GENETIC-VARIATION AT THE APOA-IV GENE LOCUS AND RESPONSE TO DIET IN FAMILIAL HYPERCHOLESTEROLEMIA

Plasma lipid response to dietary fat and cholesterol is, in part, gene tically controlled. The apolipoprotein A-IV (apoA-IV protein; APOA4, g ene) has been shown to influence the response to dietary changes in no rmolipidemic individuals. The response to diet in subjects with famili al hypercholesterolemia (FH) is also variable, and no studies are avai lable 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)-->His and Thr(347)-->Ser) on the lipid response to the Natio nal Cholesterol Education Program type I (NCEP-I) diet in 67 FH hetero zygotes (43 women and 21 men). Subjects were studied at baseline (afte r 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 ge notype 1/1 and 16 with genotype 1/2. The APOA4-2 allele was associated with marginally significantly lower (P=0,049) low density lipoprotein (LDL) cholesterol levels and significantly lower (P=0.027) apoB level s independent of diet effects. After consuming an NCEP-I diet, carrier s of the APOA4-2 allele showed a significantly lower reduction in apoB concentration (6.2%) than 1/1 subjects (14.1%, P=0.036); however, no significant differences in response were noted for LDL cholesterol. Th e APOA4-347 mutation was assessed in 63 individuals, 44 with the A/A a llele 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 group s in total, LDL, and high density Lipoprotein cholesterol and plasma a poB levels. After dietary intervention, A/A individuals showed signifi cant reductions in plasma triglyceride and very low density Lipoprotei n cholesterol levels; no changes were found in carriers of the T allel e. Haplotype analysis suggested that in these FH subjects, tile APOA4- 360-2 allele was associated with lower plasma lipid levels during the NCEP-I diet period, whereas no significant effects were observed for t he APOA4-347-T allele.