Association of non-high-density lipoprotein cholesterol trajectories with the development of non-alcoholic fatty liver disease: an epidemiological and genome-wide association study

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) shares common risk factors with cardiovascular diseases. Effects of longitudinal trends in non-high-density lipoprotein (non-HDL) cholesterol on NAFLD development are not understood. This study aimed to assess the relationship between non-HDL cholesterol trajectories and the incidence of NAFLD and to identify genetic differences contributing to NAFLD development between non-HDL cholesterol trajectory groups. METHODS: We analyzed data from 2203 adults (aged 40–69 years) who participated in the Korean Genome and Epidemiology Study. During the 6-year exposure periods, participants were classified into an increasing non-HDL cholesterol trajectory group (n = 934) or a stable group (n = 1269). NAFLD was defined using a NAFLD-liver fat score > -0.640. Multiple Cox proportional hazard regression analysis estimated the hazard ratio (HR) and the 95% confidence interval (CI) for the incidence of NAFLD in the increasing group compared with the stable group. RESULTS: A genome-wide association study identified significant single-nucleotide polymorphisms (SNPs) associated with NAFLD. During the median 7.8-year of event accrual period, 666 (30.2%) newly developed NAFLD cases were collected. Compared with the stable non-HDL group, the adjusted HR (95% CI) for the incidence of NAFLD in the increasing non-HDL cholesterol group was 1.46 (1.25–1.71). Although there were no significant SNPs, the polygenic risk score was highest in the increasing group, followed by the stable and control groups. CONCLUSION: Our study indicates that lifestyle or environmental factors have a greater effect size than genetic factors in NAFLD progression risk. Lifestyle modification could be an effective prevention strategy for NAFLD for people with elevated non-HDL cholesterol. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-023-04291-4.