Association between metabolic dysfunction-associated steatotic liver disease and risk of cardiovascular disease

Abstract

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common liver condition associated with obesity and metabolic syndrome. Although MASLD has been associated with increased cardiovascular disease (CVD) risk, the causal nature of this association remains uncertain owing to the limitations of observational studies. Although genetic approaches such as genome-wide association studies (GWAS) and Mendelian randomization (MR) have been applied using large biobanks, the findings have been inconsistent. This study investigated the association between MASLD and CVD through observational and genetic analyses, utilizing individual-level data from Korean and UK populations, as well as summary-level data from Japan. Methods: A multistep analytical strategy using data from the Korean Cancer Prevention Study (KCPS-II) cohort was applied. Steatotic Liver Disease (SLD) was defined using a fatty liver index (FLI) threshold of 30 or greater. First, a prospective observational analysis was performed using the Cox proportional hazards model to evaluate the association between MASLD and the incidence of CVD and its subtypes. Second, one-sample and bidirectional two-sample MR analyses were conducted to assess the causal effect of the MASLD on CVD using large-scale cohort data from the KCPS-II, Biobank Japan (BBJ), and the UK Biobank (UKB). Third, GWAS was conducted to identify MASLD-related genetic variants, followed by gene-based and tissue-specific expression analyses. Fourth, gene–smoking interaction analyses were performed to investigate how smoking modifies the genetic effects of MASLD. Results: In total, 111,637 participants were included (median age 39, 35.7% women). At baseline, 32,018 (28.7%) patients were diagnosed with MASLD. During the median 10.0-year follow-up, 3,926 incident CVD events occurred. Multivariable-adjusted hazard ratio (HR) of CVD was 1.69 (95% confidence interval (CI) 1.57–1.82) for MASLD. In the one-sample MR analysis using individual-level data from KCPS-II, genetically predicted MASLD was associated with a modest but statistically significant increase in overall CVD risk (HR 1.05, 95% CI 1.03–1.08) in the fully adjusted model. To further examine causality, two-sample MR analyses were conducted using summary-level data from BBJ and individual-level data from UKB. The inverse variance-weighted (IVW) method demonstrated a significant positive association between MASLD and coronary artery disease (CAD). The odds ratio (OR) was 1.08 (95% CI 1.05–1.13, p = 1.83 × 10⁻⁵) when using BBJ outcomes and 1.04 (95% CI 1.01–1.08, p = 6.03 × 10⁻³) based on UKB outcomes. In the reverse direction, genetic liability to CVD derived from the KCPS-II cohort was also significantly associated with increased MASLD risk when MASLD was defined in UKB (OR 1.15, 95% CI 1.08–1.24, p = 4.39 × 10⁻⁵). GWAS using KCPS-II data identified multiple loci associated with MASLD. GWAS identified numerous loci associated with MASLD, including FTO and CUX2. Expression profiling revealed liver-specific enrichment of GCKR, LIPC, APOA5, APOA4, APOA1, APOC3, APOE, and HNF1A, whereas RPH3A was enriched in brain tissue—functional enrichment analyses implicated lipid metabolism and coronary disease-related pathways. Variance decomposition revealed that MASLD had a total heritability of 38.6%, with 6.5% attributed to genetic factors, 5.3% to gene–smoking interactions, and 26.7% to environmental noise components. In gene–environment interaction analyses, several loci, including rs671 in ALDH2, exhibited enhanced effects in the presence of smoking. Conclusion: This study provided comprehensive evidence linking MASLD to an increased risk of CVD through both observational and genetic analyses. The MR findings support the potential causal role of MASLD in the development of CVD. The identification of MASLD-associated loci and gene–environment interactions highlights the complex genetic architecture and modifying effects of smoking. These results underscore the importance of metabolic liver health in CVD prevention and suggest that MASLD may represent a modifiable target for reducing the cardiovascular burden.