Plasma levels of remnant particles are determined in part by variation in the APOC3 gene insulin response element and the APOCI–APOE cluster

Abstract

Remnant particles of triglyceride-rich lipoproteins (RLP) are known to be a strong predictor of atherogenicity. The serum concentrations of remnant-like particle triglyceride (RLPTG) and remnant-like particle cholesterol (RLPC) have been determined in a representative sample of the Czech MONICA study (n = 285). The relationship was investigated between remnant particle triglyceride/cholesterol concentrations and polymorphisms in the genes APOC3 (−482C→T/3238C→G), APOE (ε2/ε3/ε4), APOCI (−317-321ins), APOB (signal peptide), hepatic lipase (LIPE, −480C→T), and lipoprotein lipase (LPL, S447X). Univariate analysis showed significant effects on RLPTG associated only with the APOE genotype (P = 0.009), the APOC3 −482C→T genotype (P = 0.018), and the APOCI −317-321ins (P = 0.014) genotype and significant effects on RLPC with APOE (P = 0.01) and APOCI −317-321ins (P = 0.021). The raising effect of the APOE genotype for both remnant cholesterol and triglyceride was confined to the ε2/4 (n = 6) and ε4/4 (n = 3) groups, and thus when the ε2/4 group was omitted in order to analyze by allele (ε2+/ε3+/ε4+), significance was lost (P = 0.6). There was strong linkage disequilibrium between the APOE and APOCI alleles (χ2, P < 0.001) and a multivariate ANOVA of RLPTG with all three significantly associated variants as factors demonstrated that while the APOC3 −482C→T effect was independent of the others (P = 0.003), the APOCI −317-321ins and APOE effects were not. This was also true for the APOCI −317-321ins and APOE effects on RLPC. To assess whether APOE-CI effects on RLPC were independent of their effects on total cholesterol and triglyceride levels, multiple linear regression was used. Using multiple linear regression, it appeared that the APOE-CI effects on RLPC were independent of their effects on plasma cholesterol, but the effects of APOC3 and APOE-CI on RLPTG could not be separated from their effects on plasma Tg levels.Further characterization of this remnant particle phenotype and its genetic determinants may lead to a better understanding of its metabolism and contribution to atherosclerosis.