Low Density Lipoprotein Cholesterol, Mild Elevation Of

Although rare mutations in the genes encoding low density lipoprotein (LDL) receptor (LDLR; 606945) and apolipoprotein B (APOB; 107730) account for a small proportion of variation in LDL cholesterol (LDLC), twin and adoption studies have indicated that at least 50% of the overall observed variation is genetically determined. In a heterogeneous sample of 3,227 subjects from the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study, Coon et al. (1999) found evidence for a common major gene accounting for mild elevations (1.25 standard deviations) of LDLC. Analysis favored a recessive model with a frequency of 0.52 for the gene influencing elevated LDLC, phenotypic means of 113 mg/dl for the normal genotype and 146 mg/dl for the abnormal genotype, and a significant polygenic heritability. This statistically inferred major gene accounted for 24% of the variation in LDLC, with polygenes accounting for another 28%. Using parameters for major gene transmission estimated in the segregation analysis, LDLC showed no linkage to the LDLR gene, the apolipoprotein E gene (APOE; 107741), or the cholesterol 7-alpha-hydroxylase gene (CYP7A1; 118455), indicating that the major gene effect influencing mild elevation in LDLC is not explained by any of these candidate loci.