Causal effects of body mass index on cardiometabolic traits and events: a Mendelian randomization analysis

Abstract

Elevated body mass index (BMI) associates with cardiometabolic traits on observational analysis, yet the underlying causal relationships remain unclear. We conducted Mendelian randomization analyses by using a genetic score (GS) comprising 14 BMI-associated SNPs from a recent discovery analysis to investigate the causal role of BMI in cardiometabolic traits and events. We used eight population-based cohorts, including 34,538 European-descent individuals (4,407 type 2 diabetes (T2D), 6,073 coronary heart disease (CHD), and 3,813 stroke cases). A 1 kg/m(2) genetically elevated BMI increased fasting glucose (0.18 mmol/l; 95% confidence interval (CI) = 0.12-0.24), fasting insulin (8.5%; 95% CI = 5.9-11.1), interleukin-6 (7.0%; 95% CI = 4.0-10.1), and systolic blood pressure (0.70 mmHg; 95% CI = 0.24-1.16) and reduced high-density lipoprotein cholesterol (-0.02 mmol/l; 95% CI = -0.03 to -0.01) and low-density lipoprotein cholesterol (LDL-C; -0.04 mmol/l; 95% CI = -0.07 to -0.01). Observational and causal estimates were directionally concordant, except for LDL-C. A 1 kg/m(2) genetically elevated BMI increased the odds of T2D (odds ratio [OR] = 1.27; 95% CI = 1.18-1.36) but did not alter risk of CHD (OR 1.01; 95% CI = 0.94-1.08) or stroke (OR = 1.03; 95% CI = 0.95-1.12). A meta-analysis incorporating published studies reporting 27,465 CHD events in 219,423 individuals yielded a pooled OR of 1.04 (95% CI = 0.97-1.12) per 1 kg/m(2) increase in BMI. In conclusion, we identified causal effects of BMI on several cardiometabolic traits; however, whether BMI causally impacts CHD risk requires further evidence.

Figure 1

Association between the BMI GS and Cardiometabolic Traits Effect estimates represent the beta (plotted) or regression (tabulated) coefficients (±95% CI) per 1-unit increase in weighted GS. The GS consisted of 14 SNPs taken from Guo et al. For log-transformed variables (marked by an asterisk), the regression coefficients are presented as a percent difference in the geometric mean.

Figure 2

Association between the BMI GS and Cardiometabolic Events Effect estimates represent the OR (±95% CI) for each outcome per 1-unit increase in weighted GS. The GS consisted of 14 SNPs (taken from Guo et al.²³) that associated with a 1.08 kg/m² increase in BMI (Figure 1).

Figure 3

Observational and Instrumental Variable Estimates of the Effect of BMI on Cardiometabolic Traits Effect estimates represent the beta (plotted) or regression (tabulated) coefficients (±95% CI) per 1 kg/m² increase in BMI. Observational estimates were adjusted for age, sex, and study. For log-transformed variables (marked by an asterisk), the summary estimates are presented as a percent difference in the geometric mean. Causal estimates were derived from instrumental variable (IV) analysis.

Figure 4

Observational and Instrumental Variable Estimates of the Effect of BMI on Cardiometabolic Events Effect estimates represent the OR (±95% CI) per 1 kg/m² increase in BMI. Observational estimates were adjusted for age, sex, and study. Causal estimates were derived from instrumental variable (IV) analysis.

Figure 5

Meta-analysis of Studies Investigating the Effect of BMI on CHD through Mendelian Randomization Analysis Effect estimates represent the OR (±95% CI) per 1 kg/m² increase in BMI on the odds of CHD.