To investigate the association between PNPLA3 inhibition and cardiovascular diseases (CVDs), focusing on the mediating roles of specific lipid traits such as LDL-C and TC.
Key Findings:
Genetically predicted PNPLA3 inhibition significantly increased the risk of coronary atherosclerosis (1.14, 95% CI 1.06, 1.23), coronary heart disease (1.14, 95% CI 1.08, 1.21), and myocardial infarction (1.16, 95% CI 1.08, 1.26).
Suggestive associations for increased risk of heart failure (1.09, 95% CI 1.02, 1.17) and atrial fibrillation (1.17, 95% CI 1.00, 1.36) were observed, with P-values indicating statistical significance.
Blood LDL-C and TC mediated 16% to 25%, 16% to 30%, and 14% to 22% of the associations between PNPLA3 inhibition and coronary atherosclerosis, myocardial infarction, and coronary heart disease, respectively.
Interpretation:
PNPLA3 inhibition may elevate the risk of major cardiovascular diseases, with LDL-C and TC playing significant mediating roles.
Limitations:
Long-term effects and potential side effects of ARO-PNPLA3 are not well understood, and the reliance on genetic associations may not fully capture the complexity of CVD risk.
Conclusion:
PNPLA3 inhibition is associated with increased cardiovascular risk, highlighting the need for careful consideration of lipid levels in future clinical trials and monitoring in clinical practice.
