Genetic determinants of Lp(a) and ApoB serum levels: A candidate gene approach

摘要

Coronary artery disease (CAD) is a common cause of morbidity in western countries. Multiple quantitative lipoprotein phenotypes have been identified as risk factors. High serum cholesterol level is a definitive causative factor and low density lipoprotein (LDL) is the major cholesterol containing lipoprotein. Apolipoprotein B (apoB) is the single membrane protein found on the LDL particle and mediates cellular uptake via the LDL receptor (LDL-R). ApoB serum levels have a higher correlation with CAD than serum cholesterol levels and may be a better predictive factor for CAD. ApoB levels segregate as a major gene in families, although the identity of this gene is yet unknown. Serum lipoprotein (a), Lp(a), level is also an independent risk factor for CAD. Lp(a) is a LDL particle with an apolipoprotein (a) (apo(a)) protein attached to apoB. Lp(a) levels segregate as a major gene in families, and apo(a) has been identified as the major locus determining Lp(a) levels in the general population.;The following studies use a candidate gene approach to elucidate genetic determinants of Lp(a) and apoB serum levels in the UCLA-Cedars Sinai CAD family population. This is a Caucasian population ascertained through a proband with documented CAD and one other blood relative, affected with CAD, willing to participate in the study. Genetic determinants of apoB levels were also analyzed in a single large pedigree from the Bogalusa Heart Study by both association and linkage analyses. Several important findings emerged: (1) Lp(a) serum levels were controlled by variation at the apo(a) locus not only in the general population but also in a CAD population. No linkage was detected between Lp(a) serum levels and the apoB or LDL-R loci. (2) ApoB was not the major gene contributing to variation in apoB serum levels in the CAD family population. Five other candidate loci tested, were also not linked with variation in apoB serum levels. (3) A rare apoB PvuII restriction fragment length polymorphism (RFLP) was linked to apoB serum levels in the single Bogalusa Heart Study pedigree. Four other candidate loci analyzed, did not demonstrate linkage with apoB serum levels in this family. Altogether, this data did not support apoB as the major determinant of apoB serum levels in the general population, but rare allelic variation within or near the apoB locus had a profound effect on apoB levels in one large pedigree.