Familial Aggregation of Lipids and Lipoproteins in Families Ascertained through Random and Nonrandom Probands in the Iowa Lipid Research Clinics Family Study

Abstract

The aggregation of lipids [total cholesterol (CH) and triglyceride (TG)] and lipoproteins [high-density lipoprotein cholesterol (HDL) and low-density lipoprotein cholesterol (LDL)] in families ascertained through random and nonrandom probands in the Iowa Lipid Research Clinics family study was examined. Nonrandom probands were selected because their lipid levels (at a prior screening visit) exceeded a certain pre-specified threshold. The statistical method conditions the likelihood function on the actual event that the proband’s value is beyond the threshold. This method allows for estimation of the path model parameters in randomly and nonrandomly ascertained families jointly and separately, thus enabling tests of heterogeneity between the two types of samples. Marked heterogeneity between the random and the hyperlipidemic samples is detected in the multifactorial transmission for TG and HDL, and moderate heterogeneity is detected for CH and LDL, with a pattern of higher genetic heritability estimates in the random than nonrandom samples. The observed pattern of heterogeneity is compatible with a higher prevalence in the random sample of certain dyslipoproteinemias that are associated with nonelevated lipids. For the random samples, genetic heritabilities are higher for CH and HDL (about 60%) than for TG and LDL (about 50%). For the nonrandom samples those estimates are about 45, 40, 35 and 30% for HDL, CH, LDL and TG, respectively. Little to no cultural (familial environmental) heritability is evident for CH and LDL, although 10–20% of the phenotypic variance is due to cultural factors for TG and HDL. These results suggest that the etiologies for lipids and lipoproteins may be quite different in random versus hyperlipidemic samples.

ANGPTL3 Decreases Very Low Density Lipoprotein Triglyceride Clearance by Inhibition of Lipoprotein Lipase

“…Variations in human plasma lipid levels result from both genetic and environmental factors. Genetic factors account for more than 50% of the variation in plasma lipid levels in the human population (1)(2)(3)(4). Naturally occurring mutations that affect lipid metabolism in mice have also been reported (5)(6)(7).…”

“…The expression of Angptl3 in KK/San mice was found to be 1/30 to 1/40 that of wild-type mice. Overexpression of Angptl3 using adenoviruses or by an intravenous injection of the recombinant protein in KK/San mice elicited a marked increase in circulating plasma total cholesterol, non-esterified fatty acids (NEFAs), 1 and especially triglyceride levels (12).…”

Loci controlling plasma non-HDL and HDL cholesterol levels in a C57BL /6J × CASA /Rk intercross

“…At the peaks of linkage for HDL cholesterol, the genotypic means in F2s, represented by the closest markers, were calculated for F2 males and F2 females and shown in Table 3 . For the locus on chromosome 9, homozygotes for the CASA/Rk allele had higher plasma HDL cholesterol levels than did heterozygotes and homozygotes for the C57BL/ 6J allele.…”

“…Yet, whereas much is known about the nature and effect of environmental factors including cigarette smoking, total dietary fat intake, types of dietary fatty acids, physical activity, and alcohol consumption, relatively little is known about the genetic basis of this variation. Data from twin and family studies have shown that ‫ف‬ 50% of the interindividual variability in LDL cholesterol and HDL cholesterol can be ascribed to genetic determinants; however, only some of the genes involved have so far been identified (2)(3)(4)(5)(6). Studies in pedigrees that segregate mutations in critical genes largely expand the understanding of the physiological and metabolic aspects of lipoprotein carriers of non-HDL and HDL cholesterol.…”

“…For example, Ko et al used human apolipoprotein B (apoB) transgenics in a C57BL/6 ϫ 129 cross to identify loci on chromosome 6 and chromosome 4 in linkage with plasma apoB levels, a signature apolipoprotein for plasma non-HDL cholesterol lipoproteins (7). Mehrabian et al used a C57BL/6J ϫ CAST/Ei cross to map loci on chromosomes 2, 3,5,8,9,14,16,17, and 18 in linkage with plasma HDL cholesterol (8). Here we describe two mouse strains, C57BL/ 6J and CASA/Rk, that, when fed a chow diet, display different plasma levels of non-HDL cholesterol.…”