with BMI to re-assess BMI/IHD relationships. Across the CGPS and CCHS, both representing the Danish general population, crude relationships between BMI and IHD showed that for one standard deviation (=4kg/m2) increase in BMI there were increases in the risk ratios for IHD of 1.20(95%CI 1.17,1.23) and 1.23(1.18,1.28). Instrumental variable analysis for the three studies combined (CGPS+CCHS+CIHDS) in meta-analysis using genotypes at the loci FTO (rs9939609), TMEM18 (rs6548238) and MC4R (rs17782313) to re-assess crude relationship yielded estimate for the causal effect of a 4kg/m2 increase in BMI on the risk of IHD of 1.38(95%CI 1.00,1.90).
Conclusions: In the context of large observational studies investigating the link between BMI and IHD, we show evidence for an independent and causal effect of elevated BMI on the risk of IHD. The availability of reliable genotype/BMI associations and the application of Mendelian randomisation (yielding unconfounded, non-biased effects estimates free from reverse causation) has allowed us to resolve that for every 4kg/m2 increase in BMI, IHD risk rises by approximately 38%. This has important, policy implications for public health and is a direct application of findings made following the genomewide era.
- © 2010 by American Heart Association, Inc.