High-fat diet and portal hypertension: a triangulation approach combining Mendelian randomization with retrospective clinical analysis

Background Portal hypertension is a major complication of chronic liver disease, but the causal role of dietary factors, particularly high-fat diet, remains unclear due to confounding in observational studies. This study aimed to investigate the relationship between high-fat diet and portal hypertension using a triangulation approach combining Mendelian randomization (MR) and retrospective clinical analysis. Methods We conducted a two-sample Mendelian randomization analysis using summary-level genome-wide association study (GWAS) data for dietary fat intake (n = 268,922) and portal hypertension-related traits. Eighteen independent SNPs served as genetic instruments (mean F-statistic = 34.2, collectively explaining 2.8% of phenotypic variance). Inverse variance weighted (IVW), weighted median, MR-Egger regression, and mode-based methods were employed. Sensitivity analyses included MR-Egger intercept test, Cochran’s Q statistic, MR-PRESSO, and leave-one-out analysis. Additionally, a retrospective cross-sectional clinical study was conducted on 72 patients with portal hypertension who underwent hepatic venous pressure gradient (HVPG) measurement. Results MR analysis provided evidence consistent with a causal association between genetically predicted high-fat diet and increased risk of portal hypertension (IVW OR = 1.28 per SD increase, 95% CI: 1.15–1.42, p = 1.0 × 10 -5 ). Results were consistent across multiple MR methods. Sensitivity analyses showed no evidence of directional pleiotropy (MR-Egger intercept p = 0.178), significant heterogeneity (Cochran’s Q p = 0.241), or MR-PRESSO-detected outliers (global test p = 0.312). In the clinical cohort, high-fat diet score was positively correlated with HVPG (r = 0.700, p < 0.001), and this association remained significant after multivariate adjustment (β = 0.85, 95% CI: 0.52–1.18, p < 0.001). Conclusion Using a triangulation approach, we found consistent evidence from both Mendelian randomization and retrospective clinical analysis that a high-fat diet is linked to increased portal pressure. These complementary findings strengthen the overall evidence base and highlight the potential importance of dietary fat modification in portal hypertension management.