A Genome Search Identifies Major Quantitative Trait Loci on Human Chromosomes 3 and 4 That Influence Cholesterol Concentrations in Small LDL Particles

Abstract

Abstract-Small, dense LDL particles are associated with increased risk of cardiovascular disease. To identify the genes that influence LDL size variation, we performed a genome-wide screen for cholesterol concentrations in 4 LDL size fractions. Samples from 470 members of randomly ascertained families were typed for 331 microsatellite markers spaced at Ϸ15 cM intervals. Plasma LDLs were resolved by using nondenaturing gradient gel electrophoresis 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 concentrations were estimated by staining with Sudan Black B. Linkage analyses used variance component methods that exploited all of the genotypic and phenotypic information in the large extended pedigrees. In multipoint linkage analyses with quantitative trait loci for the 4 fraction sizes, only LDL-3, a fraction containing small LDL particles, gave peak multipoint log 10 odds in favor of linkage (LOD) scores that exceeded 3.0, a nominal criterion for evidence of significant linkage. The highest LOD scores for LDL-3 were found on chromosomes 3 (LODϭ4.1), 4 (LODϭ4.1), and 6 (LODϭ2.9). In oligogenic analyses, the 2-locus LOD score (for chromosomes 3 and 4) increased significantly (Pϭ0.0012) to 6.1, but including the third locus on chromosome 6 did not significantly improve the LOD score (Pϭ0.064). Thus, we have localized 2 major quantitative trait loci that influence variation in cholesterol concentrations of small LDL particles. The 2 quantitative trait loci on chromosomes 3 and 4 are located in regions that contain the genes for apoD and the large subunit of the microsomal triglyceride transfer protein, respectively. . In addition to total LDL concentrations, many studies indicate that a small, dense LDL particle phenotype is also a risk factor for CVD. 1 In fact, several recent prospective studies have shown that LDL particle size phenotype is predictive of subsequent measurements of CVD. 2-4 However, these associations are not independent of other correlated traits, such as triglyceride concentration, which suggests small LDLs are a component of an atherogenic lipoprotein phenotype. 5 Possible mechanisms for a direct role of small LDLs in atherogenesis include heightened susceptibility to oxidation 6 and/or altered affinity for the LDL receptor. 7 LDL size phenotype is heritable 8 and most segregation analyses suggest the existence of a major locus for the trait. 9 -13 Attempts to identify the gene(s) that might influence LDL size phenotype have so far met with equivocal results. A quantitative trait locus (QTL) for the dichotomous trait for LDL size (pattern A or large buoyant LDLs versus pattern B or small dense LDLs) was found to be linked to the LDL receptor locus, 14 but not the apoB locus, 15,16 whereas QTLs for LDL peak particle size were reported to be linked to the genes for the LDL receptor, apoB, cholesteryl ester transfer protein, and manganese superoxide dismutase. 17,18 The evidence for these linkages has not been s...

Evidence for a quantitative trait locus affecting low levels of apolipoprotein B and low density lipoprotein on chromosome 10 in Caucasian families

“…Both methods of analysis produced significant LOD scores for apoB 3 cM apart at the same chromosome 10 location, 10q26.11. The peak on chromosome 6q24.3 (149 Mb) for LDL in our SOLAR analysis is in the same region as a previous LDL signal (LOD 5 2.9; P 5 0.00003) (27). To our knowledge, this is the first study to show linkage to apoB on chromosome 10, although a SNP in the region was significantly associated with several metabolic traits, including reduced serum apoB (28).…”

Genome-wide scan for quantitative trait loci influencing LDL size and plasma triglyceride in familial hypertriglyceridemia

“…However, among families of hyperlipidemic probands, and using LDL subclass phenotype classifications, strong evidence against linkage was reported (29). Using a different definition of LDL heterogeneity, results from the San Antonio Family Heart Study show an LOD score of 2.92 for cholesterol concentration in small LDL particles in the same region of chromosome 6 as reported here (33).…”

“…These and other studies have also shown that LDL size is influenced by sex, age, central obesity (22), and in women, menopausal status and hormone use (23)(24)(25). Several candidate gene studies have investigated the effects of apolipoprotein structural genes (26,27), receptors (28,29), and enzymes involved in lipoprotein metabolism (30)(31)(32)(33) on LDL size, with varying results.…”

Evidence for a QTL on chromosome 19 influencing LDL cholesterol levels in the general population

“…A further inspection of other genome scans in Caucasians from the general population (Table 4) shows that, although the reported LOD scores for chromosome 19 are not significant, they are compatible with our findings. Linkage with LDL 1 -C levels in the San Antonio Heart Study (LOD ¼ 2.26) and with LDL 2 -C levels (LOD ¼ 1.86), 33 and linkage with total cholesterol levels in the Rochester Family Heart Study (LOD ¼ 1.14). 34 No suggestion for linkage with total cholesterol or LDL-C levels, however, was found in selected samples of myocardial infarction patients, type II diabetes patients and patients with familial combined hyperlipidemia.…”