Vitamin A is linked to the expression of the AI-CIII-AIV gene cluster in familial combined hyperlipidemia.
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There is growing evidence of the capacity of vitamin A to regulate the expression of the genetic region that encodes apolipoproteins (apo) A-I, C-III, and A-IV. This region in turn has been proposed to modulate the expression of hyperlipidemia in the commonest genetic form of dyslipidemia, familial combined hyperlipidemia (FCHL). The hypothesis tested here was whether vitamin A (retinol), by controlling the expression of the AI-CIII-AIV gene cluster, plays a role in modulating the hyperlipidemic phenotype in FCHL. We approached the subject by studying three genetic variants of this region: a C1100-T transition in exon 3 of the apoC-III gene, a G3206-T transversion in exon 4 of the apoC-III gene, and a G-75-A substitution in the promoter region of the apoA-I gene. The association between plasma vitamin A concentrations and differences in the plasma concentrations of apolipoproteins A-I and C-III based on the different genotypes was assessed in 48 FCHL patients and 74 of their normolipidemic relatives. The results indicated that the subjects carrying genetic variants associated with increased concentrations of apoA-I and C-III (C1100-T and G-75-A) also presented increased plasma concentrations of vitamin A. This was only observed among the FCHL patients, which suggested that certain characteristics of these patients contributed to this association. The G3206-T was not associated with changes in either apolipoprotein concentrations or in vitamin A. In summary, we report a relationship between genetically determined elevations of proteins of the AI-CIII-AIV gene cluster and vitamin A in FCHL patients. More studies will be needed to confirm that vitamin A plays a role in FCHL which might also be important for its potential application to therapeutical approaches. (+info)
Coronary flow reserve in young men with familial combined hyperlipidemia.
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BACKGROUND: Familial combined hyperlipidemia (FCHL) is a common hereditary disorder of lipoprotein metabolism estimated to cause 10% to 20% of premature coronary heart disease. We investigated whether functional abnormalities exist in coronary reactivity in asymptomatic patients with FCHL. METHODS AND RESULTS: We studied 21 male FCHL patients (age, 34.8+/-5.4 years) and a matched group of 21 healthy control subjects. Myocardial blood flow (MBF) was measured at baseline and during dipyridamole-induced hyperemia with PET and 15O-labeled water. The baseline MBF was similar in patients and control subjects (0.79+/-0.19 versus 0.88+/-0.20 mL. g-1. min-1, P=NS). An increase in MBF was seen in both groups after dipyridamole infusion, but MBF at maximal vasodilation was lower in FCHL patients (3.54+/-1.59 versus 4.54+/-1.17 mL. g-1. min-1, P=0.025). The difference in coronary flow reserve (CFR) was not statistically significant (4.7+/-2.2 versus 5.3+/-1.6, P=NS, patients versus control subjects). Considerable variability in CFR values was detected within the FCHL group. Patients with phenotype IIB (n=8) had lower flow during hyperemia (2.5+/-1.2 versus 4.2+/-1.5 mL. g-1. min-1, P<0.05) and lower CFR (3.4+/-2.1 versus 5.4+/-2.0, P<0.05) compared with phenotype IIA (n=13). CONCLUSIONS: Abnormalities in coronary flow regulation exist in young asymptomatic FCHL patients expressing phenotype IIB (characterized by abnormalities in both serum cholesterol and triglyceride concentrations). This is in line with previous observations suggesting that the metabolic abnormalities related to the pathophysiology of FCHL are associated with the phenotype IIB. (+info)
Genomewide scan for familial combined hyperlipidemia genes in finnish families, suggesting multiple susceptibility loci influencing triglyceride, cholesterol, and apolipoprotein B levels.
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Familial combined hyperlipidemia (FCHL) is a common dyslipidemia predisposing to premature coronary heart disease (CHD). The disease is characterized by increased levels of serum total cholesterol (TC), triglycerides (TGs), or both. We recently localized the first locus for FCHL, on chromosome 1q21-q23. In the present study, a genomewide screen for additional FCHL loci was performed. In stage 1, we genotyped 368 polymorphic markers in 35 carefully characterized Finnish FCHL families. We identified six chromosomal regions with markers showing LOD score (Z) values >1.0, by using a dominant mode of inheritance for the FCHL trait. In addition, two more regions emerged showing Z>2.0 with a TG trait. In stage 2, we genotyped 26 more markers and seven additional FCHL families for these interesting regions. Two chromosomal regions revealed Z>2.0 in the linkage analysis: 10p11.2, Z=3.20 (theta=.00), with the TG trait; and 21q21, Z=2.24 (theta=.10), with the apoB trait. Furthermore, two more chromosomal regions produced Z>2.0 in the affected-sib-pair analysis: 10q11.2-10qter produced Z=2.59 with the TC trait and Z=2.29 with FCHL, and 2q31 produced Z=2.25 with the TG trait. Our results suggest additional putative loci influencing FCHL in Finnish families, some potentially affecting TG levels and some potentially affecting TC or apoB levels. (+info)
Association of plasma lipids and apolipoproteins with the insulin response element in the apoC-III promoter region in familial combined hyperlipidemia.
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The apoAI-CIII-AIV gene cluster, located on chromosome 11, contributes to the phenotype of familial combined hyperlipidemia (FCH), but this contribution is genetically complex. Combinations of haplotypes, based on three restriction enzyme polymorphisms: XmnI and MspI sites, 5' of the start site of the apoA-I gene and SstI polymorphism in the 3' untranslated region of exon 4 of the apoC-III gene, were analyzed to characterize their effect on the expression of severe hyperlipidemia. An epistatic interaction was demonstrated: the S2 allele on one haplotype was synergistic in its hyperlipidemic effect to the X2M2 allele on the other haplotype (Dallinga-Thie, G. M. et al. J. Clin. Invest. 1997. 99: 953-961). In the present study two additional polymorphic sites in the insulin response element (IRE) of the apoC-III gene promoter, T-455C: FokI restriction site, C-482T: MspI restriction site, were studied in 34 FCH pedigrees including 34 probands, 220 hyperlipidemic relatives, 300 normolipidemic relatives, and 236 spouses. In contrast to the earlier data for the other polymorphisms in this gene cluster (XmnI, MspI/AI, and SstI), there were no differences in frequency distributions of the T-455C and the C-482T variants between probands, hyperlipidemic and normolipidemic relatives and spouses. No significant associations between plasma lipid traits and DNA variants in the IRE were observed. Analysis of combinations of haplotypes based on the five polymorphisms in the gene cluster provided further evidence for a dominant role of the SstI polymorphism as a major susceptibility locus in FCH. The inclusion of the IRE markers did not improve genetic informativeness, nor our understanding of the observed synergistic relationship associated with the high risk combination of haplotypes in FCH families. (+info)
A genome scan for familial combined hyperlipidemia reveals evidence of linkage with a locus on chromosome 11.
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Familial combined hyperlipidemia (FCHL) is a common familial lipid disorder characterized by a variable pattern of elevated levels of plasma cholesterol and/or triglycerides. It is present in 10%-20% of patients with premature coronary heart disease. The genetic etiology of the disease, including the number of genes involved and the magnitude of their effects, is unknown. Using a subset of 35 Dutch families ascertained for FCHL, we screened the genome, with a panel of 399 genetic markers, for chromosomal regions linked to genes contributing to FCHL. The results were analyzed by use of parametric-linkage methods in a two-stage study design. Four loci, on chromosomes 2p, 11p, 16q, and 19q, exhibited suggestive evidence for linkage with FCHL (LOD scores of 1.3-2.6). Markers within each of these regions were then examined in the original sample and in additional Dutch families with FCHL. The locus on chromosome 2 failed to show evidence for linkage, and the loci on chromosome 16q and 19q yielded only equivocal or suggestive evidence for linkage. However, one locus, near marker D11S1324 on the short arm of human chromosome 11, continued to show evidence for linkage with FCHL, in the second stage of this design. This region does not contain any strong candidate genes. These results provide evidence for a candidate chromosomal region for FCHL and support the concept that FCHL is complex and heterogeneous. (+info)
Linkage of a candidate gene locus to familial combined hyperlipidemia: lecithin:cholesterol acyltransferase on 16q.
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Familial combined hyperlipidemia (FCHL) is a common lipid disorder characterized by elevated levels of plasma cholesterol and triglycerides that is present in 10% to 20% of patients with premature coronary artery disease. To study the pathophysiological basis and genetics of FCHL, we previously reported recruitment of 18 large families. We now report linkage studies of 14 candidate genes selected for their potential involvement in the aspects of lipid and lipoprotein metabolism that are altered in FCHL. We used highly polymorphic markers linked to the candidate genes, and these markers were analyzed using several complementary, nonparametric statistical allele-sharing linkage methodologies. This current sample has been extended over the one in which we identified an association with the apolipoprotein (apo) AI-CIII-AIV gene cluster. We observed evidence for linkage of this region and FCHL (P<0.001), providing additional support for its involvement in FCHL. We also identified a new locus showing significant evidence of linkage to the disorder: the lecithin:cholesterol acyltransferase (LCAT) locus (P<0.0006) on chromosome 16. In addition, analysis of the manganese superoxide dismutase locus on chromosome 6 revealed a suggestive linkage result in this sample (P<0.006). Quantitative traits related to FCHL also provided some evidence of linkage to these regions. No evidence of linkage to the lipoprotein lipase gene, the microsomal triglyceride transfer protein gene, or several other genes involved in lipid metabolism was observed. The data suggest that the lecithin:cholesterol acyltransferase and apolipoprotein AI-CIII-AIV loci may act as modifying genes contributing to the expression of FCHL. (+info)
Apolipoprotein B overproduction by the perfused liver of the St. Thomas' mixed hyperlipidemic (SMHL) rabbit.
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The St. Thomas' mixed hyperlipidemic (SMHL) rabbit (previously St. Thomas' Hospital rabbit) is a putative model of familial combined hyperlipidemia (FCH). When fed a low (0.08%) cholesterol diet, it exhibits elevations in both plasma cholesterol and triglyceride compared to New Zealand White (NZW) controls. To determine the mechanism for this hyperlipidemia we studied the secretion of apolipoprotein B (apoB)-containing lipoproteins from perfused livers of both young and mature rabbits. During a 3-h perfusion we measured the total cholesterol and triglyceride content of the medium and the cholesterol, triglyceride, and apoB content of very low density lipoprotein (VLDL)(1) (S(f) 60;-400), VLDL(2) (S(f) 20;-60), intermediate (S(f) 12;-20), and low (S(f) 0;-12) density lipoproteins (IDL, LDL). Lipoprotein concentrations increased linearly throughout the perfusion period. The rate of cholesterol output was 3-fold higher (459 vs. 137 ng/g liver/min, P = 0.003) in SMHL versus NZW rabbits whilst that of triglyceride was similar (841 vs. 662 ng/g liver/min, NS). VLDL(1) cholesterol output was elevated 2-fold (232 vs. 123 ng/g liver/min, P < 0.05) and VLDL(2) + IDL + LDL cholesterol output, 4.5-fold (106 vs. 23 ng/g liver/min, P < 0. 005) in SMHL versus NZW rabbits. ApoB output in VLDL1 was 38 ng/g liver per min in SMHL and 14 ng/g liver per min in NZW (NS). In SMHL VLDL(2) + IDL + LDL apoB was increased 9-fold at 53 versus 6 ng/g liver per min in NZW (P < 0.001). We conclude that the SMHL rabbit overproduces apoB-containing lipoproteins particularly in the VLDL(2) + IDL + LDL fraction, a characteristic consistent with its use as a model of FCH. (+info)
Serum leptin concentrations in patients with combined hyperlipidemia: relationship to serum lipids and lipoproteins.
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Leptin is a protein hormone produced predominantly by adipocytes. Serum leptin concentrations in healthy individuals positively correlate with the body fat content and body mass index, i.e. they are higher in obese than in lean subjects. The relations between serum leptin concentration and serum lipids and lipoproteins is not yet clear. The aim of our study was to compare serum leptin concentrations in 22 randomly selected patients with untreated combined hyperlipidemia and 19 healthy control subjects matched for age and the body mass index. The relationship was studied between serum leptin concentrations and serum lipids (total, HDL, LDL cholesterol and triglycerides) and lipoproteins (lipoprotein (a), apolipoprotein B). It was found that serum leptin levels in patients with combined hyperlipidemia did not significantly differ from those of control subjects (6.69+/-4.3 vs 5.78+/-3.2 ng.ml(-1)). Serum leptin concentrations in both groups correlated positively with the body mass index. The relationship between leptin concentrations and lipid or lipoprotein levels found in any of the studied groups was not statistically significant. We conclude that serum leptin concentrations in patients with combined hyperlipidemia as well as in healthy control subjects reflect the body fat content and have no significant relation to serum lipids or lipoproteins. (+info)