Aims/hypothesis <p>The pathogenesis of hypertriglyceridaemia is explained by a complex interplay between genetic and environmental factors. We hypothesised that intrahepatic lipid (IHL) content, which drives the production of triacylglycerol-rich VLDL particles, interacts with a polygenic risk score (PRS) for triglyceride clearance to impact the risk of hypertriglyceridaemia.</p> Methods <p>We used data from The Maastricht Study, a population-based prospective cohort study (<i>n</i>=3810; age: 60 years, 48% women, 10% hypertriglyceridaemia, 26% steatotic liver disease). We performed multivariable linear regression analyses to assess the impact of the cross-sectional interaction between IHL content (quantified by MRI) and a PRS for triglyceride clearance (based on nine SNPs) on fasting serum triglycerides, after adjustment for sociodemographic, lifestyle and cardiovascular risk factors. We subsequently explored whether a similar longitudinal interaction affects incident CVD during a 10 year follow-up.</p> Results <p>There was an impact of interaction between IHL content and the PRS for triglyceride clearance on serum triglycerides (<i>p</i>=0.005). The strength of the association between a high PRS and risk of hypertriglyceridaemia was larger in individuals with steatotic liver disease (OR 6.196; 95% CI 3.966, 9.768) than in those without (OR 1.618; 95% CI 1.110, 2.380). A similar trend was observed for incident CVD risk (<i>p</i>=0.078).</p> Conclusions/interpretation <p>Genetically predisposed individuals have a substantially higher risk of hypertriglyceridaemia when they also have steatotic liver disease. This gene–environment interaction might contribute to more personalised treatment approaches, which require further exploration in future studies.</p> Graphical Abstract <p></p>