Genetic Variation at the ApoA-IV Gene Locus and Response to Diet in Familial Hypercholesterolemia

Abstract

Abstract-Plasma lipid response to dietary fat and cholesterol is, in part, genetically controlled. The apolipoprotein A-IV (apoA-IV protein; APOA4, gene) has been shown to influence the response to dietary changes in normolipidemic individuals. The response to diet in subjects with familial hypercholesterolemia (FH) is also variable, and no studies are available on the influence of APOA4 mutations on dietary response in these subjects. We studied the effect of 2 common apoA-IV genetic variants (Gln 360 3 His and Thr 347 3 Ser) on the lipid response to the National Cholesterol Education Program type I (NCEP-I) diet in 67 FH heterozygotes (43 women and 24 men). Subjects were studied at baseline (after consuming for 1 month a diet with 35% fat [10% saturated] and 300 mg/d cholesterol) and after 3 months of consuming a low-fat diet. No sex-related differences were found, and results were combined for men and women. The APOA4-360 mutation was assessed in 67 subjects, 51 with genotype 1/1 and 16 with genotype 1/2. The APOA4-2 allele was associated with marginally significantly lower (Pϭ0.049) low density lipoprotein (LDL) cholesterol levels and significantly lower (Pϭ0.027) apoB levels independent of diet effects. After consuming an NCEP-I diet, carriers of the APOA4-2 allele showed a significantly lower reduction in apoB concentration (6.2%) than 1/1 subjects (14.1%; Pϭ0.036); however, no significant differences in response were noted for LDL cholesterol. The APOA4-347 mutation was assessed in 63 individuals, 44 with the A/A allele and 19 with the A/T and T/T alleles. No significant differences were observed in baseline or post-NCEP-I diet values for these 2 groups in total, LDL, and high density lipoprotein cholesterol and plasma apoB levels. After dietary intervention, A/A individuals showed significant reductions in plasma triglyceride and very low density lipoprotein cholesterol levels; no changes were found in carriers of the T allele. Haplotype analysis suggested that in these FH subjects, the APOA4-360-2 allele was associated with lower plasma lipid levels during the NCEP-I diet period, whereas no significant effects were observed for the APOA4-347-T allele.

Genetic polymorphisms and lipid response to dietary changes in humans

“…In the present study, subjects with the ApoA4 360‐1/2 genotype had only slightly smaller responses of LDL‐cholesterol to diet than those with the 1/1 genotype. The present differences in response between subjects with the 1/1 and 1/2 genotype are in line with those observed in some of the previous studies [20,21], albeit that other studies found a larger effect [22–24] or a small opposite effect [25,26]. One of the explanations for the difference in effect‐size is that ApoA4 360‐1/2 polymorphism may affect response in men, but not in women [20,22–24].…”

Dietary fat source alters hepatic gene expression profile and determines the type of liver pathology in rats overfed via total enteral nutrition

“…Other major KEGG pathways differing between these groups included genes involved in retinol metabolism, genes linked to the proteosome, and genes associated with antigen processing and presentation (Table 4). Genes linked to lipid homeostasis included genes encoding FASN, which is rate limiting in de novo FA synthesis from carbohydrates (19); CD36 a hepatic FA transporter (39); CYP4A1, involved in FA degradation via -hydroxylation (66); and ApoA4, a lipoprotein associated with VLDL secretion (12). Real-time RT-PCR was utilized to analyze differences in expression of mRNAs coding for genes involved in FA homeostasis including those revealed by array analysis of OO and CO groups and to further compare them with gene expression in the 5% EO group (Table 5).…”

Influence of LDL receptor gene mutations and the R3500Q mutation of the apoB gene on lipoprotein phenotype of familial hypercholesterolemic patients from a South European population

“…It should be noted that interaction with other genes 41 and environmental factors 42 could also influence the phenotype in FH patients. Pimstone et al 42 have demonstrated that Chinese FH heterozygotes living in Canada exhibit a similar phenotype to that of other FH patients from Western societies, and different to those living in China.…”