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

Abstract

The atherogenic lipoprotein phenotype (ALP) is a common heritable trait characterized by a predominance of small, dense low density lipoprotein (LDL) particles (subclass pattern B), increased levels of triglyceride-rich lipoproteins, reductions in high density lipoprotein, and a 3-fold increased risk of myocardial infarction. Significant two-point linkage was found between ALP and the LDL receptor locus on the short arm of chromosome 19 in -1 relatives of nine probands with ALP pattern B. locus (5, 6). In 301 relatives of healthy probands in 60 nuclear families, the estimated prevalence of the ALP pattern B allele was 0.25 (5), whereas in 234 relatives of seven probands with familial combined hyperlipidemia, the prevalence was estimated to be 0.3, and there was a small, multifactorial inheritance component (6). In both groups of families, the penetrance of the pattern B allele was reduced in males younger than age 20 and in premenopausal females. With this high allele frequency, ALP pattern B may be one of the most prevalent genetic traits influencing risk for coronary artery disease in the American population.To better understand the genetic and biochemical basis for ALP, we have undertaken to map the responsible locus [designated ATHS for atherosclerosis susceptibility (lipoprotein-associated)] using a "candidate gene" approach to linkage analysis. 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glucose transporter 4, apolipoprotein AII, and cholesteryl ester transfer protein (P.M.N., J. Wang, R.M.K., and J.P.J., unpublished results).In this report we present evidence that ATHS is closely linked to the LDL receptor (LDLR) and insulin receptor (INSR) loci on chromosome 19. This finding provides a framework for further genetic and biochemical analyses of affected families.MATERIALS AND METHODS Subjects. Probands were selected from subjects screened for LDL subclass pattern B (see below) at our clinic. Eleven families consisting of 72 relatives were selected for linkage studies based on evidence for segregation of ALP pattern B (Fig. 1). Informed consent was obtained from all participants. All family members found to have LDL subclass pattern B were included in the linkage analyses. Individuals with subclass pattern A were excluded when they were in age and sex categories known to have reduced penetrance of ALP pattern B (i.e., men younger than age 20 and premenopausal women) or if they were taking triglyceride-lowering drugs (nicotinic acid or fibric acid derivatives). Family members were also excluded from the linkage analyses when they had LDL subclass patterns that were indeterminate or intermediate between patterns A and B (seven subjects fell into this category; see below). In addition to the kindreds presented in Fig. 1, which were used for testing linkage of ATHS, an additional three families ...

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

“…13 INSR and LIPE are candidates for influencing triglyceride levels, but not for LDL-C levels. 11,12 Near the LDLR locus, the ATHS locus has been mapped involved in atherogenic lipoprotein phenotype pattern B, which is characterized by small, dense LDL particles, increased levels of triglycerides and decreased levels of HDL-C. 41 Since we have no indication for linkage with levels of triglycerides and HDL-C, we assume that the ATHS locus is a different locus than our LDL-C QTL.…”

Should animal fats be back on the table? A critical review of the human health effects of animal fat

“…Stable pattern B is governed by mutations at the LDLR (Austin et al 1988;Nishina et al 1992;Zhu et al 2007), which causes delays in LDL-C clearance resulting in smaller, denser particles. Unstable pattern A is due to variation at the APOE locus, where the e4 allele requires high fat levels to show pattern A Krauss and Dreon 1995), and reductions in LDL-C due to low fat diets are not accompanied by reductions in number of LDL-C particles.…”

Pleiotropic Genetic Effects on LDL Size, Plasma Triglyceride, and HDL Cholesterol in Families

“…52 Several other candidate genes, including the LDL receptor, lipoprotein lipase, and apo AI-CIII-AIV loci, have been shown to be associated with lipids and lipoproteins. [53][54][55] Additionally, the lipoprotein lipase gene has recently been linked to LDL size, with simultaneous effects on TG and HDL-C in lipoprotein lipasedeficient families. 56 Together these findings suggest that each of the 3 lipid and lipoprotein measures reflect a common underlying process that is controlled, at least in part, by shared genes and provide strong support for the existence of genes with pleiotropic effects influencing covariation in plasma lipids and lipoproteins.…”