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

Abstract

BackgroundMendelian randomization (MR) studies of body mass index (BMI) and cardiovascular health in mid-to-late life suggest causal relationships, but the nature of these has not been explored systematically at younger ages. Using complementary MR and recall-by-genotype (RbG) methodologies, our objective was to estimate the causal effect of BMI on detailed measures of cardiovascular health in a population of young healthy adults.Methods and FindingsData from the Avon Longitudinal Study of Parents and Children were used. For MR analyses, a genetic risk score (GRS) comprising 97 independent single nucleotide polymorphisms (SNPs) and constructed using external weighting was used as an instrument to test the causal effect of each unit increase in BMI (kg/m2) on selected cardiovascular phenotypes measured at age 17 (N=7909). An independent enriched sample from the same cohort participated in a RbG study at age 21, which enabled more detailed cardiovascular phenotyping (N=418; 191/227 from the lower/upper ∼30% of a genome-wide GRS distribution predicting variation in BMI). The causal effect of BMI on the additional cardiovascular phenotypes was assessed by comparing the two recalled groups. Difference in mean BMI between RbG groups was 3.85kg/m2 (95% CI: 2.53, 4.63; P=6.09×1011). In both MR and RbG analyses, results indicated that higher BMI causes higher blood pressure (BP) and left ventricular mass (indexed to height2.7, 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=3.87×10−06 and per 3.58kg/m2 using RbG: 1.65g/m2.7 95% CI: 0.83, 2.47; P=0.0001). Additionally, RbG results indicated 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). Neither analysis supported a causal role of higher BMI on heart rate.ConclusionsComplementary MR and RbG causal methodologies, together with a range of appropriate sensitivity analyses, showed that higher BMI is likely to cause worse cardiovascular health, specifically higher BP and LVMI, even in youth. These consistent results support efforts to prevent or reverse obesity in the young.

Joint modelling of individual trajectories, within-individual variability and a later outcome: systolic blood pressure through childhood and left ventricular mass in early adulthood

“…not certified by peer review) (which was The copyright holder for this preprint this version posted October 10, 2019. . https://doi.org/10.1101/19008474 doi: medRxiv preprint causally related to higher LVMI, suggesting that there is meaningful variation in cardiac structure measures in early adulthood that is likely to track across life and relate to later life cardiovascular health (36). Nevertheless, in the current study the positive association between childhood BPV and LVMI in early adulthood did not persist once childhood mean BP had been adjusted for.…”

Higher Body Mass Index in Adolescence Predicts Cardiomyopathy Risk in Midlife

“…23 Young people might not yet have accumulated these risk factors, and accordingly, they are an optimal study population in this regard. Childhood obesity has, however, independently been associated with significant changes in myocardial geometry and function, 24 which has been further strengthened in a study of obesity genes in young adults, 25 indicating an early onset of potentially unfavorable alterations in the myocardium that are independent of other cardiovascular risk factors. In this study, we found that the risk of cardiomyopathy started to increase at levels of adolescent BMI at the upper normal level, which is in accordance with recent findings with respect to early heart failure 7 and is supported by the findings by Twig et al 10 In studies of people with severe obesity, cardiomyopathy has been identified as a complication, 26,27 with severity and duration of obesity recognized as essential determinants of alterations in cardiac performance and morphology.…”

Influence of puberty timing on adiposity and cardiometabolic traits: A Mendelian randomisation study

“…Whether puberty timing is a concern for cardiometabolic health in populations, however, depends on whether it is truly causal. Higher adiposity in childhood may induce an earlier puberty [ 8 ] and track forward into adulthood [ 9 – 13 ], making it an important potential confounder. Prospective studies of puberty timing in relation to cardiometabolic outcomes tend not to account for differences in pre-pubertal adiposity [ 14 , 15 ], and the few studies that do often find substantial attenuation of puberty–outcome associations [ 4 , 16 , 17 ].…”