LDL-C and TC Mediate the Risk of PNPLA3 Inhibition in Cardiovascular Diseases

Abstract Context PNPLA3 is a promising target for the treatment of metabolic dysfunction–associated steatotic liver disease. ARO-PNPLA3 is a drug that efficiently lowers PNPLA3 expression in hepatocytes at the mRNA level, resulting in a significant reduction in liver fat in Phase I clinical trials. However, the long-term effects and potential side effects of ARO-PNPLA3 are not well understood. Objective We conducted a 2-sample, 2-step Mendelian randomization analysis to investigate the association between PNPLA3 inhibition and 10 cardiovascular diseases (CVDs), as well as the role of lipid traits as mediators. Methods We identified genetic variants near the PNPLA3 gene, which are linked to liver fat percentage, as instrumental variables for inhibiting PNPLA3. Additionally, positive control analyses on liver diseases were conducted to validate the selection of the genetic instruments. Results 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 were observed for increased risk of heart failure (1.09, 95% CI 1.02, 1.17, P = .0143) and atrial fibrillation (1.17, 95% CI 1.00, 1.36, P = .0468). Blood low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) mediated approximately 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. Conclusion This study suggests that PNPLA3 inhibition increases the risk of major CVDs. Moreover, blood LDL-C and TC may mediate a significant proportion of the associations between PNPLA3 inhibition and coronary atherosclerosis, coronary heart disease, or myocardial infarction.