Causal link between circulating beta-hydroxybutyrate and myocardial infarction: Evidence from Mendelian randomization

This study investigates the potential causal relationship between circulating ketone bodies, specifically beta-hydroxybutyrate (β-OHB), and the risk of myocardial infarction (MI), addressing limitations of confounding and reverse causation inherent in previous observational studies. We employed both univariable Mendelian randomization and multivariable Mendelian randomization (MVMR) analyses using publicly available genome-wide association study summary statistics. Genetic variants robustly associated with serum β-OHB levels (P < 5 × 10-8) served as instrumental variables. Primary analysis used the inverse-variance weighted method, supplemented by sensitivity analyses (MR-Egger, weighted median, weighted mode, MR-Lasso) and tests for pleiotropy/heterogeneity (Cochran's Q, MR-Egger intercept, MR-Pleiotropy RESidual Sum and Outlier, leave-one-out). The MVMR model adjusted for key cardiometabolic confounders: type 2 diabetes, alcohol intake, body mass index, smoking, hypertension, and blood lipids. univariable Mendelian randomization analysis indicated a significant positive association: a one-unit increase in natural log-transformed β-OHB concentration was associated with higher MI risk (IVW odds ratio [OR] = 1.407, 95% confidence interval (CI): 1.1660-1.6980, P = .0003691). Sensitivity analyses (weighted median: OR = 1.260, 95% CI: 1.0022-1.585, P = .0478442; MR-Egger: directionally consistent) supported this finding. MVMR analysis adjusting for confounders yielded divergent results. While conventional IVW showed no significant independent association (OR = 0.9787, 95% CI: 0 0.7410-1.2928, P = .8797), the MR-Lasso method revealed a significant independent positive association between β-OHB and MI risk (OR = 1.2366, 95% CI: 1.0397-1.4707, P = .0163751). This Mendelian randomization study suggests that genetically predicted, chronically elevated levels of β-OHB may confer an increased risk of MI.