Why the study?
Does lowering systolic blood pressure, overall or through specific antihypertensive drug classes, reduce the risk of metabolic dysfunction-associated fatty liver disease (NAFLD)?
Does lowering systolic blood pressure, overall or through specific antihypertensive drug classes, reduce the risk of metabolic dysfunction-associated fatty liver disease (NAFLD)?
Odds Ratio: 0.92 (95% CI 0.9–0.94)
Genetic and trial-triangulated evidence identifies elevated systolic blood pressure as a modifiable causal risk factor for NAFLD and highlights renin-angiotensin system inhibitors as the most promising antihypertensive class for preventing metabolic liver disease.
Supports BP lowering via RAS inhibition to reduce NAFLD risk; extends genetic evidence to guide antihypertensive selection in metabolic disease.
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.
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Hu et al. (2026) studied Metabolic dysfunction-associated fatty liver disease (MAFLD / NAFLD) and hypertension. Genetically proxied systolic blood pressure reduction (per 5-mm Hg lower) and antihypertensive drug-target classes (renin-angiotensin system inhibitors, beta-blockers, calcium channel blockers, and diuretics) vs. Genetically higher systolic blood pressure or non-targeted genetic variation (and placebo or active comparator in positive-control RCT meta-analyses) was evaluated on Incident metabolic dysfunction-associated fatty liver disease (NAFLD), defined by persistently elevated alanine aminotransferase levels (>40 U/L for men or >30 U/L for women on at least two occasions separated by ≥6 months within 2 years) after excluding alternative liver diseases and alcohol use disorders (OR 0.92, 95% CI 0.90-0.94).
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