Zhewen Ren^1,2,3, Anke Wesselius^4,5, M. Eline Kooi^2,6, Marleen van Greevenbroek^2,3, Pieter Dagnelie^1,2, Tos T J M Berendschot⁷, Abraham A Kroon^1,2, Alfons J H M Houben^1,2, Coen D.A. Stehouwer^1,2, Martijn C.G.J. Brouwers^1,2,8

1. Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands.
2. Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.
3. Laboratory for Metabolism and Vascular Medicine, Maastricht University, Maastricht, The Netherlands.
4. Department of Epidemiology, Maastricht University, Maastricht, The Netherlands.
5. Institute of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands.
6. Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, The Netherlands.
7. University Eye Clinic Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands.
8. Care and Public Health Research Institute (CAPHRI), Maastricht University, Maastricht, The Netherlands.

Background: The performance of polygenic risk scores (PRS) may be improved by the addition of gene-environment interactions. We hypothesized that intrahepatic lipid (IHL) content – which drives the production of VLDL particles – interacts with a PRS for VLDL particle clearance on the risk of hypertriglyceridemia.

Methods: Data from The Maastricht Study (n=3,810; age: 60 years, 49% women, 10% hypertriglyceridemia, 26% steatotic liver disease) was used. We performed multivariable linear regression analyses to assess the interaction between IHL content (quantified by MRI) and a PRS for VLDL clearance (based on nine single nucleotide polymorphisms) on fasting serum triglycerides, after adjustment for sociodemographic, lifestyle and cardiovascular risk factors. We subsequently explored whether a similar interaction affects incident cardiovascular disease (CVD) during a 10-year follow-up.

Results: There was a statistically significant interaction between IHL content and the PRS for VLDL clearance on serum triglycerides (p=0.005). The strength of the association between a high PRS and risk of hypertriglyceridemia was larger in individuals with steatotic liver disease (OR: 6.2, 95%CI:4.0; 9.8) than those without (OR: 1.6, 95%CI:1.1; 2.4). A similar, non-significant trend was observed for risk of incident CVD (p=0.078).

Conclusions: Genetically-predisposed individuals have a substantially higher risk of hypertriglyceridemia when they also have steatotic liver disease. These results allow more targeted measures in order to prevent and treat hypertriglyceridemia and to reduce cardiovascular risk.