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

Area of Science:

• Cardiovascular Research
• Metabolic Health
• Genetic Epidemiology

Background:

• Observational studies on beta-hydroxybutyrate (β-OHB) and myocardial infarction (MI) risk are limited by confounding and reverse causation.
• Understanding the causal relationship between circulating ketone bodies and cardiovascular events is crucial for public health.

Purpose of the Study:

• To investigate the potential causal effect of circulating β-OHB on the risk of MI using Mendelian randomization (MR).
• To address limitations of previous studies by employing univariable and multivariable MR analyses.

Main Methods:

• Utilized genome-wide association study summary statistics for β-OHB and MI.
• Employed inverse-variance weighted (IVW) and other MR methods (MR-Egger, weighted median, MR-Lasso) for sensitivity analyses.
• Multivariable MR (MVMR) adjusted for cardiometabolic confounders including type 2 diabetes, BMI, and lipids.

Main Results:

• Univariable MR indicated a positive association between β-OHB and MI risk (OR=1.407, P=0.0003691).
• Sensitivity analyses supported the univariable findings.
• MVMR results were divergent; IVW showed no significant association, but MR-Lasso identified a significant independent positive association (OR=1.2366, P=0.0163751).

Conclusions:

• Genetically predicted chronically elevated β-OHB levels may be associated with an increased risk of MI.
• The findings suggest a potential causal role of β-OHB in myocardial infarction development.
• Further research is warranted to elucidate the mechanisms underlying this association.