Genetic modifiers of triglyceride-mediated mortality in coronary heart disease: a large cohort study of polygenic risk and circulating triglyceride level interaction
F Xu, K L Yan, K X Zhang, M L Liu, Y J Yang, X F Lu, J Q Yuan, X Y ZhaoAbstract
Background
The relationship between triglyceride (TG) levels and adverse events in coronary heart disease (CHD) patients is debated, and the modifying role of genetic background (TG-PRS) is unclear.
Aim
This study investigated the non-linear relationship between TG and all-cause mortality across TG-PRS strata to inform personalized risk management.
Methods
4304 CHD patients undergoing PCI were enrolled. Restricted cubic spline (RCS) Cox regression analyzed the non-linear TG-mortality association in the overall population, adjusted for confounders (age, sex, BMI, hypertension, diabetes, prior PCI/CABG, COPD, PAD, CVD, hs-CRP, ACS). The population was stratified by TG-PRS tertiles (low, medium, high), with RCS repeated per stratum. Further stratified Cox regression was conducted within each PRS stratum, categorizing participants into low- and high-TG subgroups based on stratum-specific inflection points to examine differences in TG's continuous effect on mortality.
Results
Among 4304 CHD patients (mean age 57.45 ± 10.14 years, 83% male), 496 (11.5%) died after 10-year follow-up. In the overall population, TG showed an L-shaped association with mortality (P=0.0016) before adjustment, shifting to a non-significant U-shaped pattern after multivariable adjustment (P=0.1965). A significant TG and TG-PRS interaction was identified (P=0.031). Stratified RCS analyses revealed: 1. High TG-PRS: marginally significant U-shape (overall P=0.0548, non-linearity P=0.0386, inflection 1.67 mmol/L; red in Figure2); 2. Medium TG-PRS: significant U-shape (overall P=0.0191, non-linearity P=0.0112, inflection 1.44 mmol/L; orange in Figure2); 3. Low TG-PRS: no significant association (overall P=0.5504, non-linearity P=0.4773; blue in Figure2). Further interaction analyses confirmed: In high TG-PRS (P-interaction=0.0107), each 1 mmol/L TG increment reduced mortality by 48.5% in low-TG subgroups (TG<1.67 mmol/L; HR=0.515, P=0.0133), but not in high-TG subgroups (TG≥1.67 mmol/L; HR=1.057, P=0.5147). A similar pattern was seen in medium TG-PRS (P-interaction=0.0061): significant inverse association in low-TG (TG<1.44 mmol/L; HR=0.461, P=0.0258), but not high-TG (TG≥1.44 mmol/L; HR=1.275, P=0.0644). No significant interaction was found in low TG-PRS (P-interaction=0.2981).
Conclusion
TG is non-linearly associated with all-cause mortality, modified by TG-PRS. A U-shaped TG-mortality relationship was observed in medium and high TG-PRS groups. TG's protective effect in high-genetic-risk patients was confined to low-TG subgroups, highlighting that TG's clinical relevance depends on genetic background and baseline TG status. The observed association between lower TG and poorer prognosis may reflect reverse causation or disease-related factors (e.g., malnutrition, inflammation). Our findings support stratified, personalized TG management over a universal cutoff, especially for high-genetic-risk individuals.Figure1Figure2