“Genetically and Environmentally Predicted Obesity in Relation to Cardiovascular Disease: a Nationwide Cohort Study”, 2023-04-06 ():
Background: Evidence indicates that the adverse health effects of obesity differ between genetically and environmentally influenced obesity. We examined differences in the association between obesity and cardiovascular disease (CVD) between individuals with a genetically predicted low, medium, or high body mass index (BMI).
Method: We used cohort data from Swedish twins born before 1959 who had BMI measured between the ages of 40–64 years (midlife) or at the age of 65 years or later (late-life), or both, and prospective CVD information from nationwide population register linkage through 2016. A polygenic score for BMI (PGSBMI) was used to define genetically predicted BMI. Individuals missing BMI or covariate data, or diagnosed with CVD at first BMI measure, were excluded, leaving an analysis sample of 17,988 individuals. We applied Cox proportional hazard models to examine the association between BMI category and incident CVD, stratified by the PGSBMI. Co-twin control models were applied to adjust for genetic influences not captured by the PGSBMI.
Findings: 1984–26201014ya, the 17,988 participants were enrolled in sub-studies of the Swedish Twin Registry. Midlife obesity was associated with a higher risk of CVD across all PGSBMI categories, but the association was stronger with genetically predicted lower BMI (hazard ratio 1.55–2.08 for those with high and low PGSBMI, respectively). Within monozygotic twin pairs, the association did not differ by genetically predicted BMI, indicating genetic confounding not captured by the PGSBMI. Results were similar when obesity was measured in late-life, but suffered from low statistical power.
Interpretation: Obesity was associated with CVD regardless of PGSBMI category, but obesity influenced by genetic predisposition (genetically predicted high BMI) was less harmful than obesity influenced by environmental factors (obesity despite genetically predicted low BMI). However, additional genetic factors, not captured by the PGSBMI, still influence the associations.
[Keywords: obesity, cardiovascular disease, polygenic score, BMI, twins]
Evidence before this study: We searched PubMed for title and abstract keywords
((obesity) OR (adiposity) OR (BMI)) AND ((cardiovascular) OR (cardiac) OR (heart) OR (vascular)) AND ((polygenic) OR (genetic risk score) OR (genetic score))through November 2022. The association between obesity and cardiovascular disease (CVD) is indisputable, and both phenotypes strongly influenced by genetic factors. However, some recent studies highlight that genetically predicted obesity may be less harmful than obesity influenced predominantly by non-genetic factors, such as environmental and lifestyle factors.Added value of this study: By considering phenotypic obesity together with a polygenic score for body mass index (BMI; PGSBMI), we examined differences in CVD risk between a genetically predicted obesity versus obesity driven mainly by non-genetic factors. For these purposes, we used a cohort of almost 18,000 Swedish twins followed on average 18 years. There were indeed differences, with the risk increase for those with obesity influenced by lifestyle or other environmental factors (obesity despite a low PGSBMI) twice that of those with a genetically predicted obesity (obesity with a high PGSBMI; hazard rates 2.08 versus 1.55), compared to those with a healthy weight in the same PGSBMI category. Utilizing the twin design of the data, we tested the associations within monozygotic twin pairs, who by default have the same genetically predicted BMI. Here, the association between obesity and CVD was substantially attenuated, and there were no differences in the association between those with genetically predicted low versus high BMI. This indicates that the association is still influenced by genetic factors, beyond the PGSBMI.
Implications of all the available evidence: While a healthy lifestyle is always to strive for, findings from the current study and previous work indicate that obesity influenced by environmental factors may be more deleterious than obesity influenced by genetic factors. The topic is still understudied, but this heterogeneity in obesity has been seen for several important outcomes, and in data from Sweden as well as the US. This, together with the attenuated association within twin pairs, indicates that the negative health effects of obesity may be mediated by other factors, rather than driven by the obesity in itself.