Plasma lipids and lipoproteins response to a dietary challenge: analysis of four candidate genes

The possible role of four candidate genes in lipid and lipoprotein response to diet was examined in 63 male students. Four site polymorphisms (signal peptide insertion/deletion, XbaI, MspI and EcoRI) of the apo B gene, three RFLPs (AvaII, StuI, and HincII) of the LDL receptor gene, two SSCPs of the cholesterol 7 alpha-hydroxylase gene and the common apo E genotypes were determined. The average reductions induced by diet in participants homozygous for the absence of the XbaI restriction site (X-X-) of the apo B gene compared to those harboring this site (X+) were: 14.5 mg/dl and 9.4 mg/dl for total cholesterol (TC) (p < 0.09) and 15.5 mg/dl and 7.9 mg/dl for LDL-C (p < 0.003), respectively. Differences in dietary responsiveness among the apo E, LDL receptor and the cholesterol 7 alpha-hydroxylase genotypes were largely insignificant. Using the four apo B polymorphic sites, six unambiguous haplotypes were constructed and a model for their possible evolutionary relationship is presented. Genetic variation in the apo B gene region, as defined by haplotypes, accounted for 8.7% and 24.3% of the phenotypic variance in TC and LDL-C response to diet, respectively. Sequence analysis of a candidate locus, the putative LDL receptor binding region of apo B and its flanking sequences, was performed in two individuals, one homozygous for an apo B "hyper-responding" and another for the "lower-responding" haplotype, and no differences were found. In conclusion, haplotypes at the apo B gene locus are associated with dietary response of TC and LDL-C in young males. Yet, the sequence variation responsible for these differences is possibly located outside the putative LDL receptor binding domain.