Abstract
Body mass index (BMI) has been suggested to be causally related to cardiovascular health in mid-to-late life, but this has not been explored systematically at younger ages - nor with detailed cardiovascular phenotyping. Recall-by-Genotype (RbG) is an approach that enables the collection of precise phenotypic measures in smaller studies, whilst maintaining statistical power and ability for causal inference. In this study, we used a combination of conventional multivariable regression analysis, Mendelian randomization (MR) and sub-sample RbG methodologies to estimate the causal effect of BMI on gross-level and detailed cardiovascular health in healthy participants from the Avon Longitudinal Study of Parents and Children at age 17 (N=1420-3108 for different outcomes) and an independent sample from the same cohort (for RbG) study at age 21 (N=386-418). In both MR and RbG analyses, results suggested that higher BMI causes higher blood pressure (BP) and left ventricular mass index (LVMI) in young adults (e.g., difference in LVMI per kg/m2 using MR: 1.07g/m2.7; 95% CI: 0.62, 1.52; P=3.87x10-06 and per 3.58kg/m2 using RbG: 1.65g/m2.7 95% CI: 0.83, 2.47; P=0.0001). Additionally, RbG results suggested a causal role of higher BMI on higher stroke volume (SV: difference per 3.58kg/m2: 1.49ml/m2.04; 95% CI: 0.62, 2.35; P=0.001) and cardiac output (CO: difference per 3.58kg/m2: 0.11l/min/m1.83; 95% CI: 0.03, 0.19; P=0.01) but no strong evidence for a causal role on systemic vascular resistance or total arterial compliance. Neither analysis supported a causal role of higher BMI on heart rate. Complementary MR and RbG causal methodologies, together with a range of sensitivity analyses, suggest that higher BMI is likely to cause worse cardiovascular health, specifically higher BP and LVMI, even in youth. Higher BMI also resulted in increased CO in the RbG study, which appeared to be solely driven by SV, as neither MR nor RbG analyses suggested a causal effect of BMI on heart rate. These consistent results support efforts to reduce BMI from a young age to prevent later adverse cardiovascular health and illustrate the potential for phenotypic resolution with maintained analytical power using RbG.
Highlights
Body mass index (BMI) has been suggested to be causally related to cardiovascular health in mid-to-late life, but this has not been explored systematically at younger ages—nor with detailed cardiovascular phenotyping
Higher BMI resulted in increased cardiac output in the RbG study, which appeared to be solely driven by stroke volume, as neither Mendelian randomization (MR) nor RbG analyses suggested a causal effect of BMI on heart rate
Mean (SD) or BMI indicates body mass index; cIMT, carotid intima-media thickness; CPM, counts per minute; CSE, certificate of secondary education; DBP, diastolic blood pressure; LVMI, left ventricular mass indexed to height2.7; MAP, mean arterial pressure; MVPA, minutes spent in moderate-to-vigorous activity; PP, pulse pressure; PWV, pulse wave velocity; and systolic BP (SBP), systolic blood pressure
Summary
Using data from ALSPAC (Avon Longitudinal Study of Parents and Children), we aimed to use both wholesample MR and subsample RbG, alongside conventional multivariable regression analyses, to test the hypothesis that BMI causally influences variations in multiple clinically relevant measures of cardiovascular structure and function in adolescence and early adulthood. We aimed to make best use of all available data, our main analyses included the use of an aggregate GRS comprising all 97 SNPs associated with BMI, which may increase the possibility of horizontal pleiotropy
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