Linkage analysis of low‐density lipoprotein subclass phenotypes and the apolipoprotein B gene

Abstract

A common heritable phenotype has recently been identified which is characterized by a relative abundance of small, dense low-density lipoproteins (LDL), and mild elevations of plasma triglycerides and reductions in plasma high-density lipoproteins (HDL) cholesterol. This phenotype, designated LDL subclass phenotype B, has been associated with up to a three-fold increase in coronary disease risk. Complex segregation analysis in two large family studies has demonstrated that LDL subclass phenotype B is influenced by an allele at a single genetic locus with a population frequency of 0.25-0.3, and autosomal dominant inheritance, but with full penetrance only in males age 20 and over and in postmenopausal women. Since apolipoprotein B (apoB) is the principal protein component of LDL, linkage analysis was used to investigate possible linkage between the phenotype B phenotype and the apoB gene, using a variable number of tandem repeats site located 0.5 kb from the 3' end of the apoB gene. In 6 informative families including only family members in the penetrant classes, a total LOD score of -7.49 was found at a recombination fraction of 0.001. Thus, under the assumptions of the single gene model, it is unlikely that the apoB locus controls LDL subclass phenotype B.

Linkage of atherogenic lipoprotein phenotype to the low density lipoprotein receptor locus on the short arm of chromosome 19.

“…We have reported recently that ATHS shows significant nonlinkage to the gene for apoprotein B, the principal structural protein of LDL (7). Other candidate genes that have been excluded as the cause of ALP in 11 pedigrees studied to date include insulin, glucose transporter 4, apolipoprotein AII, and cholesteryl ester transfer protein (P.M.N., J. Wang, R.M.K., and J.P.J., unpublished results).…”

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

“…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 strong, with only the linkage of the dichotomous trait QTL to the LDL receptor locus 14 having a log 10 odds in favor of linkage (LOD) score that exceeded 3, a nominal criterion for significant evidence of linkage.…”

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

“…These include the LDL receptor gene (28), the apoE and apoB genes (26,27), the lipoprotein lipase gene (31), and the cholesterol ester transfer protein gene (32). Although the relatively small sample size in this study may have limited statistical power to detect the linkages, the results suggest that these candidate genes may not influence LDL size in this familial form of hypertriglyceridemia.…”

“…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.…”