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

Remnant particles of triglyceride-rich lipoproteins (RLP) are known to be a strong predictor of atherogenicity. The serum concentrations of remnant-li ke particle triglyceride (RLPTG) and remnant-like particle cholesterol (RLP C) have been determined in a representative sample of the Czech MONICA stud y (n = 285). The relationship was investigated between remnant particle tri glyceride/ cholesterol concentrations and polymorphisms in the genes APOC3 (-482C-->T/3238C-->G), APOE (epsilon 2/epsilon 3/epsilon 4), APOCI (-317-32 1ins), APOB (signal peptide), hepatic lipase (LIPE, -480C-->T), and lipopro tein 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 an d 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 cholest erol and triglyceride was confined to the epsilon 2/4 (n = 6) and epsilon 4 /4 (n = 3) groups, and thus when the epsilon 2/4 group was omitted in order to analyze by allele (epsilon 2+/epsilon 3+/epsilon 4+), significance was lost (P = 0.6). There was strong linkage disequilibrium between the APOE an d APOCI alleles (chi(2), P < 0.001) and a multivariate ANOVA of RLPTG with all three significantly associated variants as factors demonstrated that wh ile the APOC3 -482C-->T effect was independent of the others (P = 0.003), t he 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 effec ts on RLPC were independent of their effects on total cholesterol and trigl yceride levels, multiple linear regression was used. Using multiple linear regression, it appeared that the APOE-CI effects on RLPC were independent o f 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. Fu rther characterization of this remnant particle phenotype and its genetic d eterminants may lead to a better understanding of its metabolism and contri bution to atherosclerosis.