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P J Talmud

Publications and source records attributed to P J Talmud.

At least 37 records · Page 2Linked to original sources
PubMed2001

Genetic determinants of plasma triglycerides: impact of rare and common mutations.

Raised plasma triglyceride (TG) levels are an independent risk factor for coronary artery disease (CAD), and thus understanding the genetic and environmental determinants of TG levels are of major importance. TG metabolism is a process for delivering free fatty acids for energy storage or b-oxidation, and involves a number of different hydrolytic enzymes and apolipoproteins (apo). The genes encoding these proteins are, therefore, candidates for determining plasma TGs. Although rare mutations in lipoprotein lipase (LPL), the major TG-hydrolyzing enzyme, and apo CII (APOC2), its essential activator, result in extremely high plasma TG levels, their low frequency means they have little impact upon TG levels in the general population. Common mutations in LPL, apo CIII (APOC3), and apo E (APOE) have the strongest effect on plasma TG levels at the population level. In addition, environmental factors such as diet, obesity, and smoking interact with genetic determinants of TG to produce a modulating high-risk environment.

Animals↗
PubMed2001

Genetic determination of plasma lipids and insulin in the Czech population.

OBJECTIVES: To evaluate the association between plasma lipids and insulin and variation in the genes for apolipoproteins (APO) E (CfoI), B (insertion/deletion), C1 (HpaI), and C3 (C-482T, C3238G) in a population-based Czech Slavonic study. DESIGN AND METHODS: In 131 men and 154 women, polymorphisms were investigated using PCR. In the same subjects plasma lipid levels and insulin were measured. RESULTS: In the women, carriers of the e4 allele had higher apoB (p = 0.03) and triglyceride (p = 0.03) compared to e3 homozygotes, whereas in the men, the effect of the e4 allele was seen on total cholesterol (p = 0.02), LDL cholesterol (p = 0.003) and apoB (p = 0.001). Compared with SP27 (insertion) homozygotes of the APOB polymorphism, women SP24 (deletion) homozygotes had higher levels of total (p = 0.003) and LDL cholesterol (p = 0.007) and apoB (p = 0.05). No significant effect was seen in the men. Women homozygous for the APOC3 -482T allele had higher insulin levels than -482C homozygotes (p = 0.03). Men homozygous for APOC3 -482T allele have the highest plasma triglyceride level (p = 0.02). The APOC1 polymorphism exhibited no significant effect on any of the parameters studied. CONCLUSIONS: In this sample, variation at the APOE, APOB and APOC3 genes play a role in determining plasma levels of insulin and lipids, and emphasize the importance of gender-associated effects in the genetic determinations.

Adult↗
PubMed2001

Interaction of the common apolipoprotein C-III (APOC3 -482C > T) and hepatic lipase (LIPC -514C > T) promoter variants affects glucose tolerance in young adults. European Atherosclerosis Research Study II (EARS-II).

Both hepatic lipase (HL) and apolipoprotein C-III (apoC-III) influence lipid metabolism. Common variation in promoters of both genes, LIPC -514C > T and APOC3 -482C > T, respectively, have been shown to affect plasma lipids and lipoproteins and glucose tolerance. We studied the interaction between both variants on parameters of glucose tolerance and lipid metabolism in 714 healthy young males participating in the second European Atherosclerosis Research Study (EARS-II). Approximately 18% of the subjects were carriers of at least one rare LIPC and APOC3 allele. These subjects exhibited, after fasting and oral fat loading, the highest values of triglyceride-rich lipoproteins, but there was no significant interactive effect on any lipid variable. However, interaction occurred on basal diastolic blood pressure (p =0.036) and, during oral glucose tolerance testing, on peak (p = 0.0065) and area under the curve for glucose (p =0.049), and insulin (p = 0.035). This resulted in the highest diastolic blood pressure and lowest glucose tolerance in carriers of at least one rare allele of both genes. Thus gene:gene interaction between LIPC and APOC3, even in these healthy young males, leads to changes in parameters that are typically characteristic of Syndrome-X.

Adult↗
PubMed2001

Genetic polymorphisms, lipoproteins and coronary artery disease risk.

Association studies between gene variants (polymorphisms) and measured intermediate phenotypes, such as lipid/lipoprotein levels, or disease endpoints such as coronary artery disease, are commonplace in the literature. But have we learnt anything from the shortcomings in study design and analytical strategies that have resulted in much controversy in this field over the last few years? This review highlights some of these problems. Using the lipoprotein lipase gene as an example, we evaluate new approaches to identifying polymorphisms that will stand up to linkage disequilibrium/association studies with complex disorders in this post Human Genome Project age, and emphasize the importance of gene-environment interaction in assessing the impact of gene variants.

Coronary Disease↗
PubMed2001

Lipoprotein candidate genes for multivariate factors of the insulin resistance syndrome: a sib-pair linkage analysis in women twins.

The insulin resistance syndrome (IRS) is characterized by a combination of interrelated coronary heart disease risk factors, including low high-density lipoprotein cholesterol (HDLC) levels, obesity and increases in triglyceride (TG), systolic and diastolic blood pressure (BP), small low-density lipoprotein particles (LDL-size), and fasting and postload plasma insulin and glucose. Using factor analysis, we previously identified multivariate factors based on data from women participating in the Kaiser Permanente Women Twins Study: 1) Weight/Fat, 2) Insulin/Glucose, 3) Lipids, and 4) BP. The purpose of this study is to evaluate evidence for genetic linkage between the multivariate factors and candidate genes. Quantitative sib-pair analysis based on the factor scores with markers for 9 candidate genes was carried out based on data from 126 pairs of dizygotic (DZ) women twins from the second exam of the Kaiser Permanente Women Twins study. Suggestive evidence for linkage was found for the Weight/fat factor and the Apo E gene (p = 0.01), and stronger evidence for linkage with the Lipid factor and the cholesterol ester transfer protein (p = 0.002) gene. Therefore, the CETP gene appears to influence covariation in LDL size, TG, and HDL, and may account for a portion of the well-established statistical and metabolic associations observed between these risk factors.

Blood Pressure↗
PubMed2001

Age-related effects of genetic variation on lipid levels: The Columbia University BioMarkers Study.

OBJECTIVES: To examine the genotype:phenotype association in children compared with their parents. METHODS: Variations at 4 key gene loci, namely lipoprotein lipase (LPL S447X), hepatic lipase (HL -480C>T), cholesteryl ester transfer protein (CETP TaqIB), and apolipoprotein CIII (APOC3 -455T>C and -482C>T), were examined in children (n = 495) and their parents (n = 353) in the Columbia University BioMarkers Study, 1994 to 1998. RESULTS: The frequencies of the rare alleles of the HL -480C>T and APOC3 -455T>C and -482C>T (but not LPL S447X or CETP TaqIB) were significantly lower in non-Hispanic white participants compared with Hispanics. Overall, genotype effects seen in the adults were weaker in the children, although similar trends were seen. In an examination of the effect of body fat on the genotypic effects in the children, there was significant HL -480C>T:sum of skinfold interaction. CONCLUSIONS: All genotypes were associated with clear relationships to plasma lipid levels in adults, but the effects were weaker in their children, unless stressed by body fat. atherosclerosis, cardiovascular disease, child, lipids, genetics.

Adolescent↗
PubMed2001

Polymorphisms in the lipoprotein lipase and hepatic lipase genes and plasma lipid values in the Czech population.

We have determined the genotypes of two common polymorphisms in the lipoprotein lipase (S447X) and hepatic lipase (-480C/T) genes in a cohort of 285 representative selected Czech probands (131 male and 154 female), examined in 1988 and reinvestigated in 1996. The genotype distributions of both polymorphisms were in Hardy-Weinberg equilibrium and did not differ between male and female subjects. The rare allele frequency of the lipoprotein lipase polymorphism did not differ significantly from the other European populations. Compared to the German populations, the frequency of the hepatic lipase -480T allele was significantly higher in the Czech group (20% vs. 36%, p<0.0001). There were no significant associations between the lipoprotein lipase gene variants and lipid parameters measured either in 1988, or in 1996 or with changes of lipid parameters over the 8-year period. The carriers of the T-480 allele of the hepatic lipase polymorphism were found to have higher HDL cholesterol levels (p=0.02). However, this difference was confined to female subjects only. The male carriers of the -480T allele had higher concentrations of total cholesterol (p=0.03) as compared to CC-480 subjects. Both associations were observed in 1996 only. In the Slavic Czech population, a common polymorphism in the hepatic lipase gene (-480C/T), but not in the lipoprotein lipase gene (S447X), is a significant determinant of plasma HDL cholesterol in females and plasma total cholesterol in males and indicates the importance of gender-associated effects in the genetic determinations of plasma lipids.

Adult↗
PubMed2000

Characterization of recombinant wild type and site-directed mutations of apolipoprotein C-III: lipid binding, displacement of ApoE, and inhibition of lipoprotein lipase.

The physicochemical properties of recombinant wild type and three site-directed mutants of apolipoprotein C-III (apoC-III), designed by molecular modeling to alter specific amino acid residues implicated in lipid binding (L9T/T20L, F64A/W65A) or LPL inhibition (K21A), were compared. Relative lipid binding efficiencies to dimyristoylphosphatidylcholine (DMPC) were L9T/T20L > WT >K21A > F64A/W65A with an inverse correlation with size of the discoidal complexes formed. Physicochemical analysis (Trp fluorescence, circular dichroism, and GdnHCl denaturation) suggests that L9T/T20L forms tighter and more stable lipid complexes with phospholipids, while F64A/W65A associates less tightly. Lipid displacement properties were tested by gel-filtrating apoE:dipalmitoylphosphatidylcholine (DPPC) discoidal complexes mixed with the various apoC-III variants. All apoC-III proteins bound to the apoE:DPPC complexes; the amount of apoE displaced from the complex was dependent on the apoC-III lipid binding affinity. All apoC-III proteins inhibited LPL in the presence or absence of apoC-II, with F64A/W65A displaying the most inhibition, suggesting that apoC-III inhibition of LPL is independent of lipid binding and therefore of apoC-II displacement. Taken together. these data suggest that the hydrophobic residues F64 and W65 are crucial for the lipid binding properties of apoC-III and that redistribution of the N-terminal helix of apoC-III (L9T/T20L) enhances the stability of the lipid-bound protein, while LPL inhibition by apoC-III is likely to be due to protein:protein interactions.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2000

Linkage of the cholesteryl ester transfer protein (CETP) gene to LDL particle size: use of a novel tetranucleotide repeat within the CETP promoter.

BACKGROUND: A preponderance of small, dense LDL particles, elevated levels of plasma triglycerides (TG), and low levels of HDL characterize the atherogenic lipoprotein phenotype, which is associated with increased coronary artery disease (CAD) risk. Genetic and environmental factors influence LDL size, cholesteryl ester transfer protein (CETP) being one of the candidate genes. CETP mediates the transfer of cholesteryl ester from HDL to apolipoprotein (apo) B-containing lipoproteins in exchange for TG, promoting reverse cholesterol transfer and remodeling of lipoprotein particles. METHODS AND RESULTS: We have identified a tetranucleotide repeat (fragment sizes from 324 to 464 bp; heterozygosity index = 0.74) within the CETP promoter and used it in quantitative sib-pair linkage analysis in 119 female dizygotic (DZ) twins. Linkage was found to LDL size (P<0.001), TG (P<0.005), and plasma apoB (P = 0.02). The distribution of the tetranucleotide repeats was bimodal, and there was strong allelic association of the "short" alleles with the B2 allele of CETP TaqIB polymorphic site (P<0.001). CONCLUSIONS: This report of linkage of the CETP gene to LDL particle size adds to the list of candidate genes linked to LDL size, supporting the hypothesis of multigenic determination of LDL size heterogeneity. Whether this promoter variation is itself functional or is a marker for a functional site in the CETP gene remains to be determined.

Apolipoproteins↗
PubMed2000

Frequency and allelic association of common variants in the lipoprotein lipase gene in different ethnic groups: the Wandsworth Heart and Stroke Study.

The lower serum triglyceride (Tg), higher high density cholesterol (HDL-C) levels and low coronary heart disease (CHD) mortality in black populations, contrast with that in whites. By comparison, South Asian populations display a higher mortality from CHD associated with increased Tg and low HDL-C levels. Lipoprotein lipase (LPL) plays a major role in Tg metabolism. To determine if variation in the LPL gene contributes to the differences in lipid levels, we studied the frequencies and allelic associations of five common variants in the lipoprotein lipase (LPL) gene (-93T/G, D9N, N291S, S447X, and the HinddIII RFLP in intron 8) with serum Tg and HDL-cholesterol concentrations in population samples of middle-aged men and women of whites, South Asians, and blacks of African origin co-resident in South London. Significantly higher frequencies of the H(-) (P < 0.00001), N9 (P < 0.001), and -93G (P < 10(-10)) alleles were seen in blacks compared to the other two groups. Allelic association between -93G and N9, and H(+) and X447 was strong in all three groups. However, no association was observed between serum Tg and HDL-cholesterol concentrations and these variants in the three ethnic groups. A single common polymorphism in the LPL gene is unlikely to account for the differences in fasting serum Tg in populations of different ethnic background. The importance of the differences in frequencies and the mechanism(s) whereby these may contribute towards a beneficial LPL genotype in black populations remain to be determined.

Adult↗
PubMed2000

Variation in the PPARalpha gene is associated with altered function in vitro and plasma lipid concentrations in Type II diabetic subjects.

AIMS/HYPOTHESIS: Peroxisome proliferator activated receptor alpha (PPARalpha) regulates genes involved in lipid metabolism, haemostasis and inflammation, in response to fatty acids and fibrates, making it a candidate gene for risk of dyslipidaemia, atherosclerosis and coronary artery disease. Plasma non-esterified fatty acids are increased in subjects with Type II (non-insulin-dependent) diabetes mellitus, suggesting that PPARalpha could link Type II diabetes and dyslipidaemia, and affect response to fibrates. This has been investigated in association studies in healthy and diabetic subjects and in vitro studies. METHODS: The human PPARalpha gene was isolated and screened for variation by single strand conformation polymorphism analysis. Genotypes were determined for 129 Type II diabetic subjects and 2508 healthy men. The association with plasma lipid concentrations was examined. The function of the V162 variant was examined in co-transfection assays. RESULTS: We identified two polymorphisms, one in intron 3 and a missense mutation, leucine 162 to valine, in the DNA binding domain. In Type II diabetic patients, V162 allele carriers had higher total cholesterol, HDL cholesterol and apoAI whereas intron 3 rare allele carriers had higher apoAI concentrations. By contrast, no effect was observed in healthy rare allele carriers. In vitro, the V162 variant showed greater transactivation of a reporter gene construct. CONCLUSION/INTERPRETATION: Naturally occurring variation alters PPARalpha function, influencing plasma lipid concentrations in Type II diabetic patients but not healthy people. This demonstrates that PPARalpha is a link between diabetes and dyslipidaemia, and so could influence the risk of coronary artery disease, the greatest cause of morbidity and mortality in Type II diabetes.

Apolipoprotein A-I↗
PubMed2000

Substitution of asparagine for aspartic acid at residue 9 (D9N) of lipoprotein lipase markedly augments risk of ischaemic heart disease in male smokers.

Genetic variants of lipoprotein lipase (LPL), a key enzyme in the hydrolysis of triglyceride (TG)-rich particles, may contribute to ischaemic heart disease (IHD) risk. We have examined the risk of IHD in carriers of two common LPL variants, asparagine substitution for aspartic acid at residue 9 (D9N) and serine for asparagine at residue 291 (N291S) in 2708 middle-aged healthy European men, followed for over 6 years. The carrier frequencies were 2.6% for N9, and 3.9% for S291. Both variants were associated with higher plasma TG at baseline of 9% and 14%, respectively. At baseline, 28% of men were current smokers and smoking was unrelated to genotype. Associations between LPL variants and disease outcome, according to smoking status, were assessed by Cox's proportional hazards analysis. S291 carriers showed no increased risk of IHD compared to non-carriers, while there was strong evidence of interaction between D9N genotype and smoking status (P = 0.0003) in determining the risk of IHD. In 2248 non-carriers of N9, smoking increased the risk of an IHD event by 1.6 (95% CI: 1.1-2.4%) times. Among 58 N9 carriers, no IHD events occurred in 42 who were non-smokers, whereas five events were reported in 16 who smoked. The combined effect of smoking and N9 allele was to increase the risk of an IHD event by 10.4 (95% CI: 4.7-22.8%) times compared with D9 non-smokers. These findings could not be explained by confounding effects of baseline TG. Carriers of N9 appear to be especially vulnerable to the adverse effects of cigarette smoking on IHD risk, but this susceptibility is unrelated to the influence of this variant on plasma TG levels.

Asparagine↗
PubMed2000

Variants in the cholesterol ester transfer protein and lipoprotein lipase genes are predictors of plasma cholesterol response to dietary change.

There are no definitive explanations as to why individuals with hypercholesterolemia, a major cardiovascular risk factor, respond differently to dietary change. Fifty five free-living individuals completed a double crossover trial with two dietary regimens, a high saturated fat diet (providing 21% energy from saturated fat and 3% energy from polyunsaturated fat) and a high polyunsaturated fat diet (providing 11% energy as saturated fat and 10% energy as polyunsaturated fat), each phase continuing for 4 weeks. Extensive genotyping and several measures of dietary compliance have provided further insights regarding the determinants of extent of cholesterol response to changes in the nature of dietary fat. Individuals with the CETP B1B1 genotype and the LPL X447+ allele showed an average 0. 44 (95% CI: 0.22, 0.66) and 0.45 (95% CI: 0.18, 0.72) mmol/l greater change in total cholesterol, respectively, than those with one or more CETP B2 allele or homozygous for the LPL S447 allele when comparing diets high and low in saturated fat. Indices of dietary compliance including changes in reported saturated and polyunsaturated fat intake and change in triglyceride linoleate were not significantly different between the CETP genotypes. Change in reported saturated (r=0.36, P=0.04) and polyunsaturated (r=0.22, P=0. 05) fat intake and change in triglyceride linoleate (reflecting polyunsaturated fat intake) (r=0.21, P=0.07), also predicted total cholesterol response to dietary fat changes. In multivariate analyses, variation in the cholesterol ester transfer protein and lipoprotein lipase genes predicted response independent of measures of dietary compliance, suggesting that these two genes are important determinants of variation in cholesterol response to dietary change in free-living individuals.

Adult↗
PubMed2000

Effect of microsomal triglyceride transfer protein gene variants (-493G > T, Q95H and H297Q) on plasma lipid levels in healthy middle-aged UK men.

Microsomal triglyceride transfer protein (MTP) plays a central role in the synthesis of lipoproteins by shuttling lipids between phospholipid membranes to apoB. We have examined the effect of three MTP gene variants, -493G > T, Q95H and H297Q, in 2831 healthy UK middle-aged men. The rare allele frequencies were: 0.25 (95% CI 0.24-0.26) for -493T, 0.054 (95% CI 0.05-0.06) for 95H and 0.32 (95% CI 0.31-0.33) for 297Q. The three variants were in strong allelic association in all pairwise combinations (p < 0.001). None of the variant sites were associated with significant differences in cholesterol, triglyceride, apoB or apoAI levels. When stratified by tertiles of triglycerides for the H297Q variant alone there was a significant effect on apoB levels in men in the top tertile (p = 0.01). Considering the -493G > T and H297Q genotype in combination on baseline levels, individuals with three or four rare alleles had 6.6% higher mean apoB levels compared to the rest (p = 0.007). Therefore, homozygosity for 297Q at higher triglyceride (Tg) levels, or in combination with -493G > T, is associated with a raising effect on apoB levels, suggesting the importance of modest differences in MTP activity in determining hepatic secretion of lipoproteins in healthy men.

Alleles↗
PubMed2000

Lack of association between lipaemia and central adiposity in subjects with an atherogenic lipoprotein phenotype (ALP).

OBJECTIVE: To investigate the associations between indices of adiposity and cardiovascular risk factors in individuals with an atherogenic lipoprotein phenotype (ALP). SUBJECTS: Fifty-five men, aged 34-69 y, body mass index (BMI) 22-35 kg/m2, with an ALP lipid profile (triglycerides (TG) 1.5-4.0 mmol/l, HDL<1.1 mmol/l; %LDL-3>40% total LDL). DESIGN: Each participant provided a fasting blood sample and underwent an 8 h postprandial assessment and had anthropometric measurements taken. OUTCOME MEASURES: BMI, waist circumference (W), waist-to-hip ratio (W/H), sum of skinfolds (SSK), fasting and postprandial concentrations of glucose, insulin and plasma lipids, post-heparin lipase activity, and apoE genotype. RESULTS: The expected positive associations between BMI, W and SSK and fasting and postprandial insulin were observed (r=0.42-0.65). Little association between glucose responses and any measures of adiposity was evident. Unexpectedly, there were no positive associations between measures of central adiposity (W and W/H) and fasting and postprandial TG responses, with a trend towards negative associations in this study group (TG AUC vs W, r=-0.23, P=0.097; TG IAUC vs W/H, r=-0.26, P=0.068). Subgroup analysis indicated that lack of a positive association between central adiposity and postprandial TG values was more evident in those with one E4 allele (r=-0.42, P=0.077) relative to non-E4 carriers (r=-0.16, P=0.430). The expected positive associations between insulin and TG responses were not observed (r=-0.03 to -0.36). CONCLUSION: In this ALP group the expected positive association between TG responses and a centralized distribution of body fat was not observed, particularly in individuals with an apoE4 genotype. Our findings are not in line with the view that there is a clear causal relationship between insulin resistance and the lipid abnormalities associated with ALP.

Abdomen↗
PubMed2000

In-vivo and in-vitro nutrient-gene interactions.

Association studies of gene variants and response to dietary challenges represent one way of investigating gene-nutrient interactions. Several studies reported in the present review concentrate on evaluating variation at the apolipoprotein AI-CIII-AIV and apolipoprotein E gene loci, as well as the fatty acid binding protein gene. In addition, the effect of nutrients can be directly evaluated at the level of gene expression, and reports of in-vitro studies of control of fatty acid and triglycerides synthesis are discussed in the present review.

Animals↗