Mendelian randomisation analyses find pulmonary factors mediate the effect of height on coronary artery disease

Abstract

There is evidence that lower height is associated with a higher risk of coronary artery disease (CAD) and increased risk of type 2 diabetes (T2D). It is not clear though whether these associations are causal, direct or mediated by other factors. Here we show that one standard deviation higher genetically determined height (~6.5 cm) is causally associated with a 16% decrease in CAD risk (OR = 0.84, 95% CI 0.80-0.87). This causal association remains after performing sensitivity analyses relaxing pleiotropy assumptions. The causal effect of height on CAD risk is reduced by 1-3% after adjustment for potential mediators (lipids, blood pressure, glycaemic traits, body mass index, socio-economic status). In contrast, our data suggest that lung function (measured by forced expiratory volume [FEV1] and forced vital capacity [FVC]) is a mediator of the effect of height on CAD. We observe no direct causal effect of height on the risk of T2D.

Fig. 1

Flowchart of the study design. a Using individual level data from UK Biobank. b Using summary data

Fig. 2

Observational and instrumental variables estimates of the effect of height on cardiometabolic events. Effect estimates represent the OR (95% CI) per 1 standard deviation increase in height, observational estimates were adjusted for age and sex. Causal estimates were derived from instrumental variable (IV) analysis

Fig. 3

Two sample Mendelian randomisation analyses. Estimates of the effect of height on a coronary artery disease after removing variants nominally associated with BMI, lipids or blood pressure and b Type 2 diabetes adjusted for BMI. Effect estimates represent the ORs (95% CI)

Fig. 4

Multivariable separate-sample Mendelian randomisation analysis of the effect of height (per standard deviation) on CAD risk. MR-IVW: Mendelian randomisation inverse variance weighted; FG, free glucose; FI, free insulin; HbA1c, glycated haemoglobin; 2hGlu, Glucose 2 h tolerance test; HDL, High Density Lipoprotein; LDL, Low Density Lipoprotein; TG, triglycerides; TC, total cholesterol; DBP, diastolic blood pressure; PP, pulse pressure; SBP, systolic blood pressure; BMI, body mass index; fat%, body fat percentage; degree, College or University degree; TDI: Townsend deprivation index (a composite measure of deprivation based on unemployment, non-car ownership, non-home ownership and household overcrowding); income, income variable representing annual household income before tax; education, age in years at completion of full time education; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity