Hypertension (Dallas, Tex. : 1979) · 2026
Antihypertensive Treatment and Risk of Metabolic Associated Fatty Liver Disease: A Drug-Target Mendelian Randomization.
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Hu Yifan, Byrne Karl Smith-, Bidel Zeinab, Xiao Xiong, Zhao Xing, Dehghan Abbas, Canoy Dexter, Wamil Malgorzata, Conrad Nathalie, Rao Shishir, Petrazzini Ben Omega, Yang Qianqian, Gill Dipender, Walker Venexia M, Sigalas Charalampos, Malekzadeh Reza, Sundström Johan, Woodward Mark, Davey Smith George, Rahimi Kazem, Nazarzadeh Milad
Аннотация
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.
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.