Life-course obesity and heart failure: a two-sample Mendelian randomization study

Heart failure is a multifaceted clinical syndrome, with obesity identified as a significant modifiable risk factor. This study employed a two-sample Mendelian randomization (MR) design, incorporating obesity data across life stages, to elucidate the causal link between obesity and heart failure. Data on heart failure from the 2023 Finngen database and genetic predictors of obesity from the IEU OpenGWAS project were analyzed using the IVW method, MR-Egger regression, weighted median, simple mode, weighted mode, and scatter plots. Heterogeneity was assessed with Cochran's Q test, and horizontal pleiotropy with MR-Egger intercept test. Sensitivity to single-nucleotide polymorphisms (SNPs) was tested via leave-one-out analysis, and funnel plots were utilized for visual inspection of horizontal pleiotropy. Statistical powers were also calculated. The MR analysis findings indicate a significant relationship between birth weight and the likelihood of developing heart failure (Odds Ratio [OR] 1.134, 95% Confidence Interval [CI] 1.033-1.245, P = 0.008). In addition, a heightened childhood BMI was found to be a significant predictor of heart failure risk (OR 1.307, 95% CI 1.144-1.494, P = 8.51E-05), as was childhood obesity (OR 1.123, 95% CI 1.074-1.173, P = 2.37E-07). Furthermore, adult BMI sex-combined exhibited a strong correlation with the risk of heart failure (OR 2.365, 95% CI 2.128-2.629, P = 1.91E-57). Sensitivity analyses provided further support for the reliability of these results, with no significant indication of horizontal pleiotropy observed. This study shows that obesity, including childhood obesity, is linked to a higher risk of heart failure. These findings highlight the urgent need for early weight management interventions in public health and clinical settings to reduce heart failure rates.