Integrative Genomic Analysis Reveals Insulin Resistance as a Key Mediator in the Causal Link between Metabolic Dysfunction–associated Steatohepatitis and Hypertension

Abstract

Introduction: While metabolic dysfunction–associated steatohepatitis (MASH) is frequently associated with arterial hypertension, We used a multitiered Mendelian randomization (MR) framework to independently evaluate the causal link between MASH liability and hypertensive phenotypes. Methods: We performed a two-sample, two-step MR analysis leveraging genetic summary statistics from the Million Veteran Program (n = 218,595), UK Biobank (n = 735,757), and the Malignant Germ Cell International Consortium (n = 108,557). MASH liability was defined through four tiered instrument sets: (1) chronic alanine aminotransferase (cALT) proxy, (2) imaging-validated genetic instruments, (3) biopsy-validated genetic instruments, and (4) a high-stringency consensus set. Hypertensive outcomes included systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP). Multivariable MR was employed to adjust for body mass index and lipid fractions, while a two-step framework quantified the mediated effect of insulin resistance. Results: Genetic liability for MASH drove elevated blood pressure. Increased MASH was associated with elevated systolic blood pressure (SBP) (β=0.62 mm Hg; p<0.001), diastolic blood pressure (DBP) (β=0.39 mm Hg; p<0.001), and pulse pressure (PP) (β=0.28 mm Hg; p<0.01). Effects were amplified in the biopsy-validated tier (SBP: β=1.07 mm Hg; p<0.01). Insulin resistance significantly mediated these causal effects: 33.2% for SBP, 36.9% for DBP, and 30.7% for PP. Sensitivity analyses confirmed result robustness. Conclusions: MASH causally increases hypertension risk independently of traditional metabolic factors. Insulin resistance is a pivotal mediator, suggesting treating hepatic metabolic dysfunction offers systemic cardiovascular benefits.