Interaction between dietary cholesterol intake and genetic variants for cholesterol absorption in relation to coronary artery disease mortality: a prospective analysis in the Singapore Chinese Health Study

Authors:

• Shi, Shuxiao
• Chang, Xuling
• Dorajoo, Rajkumar
• Khor, Chiea Chuen
• Zhong, Victor W
• Koh, Woon-Puay

Details:

The American Journal of Clinical Nutrition, 2025-09-09

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Background Data from Western studies suggest that genetic susceptibility to cholesterol absorption may modify the association between dietary cholesterol (DC) intake and cardiovascular disease. However, such data are lacking in Asians who have different genetic background, dietary intake, and disease risk. Objectives This study aimed to investigate the interaction between DC intake and genetic susceptibility to cholesterol absorption in association with coronary artery disease (CAD) mortality in the Singapore Chinese Health Study, a prospective cohort study. Methods We used data from 21,873 Chinese adults with complete data on DC consumption at recruitment (1993–1998) and genetic susceptibility to cholesterol absorption quantified by polygenetic risk scores (PRSs) constructed using single-nucleotide polymorphisms related to low-density lipoprotein cholesterol (LDL cholesterol) and non–high-density lipoprotein cholesterol (non-HDL cholesterol). CAD mortality was identified via linkage with the nationwide death registry through 31 December 2022. Multivariable cause-specific hazard models were used to evaluate the association between DC intake and CAD mortality, overall and by different PRS levels. Results Each additional 300 mg/d of DC intake was associated with a 1.42-fold higher risk of CAD mortality [hazard ratio (HR): 1.42; 95% confidence interval (CI): 1.09, 1.86]. The HRs (95% CIs) for the association between DC intake and CAD mortality among participants with low, intermediate, and high PRS for LDL cholesterol absorption were 1.18 (0.60, 2.30), 1.27 (0.89, 1.83), and 2.32 (1.34, 4.02), respectively (P-interaction = 0.03). For PRS related to non-HDL cholesterol absorption, the respective HRs were 1.25 (0.64, 2.46), 1.30 (0.93, 1.84), and 2.07 (1.14, 3.77) (P-interaction = 0.04). Conclusions DC intake was more strongly associated with CAD mortality in Singapore Chinese with greater genetic susceptibility to cholesterol absorption.