Major Gene and Environmental Determinants of High-Density Lipoprotein Cholesterol
Since high-density lipoprotein cholesterol (HDL-C) levels are a major independent risk factor for coronary heart disease, the association of major genes with familial aggregation of both high and low HDL-C emphasizes the importance of heritability for HDL-C in relationship to coronary heart disease. Complex segregation analysis using the unified mixed model in white families from the Collaborative Lipid Research Clinics Family Study cohort was carried out to delineate the mode of familial transmission of plasma HDL-C. Two major HDL-C clusters were identified with means separated by three standard deviation units. For low HDL-C segregating in families, there was significant evidence for a recessive major gene, and there was also evidence of significant multifactorial transmission. The major gene and multifactorial components accounted for 8% and 45% of the total variation of HDL-C levels, whereas the gene frequency for low HDL-C was estimated to be 8% to 9% at the major locus. Separately, segregation analysis was performed on 14 informative nuclear families referred because of early coronary heart disease or stroke and gave clear evidence of a major gene contributing to the etiology of primary depression of HDL-C., with support for a dominant model. Recently, a DNA restriction length polymorphism has been described in the apo A-I, apo C-III, apo A-IV gene complex following PST-1 digestion. The allele frequency of this polymorphism was 2% in control subjects and 67% in index cases of kindreds with familial hypoalphalipoproteinemia. Bottom-decile HDL-C was present in 73% of subjects who were heterozygous or homozygous for the polymorphism. This polymorphism appears to be associated with one of the causes of genetic HDL deficiency that results in premature coronary artery disease. Since the common PST-1 polymorphism is associated with familial hypoalphalipoproteinemia, premature coronary artery disease, and stroke, the observation of a single major locus for low HDL-C has considerable importance. Whether familial hypoalphalipoproteinemia reflects an abnormality of the HDL regulator gene on chromosome 1, the apo A-II gene on chromosome 1, the apo A-I gene on chromosome 11, or perhaps a linkage between the regulator gene and the gene for apo A-I remains to be determined.
KeywordsMajor Gene Major Locus Premature Coronary Artery Disease Lipid Research Clinic Premature Coronary Heart Disease
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