The effect of elevated body mass index on ischemic heart disease risk: causal estimates from a Mendelian randomisation approach

Abstract

Background: Adiposity, assessed as elevated body mass index (BMI), is associated with increased risk of ischemic heart disease (IHD); however, whether this is causal is unknown. We tested the hypothesis that positive observational associations between BMI and IHD are causal.

Methods and findings: In 75,627 individuals taken from two population-based and one case-control study in Copenhagen, we measured BMI, ascertained 11,056 IHD events, and genotyped FTO(rs9939609), MC4R(rs17782313), and TMEM18(rs6548238). Using genotypes as a combined allele score in instrumental variable analyses, the causal odds ratio (OR) between BMI and IHD was estimated and compared with observational estimates. The allele score-BMI and the allele score-IHD associations used to estimate the causal OR were also calculated individually. In observational analyses the OR for IHD was 1.26 (95% CI 1.19-1.34) for every 4 kg/m(2) increase in BMI. A one-unit allele score increase associated with a 0.28 kg/m(2) (95 CI% 0.20-0.36) increase in BMI and an OR for IHD of 1.03 (95% CI 1.01-1.05) (corresponding to an average 1.68 kg/m(2) BMI increase and 18% increase in the odds of IHD for those carrying all six BMI increasing alleles). In instrumental variable analysis using the same allele score the causal IHD OR for a 4 kg/m(2) increase in BMI was 1.52 (95% CI 1.12-2.05).

Conclusions: For every 4 kg/m(2) increase in BMI, observational estimates suggested a 26% increase in odds for IHD while causal estimates suggested a 52% increase. These data add evidence to support a causal link between increased BMI and IHD risk, though the mechanism may ultimately be through intermediate factors like hypertension, dyslipidemia, and type 2 diabetes. This work has important policy implications for public health, given the continuous nature of the BMI-IHD association and the modifiable nature of BMI. This analysis demonstrates the value of observational studies and their ability to provide unbiased results through inclusion of genetic data avoiding confounding, reverse causation, and bias.

Figure 1. ORs and 95% CIs for IHD by BMI categories in the CGPS and the CCHS.

Figure 2. Meta-analysis forest plots of observational and instrumental variable causal estimates using allele score of the relationship between IHD and BMI.

The ORs are for a 4 kg/m² increase in BMI.

Figure 3. Meta-analysis forest plots of the relationships between FTO rs9939609, MC4R rs17782313, and TMEM18 rs6548238 allele score and BMI.

Analyses are stratified by IHD status.

Figure 4. Meta-analysis forest plots of the relationships between FTO rs9939609, MC4R rs17782313, and TMEM18 rs6548238 allele score and IHD.

Figure 5. Mean BMI and 95% CIs by allele score and IHD status and distribution of allele score in the CGPS and CCHS.

Left y-axis and dot with 95% CI depict BMI values as a function of allele score. Right y-axis and histogram depict frequency in percent of the different allele scores.

Figure 6. Meta-analysis forest plots of observational and instrumental variable estimates of the relationship between IHD and BMI stratified by age group.