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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. Show less

The contribution of 17 polymorphisms within 13 candidate genes on lipid trait variability was investigated by a multiplex assay in 772 men and 780 women coming for a health checkup examination. The studied genes were APOE, APOB, APOC3, CETP, LPL, PON, MTHFR, FGB, GpIIIa, SELE, ACE, and AGT. We found that APOB-Thr71Ile, APOE-(112/158), APOC3-1100C/T, and SELE-98G/T polymorphisms had a significant effect on lipid traits (P < or = 0.001 to P < or = 0.01). Genetic effects accounted for 3.5-5.7% of variation in apolipoprotein B (apoB)-related traits among men, and for 5.7-9.0% among women. The contribution of APOE polymorphism on apoB-related traits variability was two to three times more important in women than in men. We found suggestive evidence for interactive effects between genetics and age, smoking status, and oral contraceptives. Increase of LDL-cholesterol and apoB concentrations with age was stronger among the epsilon4 carriers in women, and apolipoprotein A-I (apoA-I) concentration decreased with age in epsilon4 male carriers. The effect of epsilon2 allele on LDL-cholesterol was more important in the oral contraceptive users. In nonsmokers only, the APOC3-1100C allele in women was related to lower apoB-related traits concentrations, and in men to higher apoA-I and HDL-cholesterol concentrations. In conclusion, this work, in addition to the reinforcement of the already known associations between APOB, APOE, and APOC3 genes and lipids, leads to new perspectives in the complex relationships among genes and environmental factors. The newly observed relationships between E-selectine gene and lipid concentrations support the hypotheses of multiple metabolic pathways contributing to the complexity of lipids variability. Show less

Potential mechanisms accounting for the high cardiovascular death rates observed in Asian-Indians are dyslipidemia and insulin resistance. Polymorphisms in the APOC3 promoter (-455 T/C and -482 C/T) were frequently encountered in young Asian-Indians and they correlated with reduced concentrations of apolipoprotein A-I. Show less

Previous studies with hypertriglyceridemic APOC3 transgenic mice have suggested that apolipoprotein C-III (apoC-III) may inhibit either the apoE-mediated hepatic uptake of TG-rich lipoproteins and/or the lipoprotein lipase (LPL)-mediated hydrolysis of TG. Accordingly, apoC3 knockout (apoC3(-/-)) mice are hypotriglyceridemic. In the present study, we attempted to elucidate the mechanism(s) underlying these phenomena by intercrossing apoC3(-/-) mice with apoE(-/-) mice to study the effects of apoC-III deficiency against a hyperlipidemic background. Similar to apoE(+/+) apoC3(-/-) mice, apoE(-/-)apoC3(-/-) mice exhibited a marked reduction in VLDL cholesterol and TG, indicating that the mechanism(s) by which apoC-III deficiency exerts its lipid-lowering effect act independent of apoE. On both backgrounds, apoC3(-/-) mice showed normal intestinal lipid absorption and hepatic VLDL TG secretion. However, turnover studies showed that TG-labeled emulsion particles were cleared much more rapidly in apoC3(-/-) mice, whereas the clearance of VLDL apoB, as a marker for whole particle uptake by the liver, was not affected. Furthermore, it was shown that cholesteryl oleate-labeled particles were also cleared faster in apoC3(-/-) mice. Thus the mechanisms underlying the hypolipidemia in apoC3(-/-) mice involve both a more efficient hydrolysis of VLDL TG as well as an enhanced selective clearance of VLDL cholesteryl esters from plasma. In summary, our studies of apoC3(-/-) mice support the concept that apoC-III is an effective inhibitor of VLDL TG hydrolysis and reveal a potential regulating role for apoC-III with respect to the selective uptake of cholesteryl esters. Show less

The purpose of this study was to examine the relationship between carotid intima-media thickness (CIMT) interindividual variability and 16 polymorphisms of 11 genes associated with cardiovascular risk factors (genes among lipid and homocysteine metabolisms, blood viscosity, platelet aggregation, leukocyte adhesion and renin-angiotensin system). CIMT was measured by high resolution B mode ultrasonography in an healthy population of 77 men and 84 women, aged 35-54 years and selected from a French cohort: the Stanislas cohort. The polymorphisms studied were genotyped by a multilocus approach. Statistical analysis were done by ANOVA after adjustment of CIMT for age, BMI and smoking and by multiple regression analyses. No association was found with APOB Thr71 Ile, APOC3 -482C/T, -455T/C, GpIIIa P1A, AT1R 1166A/C, AGT Met235Thr, CBS Ile278Thr, SELE 98G/T and SELE Ser128Arg, polymorphism neither in men nor in women. Although, in women we found always no association for the APOC3 3206T/G, 3175C/G, 1100C/T, the CETP Ile405Val, the MTHFR 677C/T and the fibrinogen -455G/A polymorphism's, in men these polymorphism's were associated with CIMT variability (0.01 < or = p < or = 0.05). The most interesting finding was that altogether these genes in men were able to explain a considerable part, 20.6%, of CIMT variability. Therefore, our study gives a new opportunity to understand CIMT variability. Show less

To examine the genotype:phenotype association in children compared with their parents. 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. 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. 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. Show less

Trinidadians of South Asian origin have a high prevalence of cardiovascular disease and diabetes compared to Trinidadians of African origin. The degree to which these differences are related to genetic and/or environmental factors is unclear. To determine whether there might be a genetic basis for this difference in prevalence of deleterious phenotypes we examined allele frequencies for candidate genes in atherosclerosis and diabetes. We genotyped 81 consecutive neonates of African origin and 103 consecutive neonates of South Asian origin. We evaluated common polymorphisms in 11 candidate genes for atherosclerosis and diabetes. We found differences between the two subpopulations in the allele frequencies of several candidate genes, including APOE, LIPC, APOC3, PON1, PON2, and PPP1R3. However, the differences in the allele frequencies were not all consistent with the pattern of CHD expression between these two ethnic groups in adulthood. Thus, differences in genetic architecture alone may not explain the wide disparities in disease prevalence between these two subpopulations. It is very likely that environmental factors, or unmeasured genetic factors, influence the genetic susceptibility to disease in these subpopulations. Show less

Apolipoprotein (apo) CIII participates in the regulation of the metabolism of triglyceride-rich lipoproteins and it is a major component of chylomicrons and VLDL. The APOC3 gene is on chromosome 11q23 and is highly polymorphic. The less common allele (S2) of the SstI polymorphism on the 3' untranslated region of the APOC3 gene has been previously associated with increased triglycerides, total cholesterol (TC), and apoCIII levels and cardiovascular risk on several, but not all, studies. The aim of this study was to examine the association of this polymorphism with plasma lipid levels, lipoprotein subfractions and coronary heart disease (CHD) risk in a population-based study: The Framingham Offspring Study. The frequency of the S2 allele was 0.086, consistent with previous reports in Caucasian populations. In men, the S2 allele was associated with lower concentrations of high-density lipoprotein cholesterol (HDL-C; P<0.04) and HDL2-C (P<0.02) and a significant increase in apoCIII non-HDL (P<0.05). TG levels were higher in men carriers of the S2 allele, but this association did not reach statistical significance (P=0.30). Conversely, in women, the S2 allele was associated with increased TC (P<0.03), low-density lipoprotein cholesterol (LDL-C; P<0.03), and ApoB levels (P<0.04). Lipoproteins subfractions were also examined using nuclear magnetic resonance (NMR) spectroscopy. S2 male carriers had significantly lower concentrations of large LDL and a significant reduction in LDL particle size (P<0.04). In women, there was a significant increase in intermediate LDL particles (P<0.05) with no significant effect on lipoprotein diameters. We also examined the associations between the S2 allele and biochemical markers of glucose metabolism. In men, the S2 allele was associated with elevated fasting insulin concentrations (P<0.04), whereas no significant associations were observed in women. Despite the described associations with lipid and glucose metabolism related risk factors, we did not find any significant increase in CHD risk associated with the S2 allele in this population. Show less

The purpose of this study was to examine the relationship between carotid intima-media thickness (CIMT) inter-individual variability and 16 polymorphisms of 11 genes associated with cardiovascular risk factors (genes among lipid and homocysteine metabolisms, blood viscosity, platelet aggregation, leukocyte adhesion and renin-angiotensin system). CIMT was measured by high resolution B-mode ultrasonography in an healthy population of 77 men and 84 women, aged 35-54 years and selected from a French Cohort: the Stanislas Cohort. The polymorphisms studied were genotyped by a multilocus approach. Statistical analyses were carried out by ANOVA, after adjustment of CIMT for age, body mass index, and smoking, and by multiple regression analyses. No association was found with APOB Thr71Ile, APOC3 -482C/T, -455T/C, GpIIIa P1A, AT1R 1166A/C, AGT Met235Thr, CBS Ile278Thr, SELE 98G/T, and SELE Ser128Arg, polymorphisms neither in men nor in women. Although, in women we did not find any association for APOC3 3206T/G, 3175C/G, 1100C/T, CETP Ile405Val, MTHFR 677C/T and fibrinogen -455G/A polymorphisms; in men these polymorphisms were associated with CIMT variability (p< or =0.01; p< or =0.05). The most interesting finding was that altogether these genes in men were able to explain a considerable part, 20.6%, of CIMT variability. Therefore, our study gives a new opportunity to understand CIMT variability. Show less

A multilocus assay was used to genotype up to 27 variable sites in 15 genes in French and Italian, presumed to be healthy populations (n=1480, n=162, respectively). These genes are involved in lipid metabolism (APOE, APOB, APOC3, CETP, LPL, PON), homocysteine metabolism (CBS, MTHFR), blood viscosity (Fibrinogen, FV), platelet aggregation (GpIIIa), leukocyte adhesion (SELE), and renin-angiotensin system (AT1R, ACE, AGT). Allele frequencies for all the markers were compared between the two populations. Five allele frequencies differed between the two European countries: APOB 71Ile (p < 0.001), SELE 98T (p < 0.001), SELE 128Arg (p < or = 0.01), APOE E4 (p < or = 0.01) and MTHFR 677T (p < or = 0.01), suggesting the existence of a north-south gradient in European allele frequencies. The other allele frequencies : APOC3 -482T, -455C, 1100T, 3175G, 3206G; LPL -93G, 9Asn, 291Ser; CETP 405Val; PON 192Arg; ACE Del; AGT 235Thr; AT1R 1166C; CBS 278Thr, GpIIIa P1A2; Fibrinogen -455A, FV 506Gln and SELE 554Phe, were similar between the two populations. They were also similar to those observed in other European countries. Show less

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. In 131 men and 154 women, polymorphisms were investigated using PCR. In the same subjects plasma lipid levels and insulin were measured. 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. 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. Show less

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. Show less

Fourier-transform infrared (FT-IR) spectrometry has been used to measure small molecules in plasma. We wished to extend this use to measurement of plasma proteins. We analyzed plasma proteins, glucose, lactate, and urea in 49 blood samples from 35 healthy subjects and 14 patients. For determining the concentration of each biomolecule, the method used the following steps: (a) The biomolecule was sought for which the correlation between spectral range areas of plasma FT-IR spectra and concentrations determined by comparison method was greatest. (b) The IR absorption of the biomolecule at the most characteristic spectral range was calculated by analyzing pure samples of known concentrations. (c) The plasma concentration of the biomolecule was determined using the FT-IR absorption of the pure compound and the integration value obtained for the plasma FT-IR spectra. (d) The spectral contribution of the biomolecule was subtracted from the plasma FT-IR spectra, and the resulting spectra were saved for further analyses. (e) The same method was then applied to determining the concentrations of other biomolecules by sequentially comparing the resulting FT-IR spectra. Results agreed with those obtained by clinical methods for the following biomolecules when analyzed in the following order: albumin, glucose, fibrinogen, IgG(2), lactate, IgG(1), alpha(1)-antitrypsin, alpha(2)-macroglobulin, transferrin, apolipoprotein (Apo)-A(1), urea, Apo-B, IgM, Apo-C(3), IgA, IgG(4), IgG(3), IgD, haptoglobin, and alpha(1)-acid glycoprotein. FT-IR spectrometry is a useful tool for determining concentrations of several plasma biomolecules. Show less

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. 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. 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. Show less

We have identified a G-to-A transition in exon 3 of the APOC3 gene resulting in a novel Ala23Thr apolipoprotein (apo) C-III variant, associated with apoC-III deficiency in three unrelated Yucatan Indians. The Ala23Thr substitution modifies the hydrophobic/hydrophilic repartition of the helical N-terminal peptide and hence could disturb the lipid association. In vitro expression in Escherichia coli of wild-type and mutant apoC-III enabled the characterization of the variant. Compared with wild-type apoC-III-Ala23, the mutant apoC-III-Thr23 showed reduced affinity for dimyristoylphosphatidylcholine (DMPC) multilamellar vesicles with higher amounts of free apoC-III. Displacement of apoE from discoidal apoE:dipalmitoylphosphatidycholine (DPPC) complex by apoC-III-Thr23 was comparable to wild type but the less efficient binding of the apoC-III-Thr23 to the discoidal complex resulted in a higher apoE/apoC-III (mol/mol) ratio (34%) than with wild-type/apoE:DPPC mixtures. The inhibition of lipoprotein lipase (LPL) by apoC-III-Thr23 was comparable to that of wild type, and therefore effects on LPL activity could not explain the lower triglyceride (Tg) levels in Thr-23 carriers. Thus, these in vitro results suggest that in vivo the less efficient lipid binding of apoC-III-Thr23 might lead to a faster catabolism of free apoC-III, reflected in the reduced plasma apoC-III levels identified in Thr-23 carriers, and poorer competition with apoE, which might enhance clearance of Tg-rich lipoproteins and lower plasma Tg levels seen in Thr-23 carriers. Show less

Variation within and around the apolipoprotein C-III (APOC3) gene has been associated with elevated triglyceride (Tg) levels and cardiovascular disease. The associations of 4 polymorphic variants in the APOC3 gene (3238C>G in the 3' untranslated region [SST:I], 1100C>T in exon 3, -482C>T in the insulin-responsive element, and -2854T>G in the APOC3-A4 intergenic region) with plasma Tg and cholesterol levels and their interaction with smoking have been investigated in the Second Northwick Park Heart Study (NPHSII), a large cohort of healthy men (n=2745). Analyzing the variants separately showed that 3238G, 1100T, and -482T alleles were all associated with raised Tg levels. For the 3238C>G and -482C>T sites, the Tg-raising effect appeared to depend on smoking status (test for interaction, P:=0.042 and P:=0.009, respectively), but for the 1100C>T site, the effect was constant irrespective of smoking status (test for interaction, P:=0.27). The -2854T>G site was not associated with effects on Tg levels in this sample. Because all of the variants showed significant allelic association, regression modeling was used to quantify the relative size of each effect and to assess whether the effects of the separate variants were independent. The 1100C>T variant had an independent effect on Tg levels that was not influenced by smoking status (increase of 8.2% in Tg with each T1100 allele), whereas the -482C>T variant had a separate effect that was dependent on smoking (increase of 13.7% in Tg for each -482T allele in current smokers, 8.6% in exsmokers, and -7.4% in those who never smoked). The 3238C>G variant did not show a separate independent effect on Tg concentration. Thus, by use of the regression model, it was possible to estimate how mean Tg levels would vary in groups of individuals with respect to APOC3 genotype and smoking information. Analysis in this large group of healthy men has allowed the identification of a statistically robust APOC3 genotype-smoking interaction, which now warrants further molecular study. Show less

After more than a decade of study, investigators are grappling for a consensus regarding the relationship between variation in candidate genes and plasma triglyceride concentration. Certain variants of LPL--both rare variants, in the case of loss-of-function mutations in kindreds with chylomicronemia, and common variants, in the case of the D9N and N291S variants--appear to be fairly consistently associated with an elevated plasma triglyceride level. In addition, the variation of the recognition site for Sstl within the 3'-untranslated region of APOC3 has consistently shown an association with a variation in plasma triglycerides. The LPL and APOC3 variants thus have at least a chance in future clinical applications, but this will require more study. Common variants of some other promising candidate genes, such as HL, have not shown as consistent an association with the variation in plasma triglyceride level. Finally, studies of variants of newer candidates, such as the mitochondrial genome, LMNA, and IL-6, indicate that many different genes might be important determinants of plasma triglyceride concentration in the general population. As always, the associations of genes with a complex intermediate trait such as plasma triglyceride level depend upon interactions with modulatory factors such as genetic background and/or secondary genetic effects, in addition to the effects of gender, age, hormone replacement, and postprandial status. A key attribute for increasing confidence in the biologic or potential clinical validity of the associations of candidate gene variation with plasma triglyceride will be the development of assays that will provide a more direct mechanistic link between the genetic variant and the elevated plasma triglyceride. Show less

Remnant particles of triglyceride-rich lipoproteins (RLP) are known to be a strong predictor of atherogenicity. The serum concentrations of remnant-like particle triglyceride (RLPTG) and remnant-like particle cholesterol (RLPC) have been determined in a representative sample of the Czech MONICA study (n = 285). The relationship was investigated between remnant particle triglyceride/cholesterol concentrations and polymorphisms in the genes APOC3 (-482C-->T/3238C-->G), APOE (epsilon2/epsilon3/epsilon4), APOCI (-317-321ins), APOB (signal peptide), hepatic lipase (LIPE, -480C-->T), and lipoprotein lipase (LPL, S447X). Univariate analysis showed significant effects on RLPTG associated only with the APOE genotype (P = 0.009), the APOC3 -482C-->T genotype (P = 0.018), and the APOCI -317-321ins (P = 0.014) genotype and significant effects on RLPC with APOE (P = 0.01) and APOCI -317-321ins (P = 0.021). The raising effect of the APOE genotype for both remnant cholesterol and triglyceride was confined to the epsilon2/4 (n = 6) and varepsilon4/4 (n = 3) groups, and thus when the epsilon2/4 group was omitted in order to analyze by allele (epsilon2+/epsilon3+/epsilon4+), significance was lost (P = 0.6). There was strong linkage disequilibrium between the APOE and APOCI alleles (chi(2), P < 0.001) and a multivariate ANOVA of RLPTG with all three significantly associated variants as factors demonstrated that while the APOC3 -482C-->T effect was independent of the others (P = 0.003), the APOCI -317-321ins and APOE effects were not. This was also true for the APOCI -317-321ins and APOE effects on RLPC. To assess whether APOE-CI effects on RLPC were independent of their effects on total cholesterol and triglyceride levels, multiple linear regression was used. Using multiple linear regression, it appeared that the APOE-CI effects on RLPC were independent of their effects on plasma cholesterol, but the effects of APOC3 and APOE-CI on RLPTG could not be separated from their effects on plasma Tg levels. Further characterization of this remnant particle phenotype and its genetic determinants may lead to a better understanding of its metabolism and contribution to atherosclerosis. Show less

Studies in humans on the in vivo metabolism of apolipoprotein (apo) Cs have been hampered by the highly complex nature of lipoprotein metabolism, which can be influenced by multiple genetic and environmental factors. In order to gain new insights into the function of the individual apoCs in lipoprotein metabolism, several laboratories have created mouse models lacking or overexpressing the respective APOC genes through the technologies of gene targeting and transgenesis. Until now, the only well-established in vivo metabolic function of apoC-I has been its inhibitory action on the uptake of very low-density lipoprotein (VLDL) via hepatic receptors, particularly the low-density lipoprotein (LDL) receptor-related protein. Consequently, the presence of apoC-I on the lipoprotein particle may prolong its residence time in the circulation and subsequently facilitate its conversion to LDL. ApoC-II, on the other hand, is a major activator of lipoprotein lipase, which is required for an efficient processing of triglyceride-rich lipoproteins in the circulation. However, an excess of apoC-II on the lipoprotein particle has been suggested to inhibit the lipoprotein-lipase-mediated hydrolysis of triglycerides. From studies with APOC3 transgenic and ApoC3-knockout mice, it appears that apoC-III inhibits the lipolysis of triglyceride-rich lipoproteins by hampering the interaction of these lipoproteins with the heparan sulfate proteoglycan-lipoprotein lipase complex. Subsequently, the poorly lipolyzed apoC-III-containing lipoprotein particles may accumulate in plasma because of their lower binding affinity towards hepatic receptors due to a change in lipid composition, particle size or the presence of apoC-III on the particle itself. From these data it can thus be concluded that all C apolipoproteins specifically modulate the metabolism of triglyceride-rich lipoproteins, which may contribute to the development of hyperlipidemia and other lipoprotein abnormalities in humans. Show less

Genetic studies carried out mainly in European and European-derived populations have shown that common polymorphisms in genes coding for apolipoproteins are significant determinants of serum lipoprotein-lipid levels variation. However, except for a few sporadic studies, the distribution of apolipoprotein polymorphisms and their association with serum lipoprotein-lipid levels have not been evaluated systematically in African or African-derived populations. In this investigation we have studied five apolipoprotein polymorphisms, including APOA1/MspI-75 bp, APOA1/MspI+83 bp, APOC3/PvuII, APOE, and APOH in 786 Africans (493 men, 293 women) from Nigeria. The sample is comprised of Nigerian civil servants consisting of 462 junior staff (less affluent) and 324 senior staff (more affluent) where staff status is a correlate of their socioeconomic status. We first examined genetic associations in the total sample stratified by gender to determine the role of apolipoprotein polymorphisms in affecting serum lipid profile in the general population, and then by staff status to evaluate possible gene-environment interactions. In the total sample, the APOC3/PvuII polymorphism showed significant effect on HDL-cholesterol (P = 0.029) and HDL3-cholesterol (P = 0.009) in women, and the APOE polymorphism was significantly associated with total cholesterol (P = 0.031) and LDL-cholesterol (P = 0.0006) in women. Multiple regression analyses showed that the APOC3/PvuII polymorphism accounts for about 2 and 3% of the variation in HDL-cholesterol and HDL3-cholesterol, respectively, in women; while the APOE polymorphism accounted for about 5 and 6% of the variation in total- and LDL-cholesterol, respectively, in women. Whereas the association of the APOE polymorphism was independent of the staff status, the significant affect of the APOC3/PvuII polymorphism on HDL- and HDL3-cholesterol was confined to senior staff women where it explained about 7% of their variation. We also observed an interaction between staff and the APOH polymorphism in affecting cholesterol levels. The APOH polymorphism showed significant association with total cholesterol (P = 0.010) and LDL-cholesterol (P = 0.016) in senior staff women and explained about 7 and 5% of their phenotypic variations, respectively. These data indicate that gene-environment interaction may play an important role in affecting serum lipid profile in African populations. Show less

Karyotypic and molecular data indicate that genetic alterations of the long arm of chromosome 11 (11q) are involved in the pathogenesis of malignant melanoma as well as of other malignancies. We have shown previously, by analysis of loss of heterozygosity (LOH), that a tumor-suppressor gene playing an important role in malignant melanoma is likely to be located within a 51-cM region at 11q23. Its loss appeared to be a late event in tumor progression and an indicator of a less favorable clinical outcome. To further test this hypothesis on a larger set of tumors and to refine the region(s) of common allelic loss, we analyzed 21 polymorphic microsatellite repeats on 11q. A PCR-based assay for LOH was used to study normal and tumor tissues from 53 individuals with primary cutaneous malignant melanoma or metastatic disease. Our findings indicate that in cutaneous malignant melanoma there are at least 2 distinct regions of common allelic loss on 11q, one of them centered around marker APOC3 at 11q23.1-q23.2 delineated by markers D11S1347 and D11S4142 and spanning approximately 5 Mb and a second 3-Mb region around marker D11S925 at 11q23.3 delineated by markers D11S528 and D11S1345. Both regions have been described as deletion targets or as being included within larger allelic deletions detected in several other common tumor types. Thus, these 2 putative melanoma-suppressor loci are likely to harbor tumor-suppressor genes relevant to tumorigenesis of melanoma and a number of other common human malignancies. Show less

Structural chromosomal rearrangements occur commonly in the general population. Individuals that carry a balanced translocation are at risk of having unbalanced offspring; therefore, the frequency of translocations in couples with recurrent spontaneous abortions is higher than that in the general population. The constitutional t(11;22) translocation is the most common recurrent non-Robertsonian translocation in humans and may serve as a model to determine the mechanism that causes recurrent meiotic translocations. We previously localized the t(11;22) translocation breakpoint to a region on 22q11 within a low-copy repeat, termed "LCR22." To define the breakpoint on 11q23 and to ascertain whether this region shares homology with LCR22 sequences, we performed haplotype analysis on patients with der(22) syndrome. We found that the breakpoint on 11q23 occurred between two genetic markers, D11S1340 and APOC3-tetra, both being present within a single bacterial-artificial-chromosome clone. To determine whether the breakpoint occurred within the same region among a larger set of carriers, we performed FISH mapping studies. The breakpoints were all within the same clone, suggesting that this region may harbor sequences that are prone to breakage. We narrowed the breakpoint interval, in both derivative chromosomes from two unrelated carriers, to a 190-bp, AT-rich repeat, which indicates that this repeat may mediate recombination events on chromosome 11. Interestingly, the LCR22s harbor AT-rich repeats, suggesting that this sequence motif may mediate recombination events in nonhomologous chromosomes during meiosis. Show less

Chromosomal deletions at segment 11q23-q24 have been identified in a variety of human epithelial tumors, including cervical carcinoma (CC), indicating the presence in this region of at least a tumor suppressor gene (TSG) involved in the development of these neoplasms. To localize the 11q deletion target more precisely, 54 primary cervical carcinomas were examined for loss of heterozygosity (LOH) using a panel of microsatellite DNA markers mapping to 11p.15 and spanning region 11q23-qter. Nineteen tumors were found to have LOH at chromosome 11q. The highest frequency of LOH was observed at locus APOC-3, located in 11q23.1-q23.2, which was deleted in 42% of the informative cases. In contrast, LOH was infrequent at distal 11q in current series of CC. The smallest common region of loss included APOC-3 and was defined distally by marker D11S925 in region 11q23. The present data strongly suggest that the 11q suppressor gene(s) involved in cervical tumorigenesis is likely to be located at chromosome region 11q22-q23. Show less

High frequencies of loss of heterozygosity (LOH) in chromosome 11q22-qter have been observed in various malignancies, including breast cancer. Previous studies on breast carcinomas by Winqvist et al (Cancer Res 55: 2660-2664) have indicated that a survival factor gene is located in band 11q23, and that the highly informative microsatellite polymorphism at the APOC3 locus would be a suitable tool to perform more extensive LOH studies. In this European multicentre study, we have examined the occurrence of APOC3 LOH and evaluated the effect of LOH of this chromosomal subregion on the clinical behaviour of the disease in a cohort of 766 breast cancer patients in more detail. LOH for APOC3 was found in 42% of the studied tumours, but it was not found to be significantly associated with any of the studied clinical variables, including cancer-specific survival time or survival time after recurrent/metastatic disease. According to the present findings, the putative survival factor gene on 11q23 is not located close enough to the APOC3 gene, but apparently at a more proximal location. Show less

11q23-24 chromosome is a region containing frequent allelic loss (loss of heterozygosity; LOH) in human cancers. To examine cancer-related allelic loss in the region between D11S940 and APOC3, we used 17 polymorphic markers and allotyped 28 lung cancer-derived cell lines and their corresponding matched lymphoblastoid cell lines. LOH was found in 71.4% (20/28) of the lung cancer cell lines and was localized to two distinct minimal regions of loss. One region is bracketed by markers D11S1647 and NCAM2 and contains the gene encoding the beta isoform of the A subunit of the human protein phosphatase 2A (PPP2R1B). Recently, mutations in this gene were described in lung and colon cancers, suggesting that PPP2R1B functions as a tumor-suppressor gene. A second minimal region of loss was defined between markers D11S1792 and D11S1885, a region estimated to be less than I Mb. Thus, chromosome 11 likely harbors two sites of suppressor oncogene activity in lung cancer, one defined by the PPP2R1B gene and the second located telomeric to PPP2R1B. This study facilitates the identification and cloning of a second critical tumor-suppressor gene involved in lung cancer, and possibly a variety of other cancers, on human chromosome band 11q23. Show less

To investigate the metabolism of nascent HDLs, apoA1/phosphatidylcholine (apoA1/PC) discs were infused IV over 4 hours into 7 healthy men. Plasma total apoA1 and phospholipid (PL) concentrations increased during the infusions. The rise in plasma apoA1 was greatest in small prebeta-migrating particles not present in the infusate. Total HDL unesterified cholesterol (UC) also increased simultaneously. After stopping the infusion, the concentrations of apoA1, PL, HDL UC, and small prebeta HDLs decreased, whereas those of HDL cholesteryl ester (CE) and large alpha-migrating apoA1 containing HDLs increased. ApoB-containing lipoproteins became enriched in CEs. Addition of apoA1/PC discs to whole blood at 37 degrees C in vitro also generated small prebeta HDLs, but did not augment the transfer of UC from erythrocytes to plasma. We conclude that the disc infusions increased the intravascular production of small prebeta HDLs in vivo, and that this was associated with an increase in the efflux and esterification of UC derived from fixed tissues. The extent to which the increase in tissue cholesterol efflux was dependent on that in prebeta HDL production could not be determined. Infusion of discs also reduced the plasma apoB and apoA2 concentrations, and increased plasma triglycerides and apoC3. Thus, nascent HDL secretion may have a significant impact on prebeta HDL production, reverse cholesterol transport and lipoprotein metabolism in humans. Show less

Hypertriglyceridaemia is a common metabolic disorder frequently found in patients with coronary heart disease. Numerous studies have revealed an association between the SstI polymorphism in the APOC3 gene and increased plasma apoC3 and triglyceride levels. In addition, two different variants within the promoter region have been recently suggested to be the mutations of the APOC3 gene leading to hypertriglyceridaemia. In the present study, we have applied haplotype analysis to investigate whether these promoter polymorphisms are involved in the lipid disorders of patients with distinct types of hypertriglyceridaemia: combined hyperlipidaemia (CHL), familial dysbetalipoproteinaemia (FD) and endogenous hypertriglyceridaemia (HTG). The -482 and -455 polymorphisms were significantly more frequent in FD patients (P = 0. 017) and endogenous HTG patients (P < 0.0001) than in CHL patients and a control group. The SstI polymorphism was only significantly more frequent in HTG patients (P < 0.0001). However, we did not find differences in frequencies for these polymorphisms in the APOC3 gene between CHL patients and a control group. Haplotype analysis indicates that the SstI polymorphism arose on the allele containing both promoter polymorphisms. The haplotype containing the SstI polymorphism is found five times more frequently among HTG patients (OR 5.28, 95% CI 1.65-16.90), which strongly suggests it is associated with an increased risk for severe hypertriglyceridaemia. Show less

The knowledge of genetic factors determining the age at onset of diabetes may help to delay the development of diabetes and its complications. This prompted us to use our well-characterized BB/OK rat whose age at onset of diabetes can change from 50 to more than 400 days for crossing studies to search for loci cosegregating with the age at onset. Fifty-nine diabetic first backcross hybrids resulting from crosses between diabetic BB/OK and diabetes-resistant DA and SHR rats were genotyped with PCR-analyzed microsatellite markers located on 21 chromosomes. Loci on chromosomes 6 (Ighe -D6Mgh2) and 8 (D8Mit2- Apoc3) were linked with the age at onset. Hybrids which were homozygous for the BB alleles developed significantly earlier diabetes than hybrids which were heterozygous The difference between the age at onset of heterozygous and homozygous hybrids reached a maximum at the loci Ighe on chromosome 6 (+ 32 days, p = 0.0018) and D8Mit2 on chromosome 8 (+ 28 days, p = 0.007). Candidate genes around the loci linked with the age at onset of diabetes are involved in the humoral and cellular immune response. For the first time, this study provides evidence that genetic factors can affect the age at onset of diabetes in the rat. Show less

The S2 allele of the SstI polymorphism of the apolipoprotein (apo) C-III gene has been associated with elevated triacylglycerol concentrations, high blood pressure, and increased risk of coronary artery disease, all of which are characteristic of an insulin-resistant state. To study the effect of this mutation on carbohydrate metabolism in healthy persons, we gave 41 male subjects 3 consecutive diets. The first was rich in saturated fat [15% protein, 47% carbohydrate, 38% fat (20% saturated)], the second was a National Cholesterol Education Program Step 1 diet [15% protein, 57% carbohydrate, 28% fat (< 10% saturated)], and the last was rich in monounsaturated fat [15% protein, 47% carbohydrate, 38% fat (22% monounsaturated, < 10% saturated)]. At the end of each dietary period, subjects received an oral-glucose-tolerance test (OGTT). Apo C-III genotype significantly affected basal glucose concentrations (P < 0.045) and insulin concentrations after the OGTT (P < 0.012). APOC3*S1/APOC3*S2 subjects (n = 13) had higher insulin concentrations after the OGTT than APOC3*S1/APOC3*S1 subjects (n = 28) in the 3 periods (diet 1: P < 0.0004; diet 2: P < 0.01; diet 3: P < 0.008). Multiple regression analysis showed that this polymorphism predicted the insulin response to the OGTT (P < 0.031) and the difference between basal insulin concentrations and insulin concentrations after the OGTT (P < 0.002) with the saturated fat diet. In summary, our results suggest that the mutation in the apo C-III gene affects insulin response to an OGTT, which could result in reduced sensitivity to insulin, especially when persons consume diets rich in saturated fat. Show less