Objective To construct a mediation model of non-alcoholic fatty liver disease (NAFLD)→ triglyceride-glucose (TyG) index/white blood cell count (WBC)→10-year ASCVD risk, in order to elucidate the association between NAFLD and 10-year ASCVD risk and provide potential therapeutic targets.

Methods A total of 9 019 subjects who completed health examinations at Xiang'an Hospital Affiliated to Xiamen University from June 2019 to June 2024 and met the inclusion criteria were included. Demographic, biochemical and disease history data were collected. The chi-square test and Mann-Whitney U test were used to analyze the differences between groups. Linear regression analysis was conducted on the independent variable→mediating variable→dependent variable using the glm function of the stats package in R language. The mediate function of the mediation package was used to build a mediation effect model. Stratified analysis was conducted by gender, hypertension and diabetes

Results A total of 9 019 eligible participants who underwent health check-ups were included in this study. Among them, 2 844 were diagnosed with NAFLD and 6 175 were non-NAFLD subjects. There were 3 675 males and 5 344 femaless. Multivariable linear regression analysis showed that after adjusted for age, sex, body mass index, smoking status, hypertension, diabetes, total cholesterol, and high-density lipoprotein cholesterol (HDL-C), NAFLD was independently and positively associated with the 10-year ASCVD risk score (β=0.001, 95%CI 0.001 to 0.002, P＜ 0.001). Mediation analysis indicated that both the TyG index and WBC count played significant mediating roles in the association between NAFLD and ASCVD risk. The proportion of the effect mediated by TyG index in the pathway from NAFLD to 10-year ASCVD risk was 59.46%, and the proportion of the effect mediated by WBC was 10.81%. After stratification by gender, the mediating effect only existed in the female group. In females, NAFLD was significantly associated with the risk of ASCVD (β=0.006, 95%CI 0.005 to 0.007, P＜0.001). The proportions of the effect mediated by TyG index and WBC in the NAFLD→10-year ASCVD risk pathway were 62.07% and 13.79%, respectively. In contrast, in males, the association between NAFLD and ASCVD risk was not statistically significant (β＜0.001, 95%CI ＜0.001 to 0.001, P=0.327), consequently, a valid mediation model could not be established. Further subgroup analysis among females showed significant mediating effects of TyG and WBC across different hypertension statuses (non-hypertension, untreated hypertension, treated hypertension) and in the non-diabetes and treated diabetes subgroups. The mediation proportions for TyG and WBC in the NAFLD→ASCVD risk pathway were highest in the non-hypertension subgroup, followed by the treated hypertension subgroup, and lowest in the untreated hypertension subgroup. In the diabetes stratification, the mediation proportions for TyG and WBC were higher in the non-diabetes subgroup compared to the treated diabetes subgroup.

Conclusion NAFLD may significantly increase the 10-year ASCVD risk through metabolic (TyG index) and inflammatory (WBC) pathways, particularly in female patients.