Abstract 4336116: Protein-Truncating Variants of the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Artery Disease among Patients with Heterozygous Familial Hypercholesterolemia

Backgrounds: Cholesteryl ester transfer protein (CETP) inhibition has long been attracting a lot of attention if it could reduce the risk for coronary artery disease (CAD). A previous study has demonstrated that protein-truncating variants (PTVs) were associated with lower risk for CAD, which was dependent on lower LDL cholesterol in general population. We tested this hypothesis among Japanese heterozygous FH (HeFH) patients whose CAD risk was extremely high. Methods: We investigated the clinical data of 2,344 patients diagnosed with HeFH (mean age = 50 years, males = 1,174, median LDL cholesterol = 244 mg/dL) who were examined for their genotype of CETP and phenotypes, including the presence of CAD from 1990 to 2024 at Kanazawa University Hospital. We investigated whether PTVs of the CETP were associated with plasma lipid levels and CAD among patients with HeFH. Results: We identified 42 patients (1.8 %) with a PTV of CETP in HeFH patients. Compared with non-carriers, carriers of a PTV of CETP had higher HDL cholesterol (effect size, 17.6 mg/dL; 95% confidence interval [CI], 11.4 to 23.8; P < 0.001), lower LDL cholesterol (−15.4 mg/dL; 95% CI, −24.5 to −6.3; P < 0.001), and lower lipoprotein (a) [Lp(a)] (−7.8 mg/dL; 95% CI, −12.5 to −2.5; P < 0.001). CETP PTV carrier status was associated with reduced risk for CAD (odds ratio, 0.64; 95% CI, 0.38 to 0.90; P < 0.001). Conclusion: PTVs of CETP were significantly associated with higher HDL cholesterol, lower LDL cholesterol, lower Lp(a), and lower risk for CAD among patients with HeFH.