Genetic factors affecting blood lipoproteins: the candidate gene approach.

Familial apolipoprotein A-I, C-III, and A-IV deficiency and premature atherosclerosis due to deletion of a gene complex on chromosome 11.

We have analyzed determinants of the synthesis and secretion of apolipoproteins including mRNA for apolipoproteins, in the human colon carcinoma cell line Caco-2 during differentiation in continuous culture. Significant increases in both cellular and secreted apolipoprotein A-I were observed early in the differentiation process. Increases in apolipoprotein B were limited to secreted protein and started later in the differentiation process. Levels of mRNA for apolipoproteins A-I, A-IV, B, C-III, and E increased significantly between the time cells reached confluence and 1 week postconfluence. The kinetics of mRNA accumulation were influenced by culture conditions. Nuclear extracts from postconfluent Caco-2 cells contained increased amounts of protein that bound to oligonucleotides containing the control regions of the apolipoprotein A-I and B genes. A competition experiment suggested that this protein recognized the control regions of both genes. We propose to name this protein DRIFT-1 (differentiation-related intestinal factor for transcription 1).

Increased expression of apolipoprotein genes accompanies differentiation in the intestinal cell line Caco-2

Patterns of RFLP association were studied, to identify gene regions influencing quantitative variation in lipid and lipoprotein traits (coronary artery disease [CAD] risk factors or metabolically related traits). Subjects (118 female and 229 male; age 20-59 years) were selected for health. Multiple RFLPs were used to sample variability in regions around genes for apolipoprotein (apo) B (restriction enzymes HincII, PvuII, EcoRI, and XbaI), apo AI-CIII-AIV (BamHI, XmnI, TaqI, PstI, SstI, and PvuII) and cholesterol ester transfer protein (TaqI). Separate analyses were done by gender. The sample was truncated at mean +/- 4 SD, to remove extreme outliers. There was no significant gender difference in RFLP genotype frequency distribution. After trait-level adjustment to maximize removal of concomitant variability, analysis of variance was used to estimate the percentage trait phenotypic variance explained by measured variability in the gene regions studied. Fewer gene regions were involved in men, with less influence on quantitative trait variation than in women, in whom hormone use affected association patterns. Gender differences imply that pooling genders or adjusting data for gender effects removes genetic information and should be avoided. The association patterns show that variability around the candidate genes modulates trait levels: the genes are contributors to the genetics of CAD risk variables in a healthy sample.

Patterns of association between genetic variability in apolipoprotein (apo) B, apo AI-CIII-AIV, and cholesterol ester transfer protein gene regions and quantitative variation in lipid and lipoprotein traits: influence of gender and exogenous hormones.

The genes coding for apolipoproteins A1, C3, and A4 (APOA1, APOC3, APOA4) are closely linked and tandemly organized within a 15-kilobase (kb) DNA segment on the long arm of human chromosome 11 The nucleotide variability of a 61-kb DNA segment containing these genes and their flanking sequences was studied by restriction analysis of a sample of 18 unrelated Northern Europeans using seven different genomic DNA probes Eleven restriction site polymorphisms located within this DNA segment were used for haplotype analysis of 129 Mediterranean and 67 American black chromosomes Estimation of the extent of nonrandom association between these polymorphisms indicated considerable linkage disequilibrium within the APOA1-APOC3-APOA4 gene cluster Several haplotypes arose by recombination, and the rate of recombination within this gene cluster was estimated to be at least 4 times greater than that expected based on uniform recombination The polymorphism information content of each of these polymorphisms, taken individually, ranges between 0053 and 0375, while that of their haplotypes ranges between 0858 and 0862 Therefore, DNA polymorphism haplotypes in the APOA1-APOC3-APOA4 gene cluster constitute a highly informative genetic marker on the long arm of human chromosome 11

DNA polymorphism haplotypes of the human apolipoprotein APOA1-APOC3-APOA4 gene cluster.

/pdf/dna-polymorphic-sites-in-the-human-apoai-ciii-aiv-cluster-5degfgzsrx.pdf

DNA polymorphic sites in the human ApoAI-CIII-AIV cluster: Taq I and Ava I.

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DNA polymorphic sites in the human ApoAI-CIII-AIV cluster: Taq I and Ava I.