Biomedical subjects

T W de Bruin

Publications and source records attributed to T W de Bruin.

At least 19 recordsLinked to original sources

PubMed2001

Excess coronary heart disease in Familial Combined Hyperlipidemia, in relation to genetic factors and central obesity.

AIM: To determine the prevalence of non-fatal coronary artery disease (CAD) in kindred with Familial Combined Hyperlipidemia (FCHL) in relation to various cardiovascular risk factors and DNA variation in the apo AI-CIII-AIV gene cluster. METHODS AND RESULTS: Data were collected from 18 Dutch FCHL probands, 202 living first and second degree relatives, and 175 spouses. Probands and first degree relatives showed dyslipidemia, increased plasma insulin and glucose concentrations, higher waist--hip ratio (WHR), and blood pressure, than spouses. The frequency of the minor alleles M2 and S2 was increased in probands and first degree relatives. The Odds Ratio for CAD was 5.3 in male FCHL relatives (P=0.005), and 5.1 in all FCHL relatives (P=0.001). First and second degree relatives had a markedly reduced CAD-free life-span (logrank vs. spouses: P<0.001 and P=0.03, respectively). The presence of the S2, but not M2, minor allele, showed a marked reduction in CAD-free life-span (logrank S2 present vs. S2 absent: P=0.035). CONCLUSION: Men with FCHL have a severely increased risk of CAD, that appears to be mediated through genetic relation to the proband as the strongest independent risk factor for CAD, followed by increased WHR.

Adult↗

PubMed2001

The apoAI-CIII-AIV gene cluster.

The relationship between variations in the apoAI-CIII-AIV gene cluster and plasma lipid traits has been recognized for at least 15 years. Most studies have been focused upon the association between plasma triglycerides and a genetic variation present in the 3' untranslated region of the apoC-III gene (SstI polymorphism). Although not all studies showed similar results, this variant is most consistently found in association with plasma triglycerides. The other most interesting DNA variant is the mutation present in the promoter region of the apo A-I gene at position -75 (Msp-AI polymorphism), which has been associated with differences in plasma apoA-I and HDL-cholesterol levels. In this review, we will discuss the most frequent occurring genetic variants in the apoAI-CIII-AIV gene cluster and their impact on plasma lipid traits and associations with increased risk on developing coronary artery disease.

Apolipoprotein A-I↗

PubMed2001

Familial dyslipidemic hypertension syndrome: familial combined hyperlipidemia, and the role of abdominal fat mass.

Familial combined hyperlipidemia (FCHL) is the most frequent genetic lipid abnormality in humans, with a 5- to 10-fold increased risk of early myocardial infarction. Familial combined hyperlipidemia has been proposed as the leading cause of dyslipidemia in familial dyslipidemic hypertension (FDH). It was the objective of this study to quantify and analyze the simultaneous occurrence of hypertension and hyperlipidemia in FCHL families. We assessed blood pressure (BP) and hyperlipidemia in 27 families with FCHL (235 relatives and 140 spouses, aged 30 to 60 years). Hypertension was defined as a BP more than 140/90 mm Hg, or the use of antihypertensive medication. Multiple backward linear regression analysis was used to derive a biological formula describing BP in FCHL families. One-third of 27 FCHL families were diagnosed with FDH. Sixty-four of 235 (27.2%) relatives had dyslipidemic hypertension (DH), compared to 20 of 140 (14.3%) spouses (P = .005); odds ratio = 2.25 (95% confidence interval 1.29-3.91). Multiple linear regression analysis showed that age, FCHL status, and waist circumference significantly contributed to systolic blood pressure (SBP) in female FCHL relatives. In conclusion, in FCHL we defined age, waist circumference, and hyperlipidemia as predictors of SBP. This study indicates that visceral adipose tissue strongly contributes to the high prevalence of DH in FCHL families. Reduction of visceral fat should be tested as a potential therapeutic intervention for hyperlipidemia and hypertension in FCHL individuals.

Abdomen↗

PubMed2001

Association between the alpha-adducin Gly460Trp polymorphism and systolic blood pressure in familial combined hyperlipidemia.

BACKGROUND: In a genome scan for familial combined hyperlipidemia (FCHL), a locus contributing to systolic blood pressure (SBP) has been identified on chromosome 4, containing the a-adducin gene (ADD1). In previous studies, an association has been found between the alpha-adducin Gly460Trp polymorphism and salt-sensitive hypertension. In this study, we investigated the association between the a-adducin Gly460Trp polymorphism and blood pressure in FCHL patients. METHODS: A total of 79 unrelated patients with FCHL and 121 unrelated controls (spouses) were recruited for the study. Blood pressure was measured in a standardized fashion, with the subject in sitting position after 10 min of rest. The alpha-adducin Gly460Trp polymorphism was detected by mutagenically separated polymerase chain reaction. RESULTS: The genotype frequencies of both FCHL patients and controls were in Hardy-Weinberg equilibrium. The alpha-adducin Gly460Trp polymorphism showed a significant association with FCHL, the number of subjects carrying a 460Trp allele was significantly higher in patients compared with controls (53% v 33%, chi2 = 8.0, P = .018). In FCHL patients carrying at least one 460Trp allele, SBP was significantly higher compared with patients homozygous for the 460Gly allele (140 mm Hg and 130 mm Hg respectively, P = .015). CONCLUSIONS: This study shows that the 460Trp allele is associated with FCHL. Furthermore, SBP is increased in patients carrying the 460Trp allele.

Adult↗

PubMed2001

Lipid metabolism.

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ATP-Binding Cassette Transporters↗

PubMed2001

Genome scan for blood pressure in Dutch dyslipidemic families reveals linkage to a locus on chromosome 4p.

Genes contributing to common forms of hypertension are largely unknown. A number of studies in humans and in animal models have revealed associations between insulin resistance, dyslipidemia, and elevated hypertension. To identify genes contributing to blood pressure (BP) variation associated with insulin-resistant dyslipidemia, we conducted a genome-wide scan for BP in a set of 18 Dutch families exhibiting the common lipid disorder familial combined hyperlipidemia. Our results reveal a locus on chromosome 4 that exhibits a significant lod score of 3.9 with systolic BP. In addition, this locus also appears to influence plasma free fatty acid levels (lod=2.4). After adjustment for age and gender, the lod score for systolic BP increased to 4.6, whereas the lod score for free fatty acid levels did not change. The chromosome 4 locus contains an attractive candidate gene, alpha-adducin, which has been associated with altered BP in animal studies and in some human populations. However, we found no evidence for an association between 2 intragenic alpha-adducin polymorphisms and systolic BP in this sample. We also observed suggestive evidence for linkage (lod=1.8) of diastolic BP to the lipoprotein lipase gene locus on chromosome 8p, supporting a finding previously observed in a separate insulin-resistant population. In addition, we also obtained suggestive evidence for linkage of systolic BP (lod=2.4) and plasma apolipoprotein B levels (lod=2.0) to a locus on proximal chromosome 19p. In conclusion, our genome scan results support the existence of multiple genetic factors that can influence both BP and plasma lipid parameters.

Adult↗

PubMed2000

[Prevention of lactic acidosis due to metformin intoxication in contrast media nephropathy].

Use of the oral antidiabetic drug metformin may cause lactic acidosis, a rare but life-threatening complication, especially in patients with renal function loss. Since intravenously administered iodide-containing contrast media may cause renal function disturbances precautions should be taken in metformin-treated patients for whom a radiological study with intravenous contrast media is considered. In diabetic patients who use metformin a serum creatinine concentration should be measured prior to the radiological study. If the serum creatinine is within normal limits (< 130 mumol/l), metformin can be continued and the examination performed. If the serum creatinine concentration is increased (> or = 130 mumol/l), metformin should be discontinued and replaced by another antidiabetic drug if necessary. The radiological procedure with intravenous contrast media should be postponed for 48 hours. If such a procedure cannot be postponed, additional measures to prevent lactic acidosis (hydration, monitoring of the renal function) should be taken.

Acidosis, Lactic↗

PubMed2000

Identification of TNFRSF1B as a novel modifier gene in familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCHL) is the most commonly inherited hyperlipidemia in man, with a frequency of +/-1% in the general population and approximately 10% in myocardial infarction survivors. A genomic scan in 18 Dutch FCHL families resulted in the identification of several loci with evidence for linkage. One of these regions, 1p36.2, contains TNFRSF1B which encodes one of the tumor necrosis factor receptors. An intron 4 polymorphic CA-repeat was used to confirm linkage to FCHL. Linear regression analysis using 79 independent sib pairs showed linkage with a quantitative FCHL discriminant function (P = 0.032), and, borderline, with apolipoprotein B levels (P = 0.064). Furthermore, in a case-control study, association was demonstrated since the overall CA-repeat genotype distribution was significantly different among 40 unrelated FCHL patients and 48 unrelated healthy spouse controls (P = 0.029). This difference was due to a significant increase in allele CA271 homozygotes in the FCHL patients (P = 0.019). Mutation analysis of exon 6 in 73 FCHL family members demonstrated the presence of a single nucleotide polymorphism with two alleles, coding for methionine (196M) and arginine (196R). Complete linkage disequilibrium between CA267, CA271 and CA273 and this polymorphism was detected. In 85 hyperlipidemic FCHL subjects, an association was demonstrated between soluble TNFRSF1B plasma concentrations and the CA271-196M haplotype. In conclusion, TNFRSF1B was found to be associated with susceptibility to FCHL. Our data suggest that an as yet unknown disease-associated mutation, linked to alleles 196M and CA271, plays a role in the pathophysiology of FCHL.

Adult↗

PubMed2000

Soluble receptors for tumor necrosis factor-alpha (TNF-R p55 and TNF-R p75) in familial combined hyperlipidemia.

We investigated the potential role of the 75 kD receptor for tumor necrosis factor-alpha (TNF-alpha) (TNFRSF1B, located on chromosome 1 band p36.2) as a modifier gene in familial combined hyperlipidemia (FCH), based on previous linkage and association data. Age-corrected values for the soluble (s) extracellular domain of TNF-R p75 were lower in 156 well-characterized hyperlipidemic (HL) FCH relatives than in 168 normolipidemic (NL) relatives (P<0.01). Plasma concentrations of the soluble domain of the 55 kD receptor (sTNF-R p55, the other TNF-alpha receptor) did not differ between HL and NL relatives. In conditional logistic regression analysis, plasma sTNF-R p75 concentration was the only non-lipid variable that contributed significantly to prediction of affected FCH status (regression coefficient=-0.413, P=0.01). The present findings have potentially important diagnostic and therapeutic implications in FCH.

Adult↗

PubMed2000

Caco-2 cells secrete two independent classes of lipoproteins with distinct density: effect of the ratio of unsaturated to saturated fatty acid.

Polarized Caco-2 cells can synthesize two distinct density classes of lipoproteins, i.e. chylomicron/VLDL (d<1.006 g/ml) or IDL/LDL density (1.009<d<1.068 g/ml). When saturated fatty acid in the incubation medium is replaced with unsaturated fatty acid, this results in an increase in the basolateral secretion of triglycerides from 18.6+/-3.6 nmol/filter (with 0.5 mmol/l 16:0) to 21.4+/-6.2, 27. 5+/-4.8 and 28.9+/-5.3 nmol/filter when 10, 20 or 30% of 16:0 were substituted by 18:1. The secretion of IDL/LDL-sized lipoproteins diminished and chylomicron/VLDL secretion increased in proportion to the increase of unsaturated fatty acid in the medium. To gain insight into the relationship between these lipoprotein classes, we determined their secretion at several time intervals (0-4, 4-8 and 22-26 h) after incubation with a fatty acid mixture containing 16:0 and 18:1 in a 9:1 molar ratio (total fatty acid concentration was 0.5 mmol/l). Chylomicron/VLDL secretion was detectable immediately upon the start of the incubation and persisted during all intervals. In contrast, IDL/LDL density lipoproteins were first detectable in the 4-8 h time interval and their secretion was highest in the final phase of the incubation (22-26 h). We conclude that Caco-2 cells secrete two distinct density classes of lipoproteins that show no precursor-product relation.

Caco-2 Cells↗

PubMed2000

Genome scan for adiposity in Dutch dyslipidemic families reveals novel quantitative trait loci for leptin, body mass index and soluble tumor necrosis factor receptor superfamily 1A.

OBJECTIVE: To search for novel genes contributing to adiposity in familial combined hyperlipidemia (FCH), a disorder characterized by abdominal obesity, hyperlipidemia and insulin resistance, using a 10cM genome-wide scan. DESIGN: Plasma leptin and soluble tumor necrosis factor receptor superfamily members 1A and 1B (sTNFRSF1A and sTNFRSF1B, also known as sTNFR1 and sTNFR2) were analyzed as unadjusted and adjusted quantitative phenotypes of adiposity, in addition to body mass index (BMI), in multipoint and single-point analyses. In the second stage of analysis, an important chromosome 1 positional candidate gene, the leptin receptor (LEPR), was studied. SUBJECTS: Eighteen Dutch pedigrees with familial combined hyperlipidemia (FCH) (n= 198) were analyzed to search for chromosomal regions harboring genes contributing to adiposity. RESULTS: Multipoint analysis of the genome scan data identified linkage (log of odds, LOD, 3.4) of leptin levels to a chromosomal region defined by D1S3728 and D1S1665, flanking the leptin receptor (LEPR) gene by approximately 9 and 3 cM, respectively. The LOD score decreased to 1.8 with age- and gender-adjusted leptin levels. Notably, BMI also mapped to this region with an LOD score of 1.2 (adjusted BMI: LOD 0.5). Two polymorphic DNA markers in LEPR and their haplotypes revealed linkage to unadjusted and adjusted BMI and leptin, and an association with leptin levels was found as well. In addition, the marker D8S1110 showed linkage (LOD 2.8) with unadjusted plasma concentrations of soluble TNFRSF1A. BMI gave a LOD score of 0.6. Moreover, a chromosome 10 q-ter locus, AFM198ZB, showed linkage with adjusted BMI (LOD 3.3). CONCLUSION: These data provide evidence that a human chromosome 1 locus, harboring the LEPR gene, contributes to plasma leptin concentrations, adiposity and body weight in humans affected with this insulin resistant dyslipidemic syndrome. Novel loci on chromosome 8 and 10 qter need further study.

Adult↗

PubMed2000

Contribution of the hepatic lipase gene to the atherogenic lipoprotein phenotype in familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCH) is a common genetic lipid disorder with a frequency of 1-2% in the population. In addition to the hypercholesterolemia and/or hypertriglyceridemia that affected individuals exhibit, small, dense LDL particles and decreased HDL-cholesterol levels are traits frequently associated with FCH. Recently, we reported that families with FCH and families enriched for coronary artery disease (CAD) share genetic determinants for the atherogenic lipoprotein phenotype (ALP), a profile presenting with small, dense LDL particles, decreased HDL-cholesterol levels, and increased triglyceride levels. Other studies in normolipidemic populations have shown that the hepatic lipase (HL) gene is linked to HDL-cholesterol levels and that a polymorphism within the HL promoter (-514C-->T) is associated with increased HDL-cholesterol levels as well as larger, more buoyant LDL particles. In the present study, we tested whether the HL gene locus also contributes to ALP in a series of Dutch FCH families using nonparametric sibpair linkage analysis and association analysis. Evidence for linkage of LDL particle size (P < 0.019), HDL-cholesterol (P < 0.003), and triglyceride levels (P < 0.026) to the HL gene locus was observed. A genome scan in a subset of these families exhibited evidence for linkage of PPD (LOD = 2.2) and HDL-cholesterol levels (LOD = 1.2) to the HL gene locus as well. The -514C-->T promoter polymorphism was significantly associated (P < 0.0001) with higher HDL-cholesterol levels in the unrelated males of this population, but not in unrelated females. No association was observed between the polymorphism and LDL particle size or triglyceride levels. Our results provide support that ALP is a multigenic trait and suggest that the relationship between small, dense LDL particles, HDL-cholesterol, and triglyceride levels in FCH families is due, in part, to common genetic factors.

Adult↗

PubMed1999

A genome scan for familial combined hyperlipidemia reveals evidence of linkage with a locus on chromosome 11.

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.

Adult↗

PubMed1999

Novel genes for familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCHL) is a complex genetic disorder of unknown etiology. Recently, 'modifier' genes of the FCHL phenotype, such as the apolipoprotein AI-CIII-AIV gene cluster and LPL, have been identified in several populations. A 'major' gene for FCHL has been identified in a Finnish isolate which maps to a region syntenic to murine chromosome 3 where a locus for combined hyperlipidemia has been identified. We review these and other recent studies which indicate that FCHL is genetically heterogeneous.

Age Factors↗

PubMed1999

Linkage of a candidate gene locus to familial combined hyperlipidemia: lecithin:cholesterol acyltransferase on 16q.

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.

Adult↗

PubMed1999

Menopause is associated with reduced protection from postprandial lipemia.

Deficiency of endogenous estrogens has been associated with a higher incidence of coronary heart disease (CHD) in women. We investigated whether natural menopause is associated with reduced protection from postprandial lipemia, which represents a risk indicator of CHD. Twenty-three postmenopausal women (mean age, 50+/-1 [SD] years; body mass index, 24.6+/-2.8 kg/m(2)) and 21 premenopausal women matched for age and body mass index (age, 49+/-1 years; body mass index, 24. 1+/-2.6 kg/m(2)) underwent an oral vitamin A fat-loading test. Vitamin A is a marker of the metabolism of chylomicrons and chylomicron remnants. All women were normolipidemic, were in good health, were nonsmokers, and used no medication. Postprandial lipids and vitamin A were measured at hourly intervals up to 12 hours. In postmenopausal women, plasma total cholesterol and LDL cholesterol concentrations were significantly higher. Fasting plasma triglyceride (TG) concentrations were 1.14+/-0.57 mmol/L in postmenopausal women and 0.88+/-0.33 mmol/L in premenopausal women (P=NS). In the postprandial phase, postmenopausal women had higher plasma TG (13.0+/-6.1 versus 9.5+/-3.3 mmol x L(-1) x h(-1); P=0.024) and vitamin A (54.1+/-22.9 versus 35.9+/-9.6 mg x L(-1) x h(-1); P=0. 001) responses. To correct for the possible confounding effect of fasting TG, 13 postmenopausal women were carefully matched with 19 premenopausal women. Although fasting TG levels were identical (0. 72+/-0.20 versus 0.73+/-0.21 mmol/L), differences in postprandial vitamin A (45.3+/-14.5 versus 33.0+/-7.7 mg x L(-1) x h(-1); P=0.006) and incremental TG (ie, after subtraction of baseline TG) (3.2+/-1.8 versus 2.3+/-1.0 mmol x L(-1) x h(-1); P=0.023) persisted between postmenopausal and premenopausal women. Natural menopause is associated with aggravated postprandial lipemia in women matched for age and body mass index. Higher postprandial lipemia potentially explains the relation of TGs and CHD mortality risk in postmenopausal women.

Body Mass Index↗

PubMed1999

Association of plasma lipids and apolipoproteins with the insulin response element in the apoC-III promoter region in familial combined hyperlipidemia.

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.

Adult↗

PubMed1998

Chylomicron synthesis by intestinal cells in vitro and in vivo.

Synthesis and secretion of chylomicrons by the intestine is essential to transport dietary fats in the circulation and to deliver these fats to the appropriate peripheral tissues. The assembly of chylomicrons within the enterocyte and the subsequent secretion of these lipoprotein particles into the lymph is a complex, multi-step process that includes absorption of lipids by the enterocytes, cellular lipid (re)synthesis and translocation of cellular lipid pools, synthesis and post-translational modification of various apolipoproteins and, finally, the assembly of lipid and lipoprotein components into a chylomicron. The key process in chylomicron synthesis is the intracellular association of apolipoprotein (apo)B48, the structural protein of chylomicrons, with lipids.

Animals↗