Antihypertensive Treatment and Risk of Metabolic Associated Fatty Liver Disease: A Drug-Target Mendelian Randomization

BACKGROUND: Metabolic dysfunction-associated fatty liver disease, conventionally known as nonalcoholic fatty liver disease (NAFLD), affects over a quarter of the global population and lacks approved pharmacological treatments. We investigated whether elevated blood pressure (BP) is a modifiable risk factor for NAFLD and whether antihypertensive drugs could be repurposed for prevention. METHODS: We conducted whole-genome Mendelian randomization using genetic data from over 1 million individuals of European ancestry to assess systolic BP as a risk factor for NAFLD. Drug-target Mendelian randomization was used to investigate the class-specific effects of antihypertensive agents, including renin-angiotensin system inhibitors, β-blockers, calcium channel blockers, and diuretics. NAFLD was defined by persistently elevated alanine aminotransferase levels after excluding alternative liver diseases and alcohol use disorders. Genetic estimates were compared with individual-participant meta-analyses of randomized controlled trials (n=358 636) and summary data from 104 antihypertensive drug trials (≈500 000 participants), using coronary heart disease as a positive control. RESULTS: A genetically proxied 5-mm Hg reduction in systolic BP was associated with an 8% lower risk of NAFLD (odds ratio, 0.92 [95% CI, 0.90-0.94]). Renin-angiotensin system inhibition was associated with a 27% lower risk (odds ratio, 0.73 [95% CI, 0.62-0.85]), whereas other drug classes showed no substantial associations. For coronary heart disease, effects were directionally consistent across classes in genetic and trial analyses. CONCLUSIONS: Genetically lower systolic BP is associated with reduced NAFLD risk, with renin-angiotensin system inhibition showing the most favorable association. These findings support BP lowering, particularly renin-angiotensin system inhibition, as a potential preventive strategy warranting dedicated randomized trials.