Genetics of Atherosclerosis in Mexican Americans

DESIGN NARRATIVE:

The study, which began in 1991, focuses on genes that influence the lipoprotein profile in members of randomly ascertained Mexican-American families, with particular emphasis on genetic effects on reverse cholesterol transport. An overall objective is to investigate the pleiotropic effects of these "lipoprotein genes" and their interactions with genes that affect non-insulin dependent diabetes mellitus (NIDDM) antecedents and body fat distribution. The interactions of lipoprotein genes with sex hormonal status and with environmental risk factors such as diet, exercise, and smoking are investigated. Genetic effects on standard lipoprotein variables are examined, e.g. plasma concentrations of lipoproteins and apolipoproteins. Several novel lipoprotein phenotypes also are analyzed, e.g. amounts of esterified and unesterified cholesterol and of specific apolipoproteins in lipoprotein subclasses. Molecular, biochemical, and statistical genetic approaches are used to detect, localize and characterize genes that influence quantitative phenotypes associated with lipoproteins, NIDDM, and obesity, and to quantify the effects of known candidate loci on these phenotypes.

The study was renewed in 1997. The subprojects as described in the summary statement are as follows.

In Project 1, gene mapping is performed on genes that influence quantitative phenotypes related to the development of atherosclerosis in Mexican American families in the San Antonio Family Heart Study. A genomic search using a 10 centimorgan map of 3 91 short tandem report markers distributed throughout the genome is used to determine the chromosomal location of six major genes influencing HDL cholesterol, LDL cholesterol, apo A1, apob, SHBC, and DHEAS. Evidence for major gene effects is sought for lipoprotein phenotypes for which no major genes have yet been detected. Genetic effects on carotid and fibrinolysis phenotypes are quantified using data from a recall of 750 family members. Full pedigree variance component analysis as well as penetrance-based methods are used in a genomic search to determine the chromosomal locations of genes that influence these phenotypes. To improve genetic models, strengthen evidence for linkage, and reduce the number of false positives, GxE interactions and pleiotropic and epistatic effects of major genes are quantified.

In Project 2, a genome-wide search is carried out to localize genes that contribute to quantitative variation in traits related to atherosclerosis, NIDDM, and obesity. The first, primary task is the genotyping of some 1,400 pedigree members for 391 short tandem repeat (STR) markers using semi-automated, fluorescence based genotyping on an ABI automatic sequencer. When statistical evidence of linkage has been evaluated in Projects 1 and 3 and confirmed, "additional STRs" will be typed in the region to further localize the gene. The initial map will have a 10 centimorgan resolution. Multipoint linkage analysis and gametic disequilibrium analysis will be used to further localize the region containing the gene of interest. The human gene map will then be consulted to identify candidate genes in the region, and these genes will be subjected to a more detailed molecular analysis to identify structural or functional differences that underlie the observed allelic effects.