Revealing Antihypertensive Drugs for Reducing NAFLD Risk: Genetic Evidence from a Mendelian Randomization Study

Longstanding observational work has associated Nonalcoholic Fatty Liver Disease (NAFLD) with hypertension and suggested that antihypertensive therapy may slow NAFLD progression. However, confounding and reverse causation in these studies obscure the effects on the risk for NAFLD. To tackle this problem, the study utilized Mendelian randomization (MR) to test the causal antihypertensive effects of drug targets on NAFLD and to evaluate safety.

A total of 37 antihypertensive drug targets from genome-wide association studies (GWAS) were used to instrument Single-Nucleotide Polymorphisms (SNPs) and perform MR to estimate causal relationships with NAFLD risk and possible adverse outcomes. The study examined robustness through heterogeneity tests, assessments of horizontal pleiotropy, leave-one-out analyses, and meta-analysis. Meanwhile, the study profiled possible side effects of prioritised targets with phenome-wide association studies (PheWAS).

Genetic proxies for beta-1 adrenergic receptor (ADRB1) antagonists, solute carrier family 12 member 1 (SLC12A1) inhibitors, and neuraminidase 1 (NEU1) inhibitors were associated with reduced NAFLD risk in three distinct analyses, according to MR and meta-analysis data. Combining MR and PheWAS results indicates that the known classes, ADRB1 antagonists and SLC12A1 inhibitors, may be safer.

Compared with previous studies, this study provided a more comprehensive genetic analysis of existing antihypertensive drug targets, suggesting that inhibition of ADRB1, SLC12A1, and NEU1 can significantly reduce the risk of NAFLD while assessing their safety. Based on the results of this study, future clinical translation must carefully balance the benefits and risks and achieve precise intervention through an individualized medication strategy.

This study, according to current knowledge, offers the first genetic evidence that antihypertensive drugs can lower NAFLD risk. ADRB1 and SLC12A1 appear to be promising therapeutic targets for NAFLD, whereas NEU1 inhibition warrants a more cautious appraisal to balance efficacy with safety.