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. 2025 Jun 27.
doi: 10.1007/s00125-025-06479-3. Online ahead of print.

Steatotic liver disease interacts with a polygenic risk score for triglyceride clearance to impact the risk of hypertriglyceridaemia: The Maastricht Study

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 Berendschot  7 , Abraham A Kroon  1   2 , Alfons J H M Houben  1   2 , Coen D A Stehouwer  8 , Martijn C G J Brouwers  9   10   11
Affiliations

Steatotic liver disease interacts with a polygenic risk score for triglyceride clearance to impact the risk of hypertriglyceridaemia: The Maastricht Study

Zhewen Ren et al. Diabetologia. .

Abstract

Aims/hypothesis: 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.

Methods: We used data from The Maastricht Study, a population-based prospective cohort study (n=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.

Results: There was an impact of interaction between IHL content and the PRS for triglyceride clearance on serum triglycerides (p=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 (p=0.078).

Conclusions/interpretation: 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.

Keywords: Hypertriglyceridaemia; Interaction; Polygenic risk score; Steatotic liver disease.

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Conflict of interest statement

Acknowledgements: We thank all the participants in The Maastricht Study and all the co-authors for contributions. Some of the data were presented as an abstract at the Annual Dutch Diabetes Research Meeting in 2024. Data availability: Data are available from The Maastricht Study for any researcher who meets the criteria for access to confidential data; the corresponding author may be contacted to request data. Funding: ZR was supported by the Chinese Scholarship Council. The Maastricht Study was supported by the European Regional Development Fund via OP-Zuid, the Province of Limburg, the Dutch Ministry of Economic Affairs (grant 31O.041), Stichting De Weijerhorst (Maastricht, the Netherlands), the Pearl String Initiative Diabetes (Amsterdam, the Netherlands), Cardiovascular Research Institute Maastricht (CARIM; Maastricht, the Netherlands), the Care and Public Health Research Institute (CAPHRI; Maastricht, the Netherlands), Institute of Nutrition and Translational Research in Metabolism (NUTRIM; Maastricht, the Netherlands), Stichting Annadal (Maastricht, the Netherlands) and the Health Foundation Limburg (Maastricht, the Netherlands), and by unrestricted grants from JanssenCilag B.V. (Tilburg, the Netherlands), Novo Nordisk Farma B.V. (Alphen aan den Rijn, the Netherlands), Sanofi-Aventis Netherlands B.V. (Gouda, the Netherlands) and Medtronic (Tolochenaz, Switzerland). Authors’ relationships and activities: The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. Contribution statement: ZR, AW, CDAS and MCGJB were involved in conception and design of the study; MEK, MvG, PD, TTJMB, AAK and AJHMH were involved in data acquisition; ZR, AW, CDAS and MCGJB analysed and interpreted data. ZR and MCGJB drafted the article. All authors critically reviewed the article for important intellectual content and approved the final version of the manuscript to be published. MCGJB is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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