A genome search identifies major quantitative trait loci on human chromosomes 3 and 4 that influence cholesterol concentrations in small LDL particles

Small, dense LDL particles are associated with increased risk of cardiovasc ular disease. To identify the genes that influence LDL size variation, we p erformed a genome-wide screen for cholesterol concentrations in 4 LDL size fractions. Samples from 470 members of randomly ascertained families were t yped for 331 microsatellite markers spaced at approximate to 15 cM interval s. Plasma LDLs were resolved by using nondenaturing gradient gel electropho resis into 4 fraction sizes (LDL-1, 26.4 to 29.0 nm; LDL-2, 25.5 to 26.4 nm ; LDL 3, 24.2 to 25.5 nm; and LDL-4, 21.0 to 24.2 nm) and cholesterol conce ntrations were estimated by staining with Sudan Black B. Linkage analyses u sed Variance component methods that exploited all of the genotypic and phen otypic information in the large extended pedigrees. In multipoint linkage a nalyses with quantitative trait loci for the 4 fraction sizes, only LDL-3, a fraction containing small LDL particles, gave peak multipoint log(10) odd s in favor of linkage (LOD) scores that exceeded 3.0, a nominal criterion f or evidence of significant Linkage. The highest LOD scores for LDL-3 were f ound on chromosomes 3 (LOD=4.1), 4 (LOD=4.1), and 6 (LOD=2.9). In oligogeni c analyses, the 2-locus LOD score (for chromosomes 3 and 4) increased signi ficantly (P=0.0012) to 6.1, but including the third locus on chromosome 6 d id not significantly improve the LOD score (P=0.064). Thus, we have localiz ed 2 major quantitative trait loci that influence variation in cholesterol concentrations of small LDL particles. The 2 quantitative trait loci on chr omosomes 3 and 4 are located in regions that contain the genes for apoD and the large subunit of the microsomal triglyceride transfer protein, respect ively.