Causal insights into how NAFLD progression drives abdominal aortic aneurysm: A bidirectional MR study integrating genetic and multi-omics profiling.

A well-defined causal relationship between nonalcoholic fatty liver disease (NAFLD) and abdominal aortic aneurysm (AAA) is lacking, and it remains unknown whether AAA risk varies across different NAFLD stages. This study applied Mendelian randomization (MR) to evaluate the stratified effects of different NAFLD stages on AAA. Multi-omics data were integrated to identify potential mediating pathways. Large-scale genome-wide association study summary data were analyzed using inverse-variance weighted as the primary MR method. MR-Egger and weighted median MR methods were employed as complementary approaches. Sensitivity analyses were conducted using MR-PRESSO (Mendelian randomization pleiotropy residual sum and outlier), Cochran Q test, and MR-Egger testing. To further ensure the robustness of MR results, funnel plots, scatter plots and leave-one-out analyses were also constructed. Further analyses were conducted to assess the causal effects of NAFLD/NASH on thoracic aortic aneurysm (TAA) and aortic aneurysm (AA). Multi-omics integration helped identify intermediate molecular traits. Bidirectional MR analysis demonstrated a positive causal effect of NAFLD/NASH on AAA risk (odds ratio = 1.05, 95% confidence interval: 1.01-1.09; P = .017), with no evidence for reverse causation. Validation analyses showed a reverse causal association between liver fat content and AAA, while other associations were nonsignificant. Further MR analyses revealed no significant causal effects of NAFLD/NASH on thoracic aortic aneurysm or unclassified aortic aneurysm. Multi-omics integration identified 1 metabolite and 2 lipid species associated with NAFLD/NASH; however, none directly caused AAA. NAFLD/NASH exerts a positive causal effect on AAA, predominantly in advanced disease stages such as NASH and fibrosis. Multi-omics evidence suggests that certain metabolites and lipid species may serve as biomarkers or indirectly promote AAA by driving NAFLD progression, influencing AAA risk indirectly through promoting progression of NAFLD/NASH. These findings provide genetic evidence for NAFLD-driven AAA pathogenesis, underscoring the importance of risk stratification and early intervention in advanced NAFLD.