Genetic variations in apolipoprotein B and apolipoprotein A-I associated with risk of coronary artery disease

Increased plasma concentrations of apolipoprotein B (apoB) and low density lipoproteins (LDL) are directly associated with increased total cholesterol concentrations and increased risk of coronary artery disease (CAD). An inverse association exists between apolipoprotein A-I (apoA-I) and high density lipoprotein (HDL) concentrations with CAD. I hypothesized that common variations present in apoB and apoA-I account for the interindividual variance in LDL and HDL levels, respectively, and are associated with dyslipidemia and CAD. Seven genetic variations within the putative receptor - binding domain of apoB were identified. Only two variations, Arg 3500 Gln and Arg 3531 Cys were associated with familial defective apoB-100 binding to the LDL receptor. Combined they account for nearly one percent of hypercholesterolemia and one to two percent of CAD; a frequency equivalent to the sum of all known LDL receptor mutations. Mutations in the putative receptor binding domain of apoB do not account for the previously observed monogenic contribution of the apoB gene locus or plasma LDL variance. In addition, carriers of the apoB 3500-Gln allele do not necessarily express hypercholesterolemia or CAD; indicating that mutations in apoB act within the context of other genetic and environmental factors. A common polymorphism within the promoter of the apoA-I gene is associated with elevated apoA-I and HDL plasma concentrations, suggesting either a direct effect on promoter activity or linkage disequilibrium with another causal mutation elsewhere in the gene. The impact this polymorphism has on apoA-I expression was examined. The G(-78)A substitution exerted a significant effect on promoter activity in in vitro studies, but the direction (G > A or A >G) and magnitude of the difference observed depended on the promoter segment examined. At least three transacting factors, including Sp1 and Sp3 bind to the sequence surrounding G(-78)A. These differences in transcriptional activity as a function of promoter length are dependent on interactions of trans-acting factors with cis-elements presented within the apo A-I promoter. The evidence documents a significant effect of the G(-78)A on apoA-I promoter function in vitro, but the complexity of the noted effects precludes the formulation of specific inferences in humans.