title: 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 (epsilon2/epsilon3/epsilon4), 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 epsilon2/4 (n = 6) and varepsilon4/4 (n = 3) groups, and thus when the epsilon2/4 group was omitted in order to analyze by allele (epsilon2+/epsilon3+/epsilon4+), significance was lost (P = 0.6). There was strong linkage disequilibrium between the APOE and APOCI alleles (chi(2), 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.
authors.affiliation: Centre for Cardiovascular Genetics, RFUCLMS, London, UK.
authors.forename: D M
authors.initials: DM
authors.lastname: Waterworth
authors.forename: J A
authors.initials: JA
authors.lastname: Hubacek
authors.forename: J
authors.initials: J
authors.lastname: Pitha
authors.forename: J
authors.initials: J
authors.lastname: Kovar
authors.forename: R
authors.initials: R
authors.lastname: Poledne
authors.forename: S E
authors.initials: SE
authors.lastname: Humphries
authors.forename: P J
authors.initials: PJ
authors.lastname: Talmud
mesh_terms: D000328:Adult; D001055:Apolipoproteins B / Q000235:genetics; D001056:Apolipoproteins C / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics*; D001161:Arteriosclerosis / Q000209:etiology; D002784:Cholesterol / Q000097:blood; D053298:Chylomicron Remnants; D002914:Chylomicrons / Q000097:blood*; D003327:Coronary Disease / Q000209:etiology; D018153:Czech Republic; D004041:Dietary Fats; D005260:Female; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D008049:Lipase / Q000235:genetics; D008074:Lipoproteins / Q000097:blood*; D008297:Male; D008875:Middle Aged; D005810:Multigene Family; D011110:Polymorphism, Genetic; D019518:Postprandial Period; D020218:Response Elements; D014280:Triglycerides / Q000097:blood
chemical_list: D001055:Apolipoproteins B; D001056:Apolipoproteins C; D001057:Apolipoproteins E; D053298:Chylomicron Remnants; D002914:Chylomicrons; D004041:Dietary Fats; D007328:Insulin; D008074:Lipoproteins; D014280:Triglycerides; D002784:Cholesterol; D008049:Lipase