Assessing the causal role of body mass index on cardiovascular health in young adults: Mendelian randomization and recall-by-genotype analyses

Wade, K. H. et al. (2018) Assessing the causal role of body mass index on cardiovascular health in young adults: Mendelian randomization and recall-by-genotype analyses. Circulation, 138(20), pp. 2187-2201. (doi: 10.1161/CIRCULATIONAHA.117.033278) (PMID:30524135) (PMCID:PMC6250296)

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. Conclusions: 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.

• Item Type: Articles
• Additional Information: Professor Timpson is a Wellcome Trust Investigator (202802/Z/16/Z), is a program lead in the Medical Research Council Integrative Epidemiology Unit (MC_ UU_12013/3), and works within the University of Bristol National Institute for Health Research Biomedical Research Center. The UK Medical Research Council and the Wellcome Trust (102215/2/13/2) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors, and Dr Wade and Professor Timpson serve as guarantors for the contents of this paper. This research was specifically funded through grants from the British Heart Foundation (RG/10/004/28240, PG/06/145, and CS/15/6/31468) and the UK Medical Research Council, University of Bristol, and Wellcome Trust (MC_UU_12013/1–9 and 096989/Z11/Z to Dr Wade, 086676/7/08/Z to Professor Hughes and MR/ M009351/1 to Dr Fraser, and MR/M020894/1 to Dr Howe).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Sattar, Professor Naveed
• Authors: Wade, K. H., Chiesa, S. T., Hughes, A. D., Chaturvedi, N., Charakida, M., Rapala, A., Muthurangu, V., Khan, T., Finer, N., Sattar, N., Howe, L. D., Fraser, A., Lawlor, D. A., Davey Smith, G., Deanfield, J. E., and Timpson, N. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Circulation
• Publisher: American Heart Association
• ISSN: 0009-7322
• ISSN (Online): 1524-4539
• Published Online: 30 July 2018
• Copyright Holders: Copyright © 2018 The Authors
• First Published: First published in Circulation 138(20): 2187-2201
• Publisher Policy: Reproduced under a Creative Commons License