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P J Talmud

Publications and source records attributed to P J Talmud.

At least 19 recordsLinked to original sources
PubMed2006

The apolipoprotein A-V genotype and plasma apolipoprotein A-V and triglyceride levels: prospective risk of type 2 diabetes. Results from the Northwick Park Heart Study II.

AIMS/HYPOTHESIS: We sought to establish the relationship between plasma apolipoprotein A-V (APOA5, previously known as apoA-V) and triglyceride levels and to determine the impact of the APOA5 genotype on APOA5 levels and development of type 2 diabetes in a 15-year follow-up study of healthy UK men. MATERIALS AND METHODS: APOA5 -1131T>C and S19W genotypes were determined in 2,490 men, of whom 145 subsequently developed type 2 diabetes. In a subset of 299 men, we also determined APOA5 levels. RESULTS: Plasma APOA5 levels positively correlated with triglycerides (r=0.18, p<0.002) and were not different in men who subsequently developed type 2 diabetes compared with healthy men (p=0.7). Carriers of either APOA5 W19 or -1131C had, as expected, higher plasma triglycerides. However, while W19 carriers had significantly higher APOA5 levels (p=0.0003), APOA5 levels were not associated with -1131T>C (p=0.63), reinforcing the idea that the reported -1131C association with triglycerides levels is due to linkage disequilibrium with variants in the APOC3 gene, and not due to the direct effect on APOA5 levels. Overall no effect of APOA5 -1131T>C or S19W was found on type 2 diabetes risk. CONCLUSIONS/INTERPRETATION: In contrast to animal studies, in man, plasma APOA5 positively correlates with plasma triglyceride levels. In prospective analysis, with the caveat that numbers were small, APOA5 genotypes do not appear to have an impact on risk of development of type 2 diabetes.

Apolipoprotein A-V↗
PubMed2006

Lp-PLA2 activity and PLA2G7 A379V genotype in patients with diabetes mellitus.

Lipoprotein associated phospholipase A2 (Lp-PLA2) modulates low-density lipoprotein (LDL) oxidation by hydrolysing oxidised phospholipids present on particle surfaces. We investigated whether Lp-PLA2 activity and PLA2G7 A379V genotype were related to mediators of atherosclerosis in a diabetic study. Plasma Lp-PLA2 activity (taken in men only) and A379V genotype were investigated with regards to metabolic syndrome (MS), UKPDS risk score, and oxidised LDL (oxLDL/LDL), in a cohort of Caucasian men and women (n=783, age 62.5+/-13.7 years). After adjustment for type of diabetes, CHD status, and statin use, those individuals with features defining the MS (WHO guidelines) had higher Lp-PLA2 activity (35.6+/-11.9 nmol/min/ml) compared to those without (33.0+/-10.8 nmol/min/ml) (p=0.02). Quartiles of UKPDS coronary heart disease (CHD) risk score were also positively associated with Lp-PLA2 activity (p=0.006, p=0.004 linear trend). Those men in the highest quartile of oxLDL/LDL level had the lowest Lp-PLA2 activity (31.3+/-10.5 nmol/min/ml) when compared to the middle two (32.3+/-9.8 and 35.9+/-10.9 nmol/min/ml, respectively) and lowest quartile (35.6 +/-12.5 nmol/min/ml; p=0.03, p=0.004 linear trend). There was no significant association between A379V genotype and Lp-PLA2 enzyme activity (p=0.34) or oxLDL/LDL (p=0.32). Lp-PLA2 activity is an independent predictor of CHD risk and MS in a sample of subjects with diabetes mellitus. The association of Lp-PLA2 activity with oxLDL/LDL suggests that Lp-PLA2 may be a modulating factor in the process of atherosclerosis.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2006

Apo B versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-person/ten-country panel.

There is abundant evidence that the risk of atherosclerotic vascular disease is directly related to plasma cholesterol levels. Accordingly, all of the national and transnational screening and therapeutic guidelines are based on total or LDL cholesterol. This presumes that cholesterol is the most important lipoprotein-related proatherogenic risk variable. On the contrary, risk appears to be more directly related to the number of circulating atherogenic particles that contact and enter the arterial wall than to the measured concentration of cholesterol in these lipoprotein fractions. Each of the atherogenic lipoprotein particles contains a single molecule of apolipoprotein (apo) B and therefore the concentration of apo B provides a direct measure of the number of circulating atherogenic lipoproteins. Evidence from fundamental, epidemiological and clinical trial studies indicates that apo B is superior to any of the cholesterol indices to recognize those at increased risk of vascular disease and to judge the adequacy of lipid-lowering therapy. On the basis of this evidence, we believe that apo B should be included in all guidelines as an indicator of cardiovascular risk. In addition, the present target adopted by the Canadian guideline groups of an apo B <90 mg dL(-1) in high-risk patients should be reassessed in the light of the new clinical trial results and a new ultra-low target of <80 mg dL(-1) be considered. The evidence also indicates that the apo B/apo A-I ratio is superior to any of the conventional cholesterol ratios in patients without symptomatic vascular disease or diabetes to evaluate the lipoprotein-related risk of vascular disease.

Apolipoproteins B↗
PubMed2005

APOE polymorphism, socioeconomic status and cognitive function in mid-life--the Whitehall II longitudinal study.

OBJECTIVE: The aim of this study was to investigate the association of the common apolipoprotein E gene (APOE) variants with cognitive function and cognitive decline in adult mid-life and explore the possibility that APOE genotype mediates the link between socioeconomic status (SES) and cognitive function. METHODS: Data on cognitive function, as measured by five cognitive tests, together with APOE genotype were obtained in an occupational cohort (the Whitehall II study) of 6,004 participants aged 44-69 years (1997-1999). Cognitive change was examined in 2,717 participants who had cognitive function measured at baseline (1991-1993). RESULTS: SES based on civil service employment grade was strongly related to cognitive function. There was no association between APOE genotype and employment grade. In women, participants with APOE-epsilon4 had a lower memory score (p<0.05), but the result was sensitive to data from a small number of individuals. A marginal cross-sectional difference in the semantic fluency score was found (p=0.07), and there was a relative decline at follow-up (p<0.001, net change=-1.19; 95% CI, -1.90 to -0.49) in those with APOE-epsilon4 genotypes. CONCLUSIONS: APOE-epsilon4 has little influence on cognitive decline in mid-life, whereas SES is a strong determinant, although APOE genotype may emerge as an important factor in cognitive function in later life.

Adult↗
PubMed2005

Cholesteryl ester transfer protein TaqIB variant, high-density lipoprotein cholesterol levels, cardiovascular risk, and efficacy of pravastatin treatment: individual patient meta-analysis of 13,677 subjects.

BACKGROUND: Several studies have reported that the cholesteryl ester transfer protein (CETP) TaqIB gene polymorphism is associated with HDL cholesterol (HDL-C) levels and the risk of coronary artery disease (CAD), but the results are inconsistent. In addition, an interaction has been implicated between this genetic variant and pravastatin treatment, but this has not been confirmed. METHODS AND RESULTS: A meta-analysis was performed on individual patient data from 7 large, population-based studies (each >500 individuals) and 3 randomized, placebo-controlled, pravastatin trials. Linear and logistic regression models were used to assess the relation between TaqIB genotype and HDL-C levels and CAD risk. After adjustment for study, age, sex, smoking, body mass index (BMI), diabetes, LDL-C, use of alcohol, and prevalence of CAD, TaqIB genotype exhibited a highly significant association with HDL-C levels, such that B2B2 individuals had 0.11 mmol/L (0.10 to 0.12, P<0.0001) higher HDL-C levels than did B1B1 individuals. Second, after adjustment for study, sex, age, smoking, BMI, diabetes, systolic blood pressure, LDL-C, and use of alcohol, TaqIB genotype was significantly associated with the risk of CAD (odds ratio=0.78 [0.66 to 0.93]) in B2B2 individuals compared with B1B1 individuals (P for linearity=0.008). Additional adjustment for HDL-C levels rendered a loss of statistical significance (P=0.4). Last, no pharmacogenetic interaction between TaqIB genotype and pravastatin treatment could be demonstrated. CONCLUSIONS: The CETP TaqIB variant is firmly associated with HDL-C plasma levels and as a result, with the risk of CAD. Importantly, this CETP variant does not influence the response to pravastatin therapy.

Cardiovascular Diseases↗
PubMed2005

The significant increase in cardiovascular disease risk in APOEepsilon4 carriers is evident only in men who smoke: potential relationship between reduced antioxidant status and ApoE4.

Data from 1668 men (316 cardiovascular disease events) from the Framingham Offspring Study was reanalysed, specifically examining APOE:smoking interactions. Overall hazard ratio (HR) for smoking was 1.95 (1.52, 2.50) compared to non-smokers. Using epsilon3/3 as a referent group, in non-smokers HRs for epsilon2 carriers (epsilon2+; 1.04 (0.61, 1.76) and epsilon4 carriers (epsilon4+; 1.04 (0.70, 1.54) showed no major risk increase. In smokers, HRs were 1.96 (1.26, 2.78) in epsilon3epsilon3 men, 3.46 (2.14, 5.60; p = 0.09 for interaction) in epsilon2+ and 3.81 (2.49, 5.84; p = 0.01 for interaction), with a significant interaction between daily cigarette consumption and APOE genotype on risk (p = 0.03). The potential mechanism for this APOEepsilon4:smoking interaction was examined in a second study of 728 Caucasian patients with diabetes, where markers of reactive oxygen species were available. APOE genotype was not associated with plasma OX-LDL or total antioxidant status (TAOS) in non-smokers. However, in smokers epsilon4+ had 26.7% higher plasma OX-LDL than other genotypes (APOE:smoking interaction p = 0.04), while epsilon2+ had 28.4% higher plasma TAOS than epsilon3epsilon3 and epsilon4+ combined (APOE:smoking interaction p = 0.026). Although direct extrapolation needs to be considered with caution, these results identify that the cardiovascular disease risk-raising effect of epsilon4+ is confined to smokers, and a feasible mechanism is presented by the reduced antioxidant capacity/increased OX-LDL of apoE4.

Adult↗
PubMed2004

Heritability of C-reactive protein and association with apolipoprotein E genotypes in Japanese Americans.

Numerous studies have demonstrated that increased C-reactive protein (CRP) levels predict coronary heart disease, stroke, peripheral vascular disease, and diabetes, and are associated with features of the metabolic syndrome. Only three previous studies have investigated the heritability of CRP levels, primarily in samples of Caucasian families. The purpose of the present study was to estimate the magnitude of genetic influences on CRP levels, and to examine potential associations between variation in the APOE gene and CRP levels, using a sample of 562 individual Japanese Americans from 68 extended kindreds. In general, correlation coefficients between first-degree relatives for CRP were approximately 0.2, and spouse correlations did not differ from zero, consistent with genetic influences. Heritability estimates were approximately 0.3 (p < 0.01), even with adjustment for factors known to influence CRP levels. A significant relationship was seen between unadjusted CRP levels and APOE genotypes (p = 0.02), with the highest mean CRP level among epsilon2 carriers (1.20 mg/L), and nearly the same mean levels among epsilon3/epsilon3 subjects and epsilon4 carriers (0.72 and 0.74 mg/L, respectively). However, this relationship was diminished with adjustment for covariates (p = 0.07). These results demonstrate the presence of both genetic and environmental effects on CRP levels among Asian Americans, and additional studies are needed to determine if the APOE gene contributes to these genetic influences.

Adult↗
PubMed2003

Variants in the APOC3 promoter insulin responsive element modulate insulin secretion and lipids in middle-aged men.

Variation in the insulin responsive element (IRE) of the APOC3 promoter has been shown to be associated with insulin and glucose concentrations after an oral glucose tolerance test (OGTT) in young healthy men. We evaluated two variants in the IRE (-455T>C and -482C>T) in the Ely study, a prospective cohort study of middle-aged men (n=223) and women (n=279), to determine if the effect of these variants on glucose homeostasis could be explained by altered nonesterified fatty acid (NEFA) levels and if these effects are modulated by age and gender. Both variants had significant effects on the 30-min insulin incremental response in men alone (-482C>T, P=0.007; -455T>C, P=0.0155), with rare allele homozygotes having a 33.3% and 23.3% lower insulin increment as compared to common allele homozygotes, respectively. Thirty-minute NEFA concentrations were also significantly associated with genotype in men and levels were approximately 10% higher in carriers homozygous for the rare alleles as compared to subjects homozygous for the common alleles (-482C>T, P=0.04; -455T>C, P=0.006). In addition, there was a strong interaction between both variants and cigarette smoking affecting fasting triglyceride levels in both men (interaction: -455T>C, P=0.02; -482C>T, P=0.008) and women (interaction: -455T>C, P=0.007; -482C>T, P=0.013). Taken together, the data shows that men who carry the rare alleles of the IRE variants have disturbed glucose homeostasis and an unfavourable lipid phenotype. The finding of an elevated 30-min NEFA may be an important mechanistic link between triglyceride-rich lipoprotein (TRL) metabolism and glucose homeostasis.

Apolipoprotein C-III↗
PubMed2003

Family history is a coronary heart disease risk factor in the Second Northwick Park Heart Study.

We have estimated the risk of coronary heart disease (CHD) from family history of CHD (FHCHD) in 2827 healthy European middle-aged men, and explored the extent to which this can be explained by classical and genetic risk factors. Men with FHCHD (obtained by questionnaire) had a hazard ratio of CHD of 1.73 (95% confidence interval: 1.30, 2.31) compared to those without FHCHD; after adjusting for classical risk factors this did not change substantially. Those with FHCHD had 2.3% lower Factor VIIc (p = 0.03) and 1.14% higher systolic and 1.21% higher diastolic blood pressure (p = 0.04 and p = 0.02), with evidence of interaction between blood pressure and FHCHD status on risk (p = 0.01). The risk for those with a positive family history who were also current smokers was 3.01 compared to non-smokers without FHCHD, which is greater than the risk posed by smoking or FHCHD alone (1.96 and 2.05 respectively compared to non-smokers without FHCHD), but not significantly different from a multiplicative model (p-value for interaction 0.33). Allele frequencies for 13 candidate gene variants were not significantly different between those with and without FHCHD. In those with FHCHD, current smokers who carried the APOE4 allele (e4+) had a hazard ratio of 5.66 compared to non-smokers who had no FHCHD and were not APOE4+, with a significant interaction between smoking and APOE4 in those with FHCHD p = 0.001. These data demonstrate the complex interaction between genetic and environmental factors in determining CHD risk, and suggest that the causes of the familial clustering of CHD remain largely unexplained.

Adult↗
PubMed2002

Genetic and environmental determinants of plasma high density lipoprotein cholesterol and apolipoprotein AI concentrations in healthy middle-aged men.

The effects of common variants of cholesteryl ester transfer protein (CETP) (TaqIB), hepatic lipase (HL) (-514C>T), lipoprotein lipase (LPL) (S447X) and lecithin cholesterol acyl transferase (LCAT) (S208T) on the determination of high density lipoprotein cholesterol (HDL-C) and apolipoprotein AI (apoAI) levels were examined in 2773 healthy middle-aged men participating in the second Northwick Park Heart Study. The extent of gene:gene, gene:smoking and gene:alcohol interactions were determined. For HDL-C levels, only CETP genotype was associated with significant effects (p&0.0001), with the B2 allele being associated with higher levels in both smokers and non-smokers. This interaction was significant at the lowest tertile of TG, suggesting that TG levels were rate limiting. As previously reported, CETP, LPL and HL genotypes were all associated with significant effects on apoAI levels (all p&0.01), with carriers of the rare alleles having higher levels and with no evidence of heterogeneity of effects in smokers and non-smokers. LCAT genotype was not associated with significant effects on either trait. There was no significant interaction between any of the genotypes and alcohol consumption on either HDL-C or apoAI levels. All genotypic effects were additive for HDL-C and apoAI. Environmental and TG levels explained more than 20% and 5.5% of the variance in HDL-C and apoAI, respectively. The novel aspect of this finding is that genetic variation at these loci explained in total only 2.5% of the variance in HDL-C and 1.89% of the variance in apoAI levels. Thus despite the key roles played by these enzymes in HDL metabolism, variation at these loci, at least as detected by these common genotypes, contributes minimally to the variance in HDL-C and apoAI levels in healthy men, highlighting the polygenic and multifactorial control of HDL-C.

Alcohol Drinking↗
PubMed2002

Lipid-interacting properties of the N-terminal domain of human apolipoprotein C-III.

The lipid-interacting properties of the N-terminal domain of human apolipoprotein C-III (apo C-III) were investigated. By molecular modeling, we predicted that the 6-20 fragment of apo C-III is obliquely orientated at the lipid/water interface owing to an asymmetric distribution of the hydrophobic residues when helical. This is characteristic of 'tilted peptides' originally discovered in viral fusion proteins and later in various proteins including some involved in lipoprotein metabolism. Since most tilted peptides were shown to induce liposome fusion in vitro, the fusogenic capacity of the 6-20 fragment of apo C-III was tested on unilamellar liposomes and compared with the well characterized SIV fusion peptide. Mutants were designed by molecular modeling to assess the role of the hydrophobicity gradient in the fusion. FTIR spectroscopy confirmed the predominantly helical conformation of the peptides in TFE solution and also in lipid-peptide complexes. Lipid-mixing experiments showed that the apo C-III (6-20) peptide is able to increase the fluorescence of a lipophilic fluorescent probe. The vesicle fusion was confirmed by core-mixing and leakage assays. The hydrophobicity gradient plays a key role in the fusion process because the mutant with no hydrophobic asymmetry but the same mean hydrophobicity as the wild type does not induce significant lipid fusion. The apo C-III (6-20) fragment is, however, less fusogenic than the SIV peptide, in agreement with their respective mean hydrophobicity. Since lipid fusion should not be the physiological function of the N-terminal domain of apo CIII, we suggest that its peculiar distribution of hydrophobic residues is important for the lipid-binding properties of apo C-III and should be involved in apolipoprotein and lipid exchanges crucial for triglyceride metabolism.

Apolipoprotein C-III↗
PubMed2002

Loci for CETP, LPL, LIPC, and APOC3 affect plasma lipoprotein size and sub-population distribution in Hispanic and non-Hispanic white subjects: the Columbia University BioMarkers Study.

BACKGROUND AND AIM: The effect of genetic variation on plasma lipoproteins and their subfraction distribution was examined. METHODS AND RESULTS: Forty Hispanic men and 223 women and 42 non-Hispanic white men and 53 women participated in the study. Genotypes for cholesteryl ester transfer protein (CETP TaqIB), hepatic lipase (LIPC -480 C > T), lipoprotein lipase (LPL S447X), and apolipoprotein CIII (APOC3--455T > C) were determined by polymerase chain reaction. Lipoprotein particle size distribution was determined by nuclear magnetic resonance. For all but APOC3, genotype effects were homogeneous in the ethnic/racial groups and men and women. Effects were seen primarily in the women. Compared to women carriers of the common CETP B1 allele, B2B2 women had significantly higher plasma levels of high-density lipoprotein cholesterol (HDL-C) (16.4.0%, p = 0.001), reflected in the level of larger HDL particles (21.9%, p = 0.001), and larger mean particle size of HDL (2.3%, p = 0.01) and low-density lipoproteins (LDL) (1.3%, p = 0.02). Compared to LPL 447S homozygous women carriers of the LPL 447X allele had significantly lower levels of very-low-density lipoprotein-triglyceride (VLDL-TG) (21.0%, p = 0.02). For APOC3, there was significant gender:genotype interaction with the genotype differences seen only in the men. Compared to men homozygous for the -455T allele, carriers of -455C had higher levels of VLDL-TG (71.4%, p = 0.0001), reflected in a larger mean VLDL particle size (13.7%, p = 0.009). LIPC genotype was not associated with significant effects on any of these traits. CONCLUSION: These data confirm the role of genetic variants of CETP, LPL and APOC3 in determining the relationship between VLDL, LDL and HDL particles.

Adult↗
PubMed2002

Association of the hormone sensitive lipase -60C > G variant with fasting insulin levels in healthy young men.

BACKGROUND AND AIM: Hormone sensitive lipase (HSL) is the rate-limiting enzyme in triglyceride intracellular lipolysis, generating free fatty acids for energy utilisation. HSL is also expressed in pancreatic beta-cells where its activity may affect insulin secretion. We previously identified an HSL promoter variant, -60C > G, which in vitro exhibits 40% reduced promoter activity. METHODS AND RESULTS: In this study we examined the association of the HSL -60C > G on fasting lipid, insulin and glucose levels and the response to an oral fat tolerance test and an oral glucose tolerance test in 744 healthy young men participating in the second European Atherosclerosis Study. There was no case control difference in frequency of the rare -60G allele, however there was a North-to-South gradient in the frequency of the -60G allele, ranging from 0.037 (95% CI 0.01-0.07) in the Baltic regions to 0.087 (95% CI 0.05-0.12) in the South of Europe. When the group was analysed as a whole, there was no significant difference in fasting lipid or glucose values, body mass index, waist/hip ratio or blood pressure and no significant heterogeneity between cases and controls. There was, however, a significant association with fasting insulin measures [-60CC (n = 608) 11.95 mU/L vs -60 CG + GG (n = 79) 10.62 mU/L p = 0.01] and with the homeostasis model assessment of insulin resistance (HOMA-IR) (p = 0.04) and the homeostatic assessment of beta-cells function (HOMA-B); (p = 0.008). CONCLUSION: Even in these healthy young men, HSL-60 C > G allele was associated with effects on fasting insulin measures, and differences in insulin resistance and beta-cells function.

Adolescent↗
PubMed2001

Variation in the promoter of the human hormone sensitive lipase gene shows gender specific effects on insulin and lipid levels: results from the Ely study.

We previously identified a hormone sensitive lipase (HSL) promoter variant, -60C>G, which in vitro exhibits 40% reduced promoter activity. In this study we examined the effect of the -60C>G on glycemic and lipid measures in the population based Ely study of metabolic function and insulin resistance in 218 middle-aged men and 276 middle-aged women. Adipose tissue HSL is the rate-limiting step in triglyceride lipolysis, generating free fatty acids for energy utilization. HSL is also expressed in pancreatic beta-cells where its activity therefore may affect insulin secretion. In the women, carriers of the HSL -60G allele had significantly lower fasting insulin levels (P=0.0005) and a lower total area under the curve for insulin during the oral glucose tolerance test (P=0.005). There was no demonstrable association in men with these measures of insulin sensitivity but carriers of the -60G allele had significantly lower fasting non-esterified fatty acid (NEFA) levels (P=0.025) and higher low density lipoprotein cholesterol levels (P=0.02) than men who were non-carriers. This study provides additional evidence for a role for HSL in the development of insulin resistance, from which carriers of the -60G allele, associated here with markers of insulin sensitivity in women, and with lower NEFA levels in men, might be protected.

Diabetes Mellitus, Type 2↗
PubMed2001

Apolipoprotein E4 and coronary heart disease in middle-aged men who smoke: a prospective study.

BACKGROUND: The common isoforms of apolipoprotein E (apoE), E2, E3, and E4, are important determinants of plasma lipid concentrations, and the epsilon4 allele is associated with raised risk of coronary heart disease. We investigated whether the effect of smoking on coronary heart disease risk is affected by APOE genotype. METHODS: We enrolled 3052 middle-aged men who were free of coronary heart disease for prospective cardiovascular surveillance in the second Northwick Park Heart Study (NPHSII). Smoking habit was ascertained at baseline and yearly by questionnaire. APOE genotype was identified by PCR and restriction enzyme digestion. Endpoints were fatal coronary heart disease, non-fatal myocardial infarction, and coronary artery surgery and silent myocardial infarction at follow-up. FINDINGS: During 18836 person years of surveillance, 96 men had an acute myocardial infarction, 26 needed coronary artery surgery, and 14 had silent myocardial infarctions. Compared with never-smokers, risk of coronary heart disease in ex-smokers was 1.34 (95% CI 0.86-2.08) and in smokers it was 1.94 (1.25-3.01). This risk was independent of other classic risk factors. In never-smokers, risk was closely similar in men with different genotypes. Risk in men homozygous for the epsilon3 allele was 1.74 (1.10-2.77) in ex-smokers and 1.68 (1.01-2.83) in smokers, whereas in men carrying the epsilon4 allele risk was 0.84 (0.40-1.75) and 3.17 (1.82-5.50), respectively, with no significant differences in risk in the epsilon2 carriers. For the epsilon3 group, the genotype effect on risk was no longer significant after adjustment for classic risk factors (including plasma lipids). However, even after adjustment, smokers who were carriers of the epsilon4 allele, showed significantly raised risk of coronary heart disease compared with the non-smoking group (2.79, 1.59-4.91, epsilon4-smoking interaction p=0.007). INTERPRETATION: Smoking increases the risk of coronary heart disease in men of all genotypes but particularly in men carrying the epsilon4 allele.

Apolipoprotein E4↗
PubMed2001

Variation in the human ApoB signal peptide modulates ApoB17 translocation.

The functional effects of the common 27- or 24-amino-acid (aa) variants in the human apoB signal peptide (SP) on intracellular and secreted apoB17 were investigated in vitro. Only in the presence of oleate was a significant difference in intracellular and secreted SP27-B17 compared to SP24-B17 observed (P = 0.01 and P < 0.0007, respectively), although in the presence or absence of oleate mRNA levels from the two constructs were similar. After fractionation, oleate treatment enhanced microsomal SP27-B17 by 150% (P < 0.0005) with a modest but significant effect on SP24-B17 (32% P = 0.007). Oleate stimulated SP24-B17 accumulation in the nonmicrosomal fraction. The data suggest that the presence of oleate leads to inefficient translocation of the 24-amino-acid signal peptide, possibly resulting in increased retrograde translocation into the cytoplasm and reduced intracellular and secreted levels compared to the "wildtype" 27 aa SP. This implies a direct role of the SP variants in the regulation of apoB intracellular metabolism.

Animals↗
PubMed2001

Variable effects of the APOC3-482C > T variant on insulin, glucose and triglyceride concentrations in different ethnic groups.

AIMS/HYPOTHESIS: The apolipoprotein C3-482C> T variant modulates insulin and glucose concentrations after an oral glucose tolerance test (OGTT) in young healthy white men. We evaluated the effect of this variant in different ethnic groups with different rates of Type II (non-insulin-dependent) diabetes mellitus and coronary heart disease. METHODS: We investigated the -482C > T in a population-based cross-sectional study of white subjects (n = 462), South Asians (n = 442) and subjects of West African and Afro-Caribbean origin (n = 462), whose OGTT and fasting plasma triglyceride concentrations had been measured. RESULTS: The -482T allele frequency differed between the three groups: 0.25 (95 % CI 0.22-0.28) in white subjects, 0.44 (0.41-0.47) in South Asians and 0.71 (0.68-0.74) in black subjects (p < 0.0001). A positive association was found between body mass index and genotype in black women (p = 0.009) and in black men (p = 0.056) but not in white subjects or South Asians. Associations between -482C > T and fasting insulin were found in white subjects, where -482T allele carriers had higher concentrations (adjusted for age and sex, p = 0.007, also including smoking and body mass index, p = 0.038). Higher triglyceride concentrations (p = 0.004 and p = 0.007 in the two models) but not glucose concentrations were also associated with -482C > T. In black subjects, decreased fasting insulin (p = 0.04) and fasting glucose (p = 0.004) were associated with -482C > T. No relation was observed between genotype and any post-load measured. CONCLUSIONS/INTERPRETATION. Allele frequencies of the -482C > T and associations with insulin, glucose and triglyceride concentrations vary considerably among ethnic groups. Although the results are consistent among white subjects across different studies, the associations among black subjects and South Asians differ.

Adult↗