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Assessing the Causal Role of Body Mass Index on Cardiovascular Health in Young Adults: Mendelian Randomization and Recall-by-Genotype Analyses

Wade, KH; Chiesa, ST; Hughes, AD; Chaturvedi, N; Charakida, M; Rapala, A; Muthurangu, V; ... Timpson, NJ; + view all (2018) Assessing the Causal Role of Body Mass Index on Cardiovascular Health in Young Adults: Mendelian Randomization and Recall-by-Genotype Analyses. Circulation , 132 (20) pp. 2187-2201. 10.1161/CIRCULATIONAHA.117.033278. Green open access

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Abstract

BACKGROUND: 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, while maintaining statistical power and ability for causal inference. METHODS: In this study, we used a combination of conventional multivariable regression analysis, Mendelian randomization (MR), and subsample 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 years (N=1420–3108 for different outcomes) and an independent sample from the same cohort (for RbG) study at age 21 years (N=386–418). RESULTS: In both MR and RbG analyses, results suggested that higher BMI causes higher blood pressure and left ventricular mass index in young adults (eg, difference in left ventricular mass index per 1 kg/m2 using MR: 1.07 g/m2.7; 95% CI, 0.62–1.52; P=3.87×10-06 and per 3.58 kg/m2 using RbG: 1.65 g/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 (difference per 3.58 kg/m2: 1.49 mL/m2.04; 95% CI, 0.62–2.35; P=0.001) and cardiac output (difference per 3.58 kg/m2: 0.11 L·min-1·m-1.83; 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. CONCLUSION: 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 blood pressure and left ventricular mass index, even in youth. Higher BMI also resulted in increased cardiac output in the RbG study, which appeared to be solely driven by stroke volume, 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 analytic power using RbG.

Type: Article
Title: Assessing the Causal Role of Body Mass Index on Cardiovascular Health in Young Adults: Mendelian Randomization and Recall-by-Genotype Analyses
Open access status: An open access version is available from UCL Discovery
DOI: 10.1161/CIRCULATIONAHA.117.033278
Publisher version: https://www.ahajournals.org/doi/10.1161/CIRCULATIO...
Language: English
Additional information: © 2018 The Authors. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
Keywords: cardiovascular system, body mass index, epidemiology, causality, genetics
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science > Children's Cardiovascular Disease
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science > Clinical Science
URI: https://discovery.ucl.ac.uk/id/eprint/10053027
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