Linkage of the cholesteryl ester transfer protein (CETP) gene to LDL particle size - Use of a novel tetranucleotide repeat within the CETP promoter

Background-A preponderance of small, dense LDL particles, elevated levels o f plasma triglycerides (TG), and low levels of HDL characterize the atherog enic lipoprotein phenotype, which is associated with increased coronary art ery disease (CAD) risk. Genetic and environmental factors influence LDL siz e, cholesteryl eater transfer protein (CETP) being one of the candidate gen es. CETP mediates the transfer of cholesteryl ester from HDL to apolipoprot ein (apo) B-containing lipoproteins in exchange for TG, promoting reverse c holesterol transfer and remodeling of lipoprotein particles. Methods and Results-We have identified a tetranucleotide repeat (fragment s izes from 324 to 464 bp; heterozygosity index=0.74) within the CETP promote r and used it in quantitative sib-pair linkage analysis in 119 female dizyg otic (DZ) twins. Linkage was found to LDL size (P<0.001), TG (P<0.005), and plasma apoB (P=0.02). The distribution of the tetranucleotide repeats was bimodal, and there was strong allelic association of the "short" alleles wi th the B2 allele of CETP TaqIB polymorphic site (P<0.001). Conclusions-This report of linkage of the CETP gene to LDL particle size ad ds to the List of candidate genes linked to LDL size, supporting the hypoth esis of multigenic determination of LDL size heterogeneity. Whether this pr omoter variation is itself functional or is a marker for a functional site in the CETP gene remains to be determined.