Apolipoprotein E polymorphism in the Tunisian population: frequency and effect on lipid parameters

OBJECTIVES: We determined the frequencies of apolipoprotein E (apo E) gene alleles and examined the association between apo E polymorphism and lipid parameters in a sample of the Tunisian population. DESIGN AND METHODS: Apo E polymorphism was investigated using PCR, and plasma lipid parameters were measured in 122 men and 111 women aged 35 to 87 years. RESULTS: The allele frequencies were epsilon2: 7.3%, epsilon3: 84.6%, and epsilon4: 8.1%. Apo E polymorphism was associated with significant differences (P<0.001) in total cholesterol, apo B and LDL cholesterol in both men and women. epsilon2 carriers had the lowest mean total cholesterol, apo B and LDL-C concentrations, and subjects with the epsilon4 allele had the highest levels. Triglycerides levels increased with the epsilon4 allele, but this did not reach statistical significance. These results remained unchanged after adjustment for age, body mass index, sex, hypertension, diabetes and smoking. However, in obese subjects (BMI>30 kg/m2), TG concentrations were significantly lower in individuals homozygous for the epsilon3 allele compared to those with the alleles epsilon2 or epsilon4. CONCLUSION: In this sample of the Tunisian population, the distribution of apo E gene alleles is similar to that observed in Southern European populations with low prevalence of the epsilon4 allele. Variations in the apo E gene play a role in determining plasma lipid levels. These data also suggest that effects of apo E alleles on lipids levels are partly dependent on environmental variables such as BMI. These findings highlight the importance of the gene/environment interaction on the deleterious effect of obesity on cardiovascular risk factors.     

Influence of apolipoprotein E polymorphism on plasma vitamin A and vitamin E levels

BACKGROUND: Plasma concentrations of vitamins A and E are positively correlated with those of concurrent lipids and, on the other hand, lipid levels are influenced by apolipoprotein E polymorphism. Therefore, the effect of this polymorphism on both vitamins was analysed in an adult population. MATERIALS AND METHODS: Subjects were recruited from a working population. Their anthropometric, lifestyle and dietary intake variables and menopausal status were recorded. Their apolipoprotein E phenotype and their plasma vitamins A and E (by high-performance liquid chromatography) and lipid (enzymatically) concentrations were determined after an overnight fast. The associations of the phenotype with vitamins and lipids were studied in men and women separately and controlling for significant covariates. RESULTS: The apolipoprotein E phenotype was associated with the concentrations of total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol in women, whereas no associations with lipids were found in men. Vitamin A and vitamin E levels were higher in men than in women, but only the difference in the former persisted after lipid adjustment. Apolipoprotein E2 slightly increased vitamin A levels in women, an effect which was still evident with lipid adjustment. Actually, both the apolipoprotein E phenotype and triglyceride were selected as significant predictors of this vitamin by multiple regression. This phenotype did not affect vitamin E levels in either sex. CONCLUSIONS: Lipids do not mediate the effect of gender on vitamin A levels. Apolipoprotein E polymorphism is an independent determinant of vitamin A levels in women. Pending confirmation by others, we propose that enhancement of this vitamin may contribute to the beneficial impact of the epsilon2 allele on human ageing and health.     

Apolipoprotein E in apolipoprotein B (apo B)- and non-apo B-containing lipoproteins in 3523 participants in the Stanislas cohort: biological variation and genotype-specific reference limits.

BACKGROUND: Apolipoprotein (apo) E is a component of two major classes of plasma lipoproteins, apo B- (apo E-LpB) and non-apo B-containing (apo E-Lp-non-B) lipoproteins. The factors that affect total apo E in particles [lipoprotein E (LpE), apo E-Lp-non-B, and apo E-LpB], are incompletely characterized. METHODS: We studied the determinants of these lipoparticles in a sample population of presumably healthy individuals: 1784 children (age range, 8-18 years) and 1739 adults (age range, 19-50 years). Serum concentrations of LpE and apo E-Lp-non-B were measured by electroimmunoassays, and the concentration of apo E-LpB was calculated by a difference method. RESULTS: Serum LpE and apo E-Lp-non-B were higher in females than in males. Their concentrations decreased with age until 20-25 years and then increased in men but not in women. apo E-LpB concentrations increased up to 20-25 years and were similar in both sexes. Thereafter, adult men had higher values than women. Individuals carrying the epsilon2 allele had higher mean apo E-Lp-non-B concentrations and lower apo E-LpB concentrations than did individuals carrying the epsilon3 allele. Individuals with the epsilon4 allele showed an inverse profile compared with those with the epsilon2 allele. Age, gender, the common apo E polymorphism, puberty, serum lipid concentrations, and alcohol consumption were significantly associated with total LpE, apo E-Lp-non-B, and apo E-LpB concentrations. Reference limits were established according to age, gender, and the common apo E polymorphism. CONCLUSIONS: Because measurements of LpE, apo E-Lp-non-B, and apo E-LpB concentrations may improve cardiovascular risk assessment, the proposed reference limits will aid interpretation of the results in clinical or therapeutic trials.     

The effect of a gender difference in the apolipoprotein E gene DNA polymorphism on serum lipid levels in a Serbian healthy population.

To date, no data have been available on relationship between apolipoprotein E polymorphism and lipid levels in Serbian populations. Blood samples were obtained from 591 healthy normal individuals (193 women and 398 men). A 244 bp sequence of the apolipoprotein E gene including the two polymorphic sites was amplified by polymerase chain reaction. After digestion with Hhal, DNA fragments were visualized by microplate array diagonal gel electrophoresis. In men, levels of both total and low-density lipoprotein cholesterol among the three apolipoprotein E genotype groups differed significantly (p <0.05). The epsilon2 allele was associated with lower concentrations of both total and low-density lipoprotein cholesterol, where the epsilon4 allele had the opposite effects. No significant effects of apolipoprotein E polymorphism on serum lipid levels were observed in women. The presented data could be taken into consideration in any future disease risk evaluation in this population.     

Hypertriglyceridemia and cholesteryl ester transfer protein interact to dramatically alter high density lipoprotein levels, particle sizes, and metabolism. Studies in transgenic mice.

Several types of transgenic mice were used to study the influence of hypertriglyceridemia and cholesteryl ester transfer protein (CETP) expression on high density lipoprotein (HDL) levels, particle sizes, and metabolism. The presence of the CETP transgene in hypertriglyceridemic human apo CIII transgenic mice lowered HDL-cholesterol (HDL-C) 48% and apolipoprotein (apo) A-I 40%, decreased HDL size (particle diameter from 9.8 to 8.8 nm), increased HDL cholesterol ester (CE) fractional catabolic rate (FCR) 65% with a small decrease in HDL CE transport rate (TR) and increased apo A-I FCR 15% and decreased apo A-I TR 29%. The presence of the CETP transgene in hypertriglyceridemic mice with human-like HDL, human apo A-I apo CIII transgenic mice, lowered HDL-C 61% and apo A-I 45%, caused a dramatic diminution of HDL particle size (particle diameters from 10.3 and 9.1 to 7.6 nm), increased HDL CE FCR by 107% without affecting HDL CE TR, and increased apo A-I FCR 35% and decreased apo A-I TR 48%. Moreover, unexpectedly, hypertriglyceridemia alone in the absence of CETP was also found to cause lower HDL-C and apo A-I levels primarily by decreasing TRs. Decreased apo A-I TR was confirmed by an in vivo labeling study and found to be associated with a decrease in intestinal but not hepatic apo A-I mRNA levels. In summary, the introduction of the human apo A-I, apo CIII, and CETP genes into transgenic mice produced a high-triglyceride, low-HDL-C lipoprotein phenotype. Human apo A-I gene overexpression caused a diminution of mouse apo A-I and a change from monodisperse to polydisperse HDL. Human apo CIII gene overexpression caused hypertriglyceridemia with a significant decrease in HDL-C and apo A-I levels primarily due to decreased HDL CE and apo A-I TR but without a profound change in HDL size. In the hypertriglyceridemic mice, human CETP gene expression further reduced HDL-C and apo A-I levels, primarily by increasing HDL CE and apo A-I FCR, while dramatically reducing HDL size. This study provides insights into the genes that may cause the high-triglyceride, low-HDL-C phenotype in humans and the metabolic mechanisms involved.     

Association of oxidative stress and PON1 with LDL and HDL particle size in middle-aged subjects

BACKGROUND: Alterations in plasma lipoprotein subclass distributions affect atherosclerosis risk. Smaller, denser low-density lipoprotein (LDL) particles (sdLDL) are more susceptible to oxidation. In contrast, most of the protective effects of high-density lipoproteins (HDL) are attributable to larger particles. This study investigates the connection between LDL and HDL particle heterogeneity and oxidative stress, antioxidative defence (AOD) and paraoxonase (PON1) status in a healthy middle-aged Serbian population. MATERIALS AND METHODS: LDL and HDL particle sizes and subclass distributions were measured by gradient gel electrophoresis in 104 men and 103 women, aged 53 +/- 9.4 years. PON1 activities and PON1(Q192R) phenotypes were determined with paraoxon and diazoxon as substrates. The oxidative stress/AOD status was estimated by measuring malondialdehyde (MDA) and superoxide-anion (O2*(-)) levels and superoxide-dismutase (SOD) activity. RESULTS: Subjects with sdLDL had significantly higher MDA (P < 0.001) and O2*(-)(P < 0.05) levels and greater diazoxonase (DZOase) activity (P < 0.05) compared to subjects with larger LDL particles. A high MDA concentration was a significant predictor of the sdLDL phenotype (P < 0.005). Increased levels of and MDA were associated with smaller HDL(3) subclass abundance. Reduced HDL particle size was associated with lower DZOase activity (P < 0.01). CONCLUSIONS: Even in the absence of symptoms of atherosclerosis, sdLDL particles are associated with increased oxidative stress, which may stimulate a compensatory rise in PON1 DZOase activity. Elevated oxidative stress may significantly affect HDL subclass distribution, resulting in the accumulation of smaller, denser HDL particles with diminished antioxidative capacity.     

Influence of apolipoprotein E polymorphism on serum lipid and lipoprotein changes: a 21-year follow-up study from childhood to adulthood. The Cardiovascular Risk in Young Finns Study.

BACKGROUND: We examined the influence of apolipoprotein E (apoE) polymorphism on longitudinal changes in serum lipids by following the subjects participating in The Cardiovascular Risk in Young Finns Study over a 21-year period. METHODS: Serum lipids were determined in randomly selected Finnish children and adolescents in 1980 and the subjects were re-examined in 1983, 1986 and after 21 years in 2001. ApoE polymorphism was determined in 1736 participants, and serum lipid values and apoE phenotypes were available for 1233 subjects. RESULTS: ApoE phenotype-related differences in serum total and low-density lipoprotein (LDL)-cholesterol were maintained throughout the 21-year follow-up from childhood to adulthood, i.e., the apoE epsilon2 allele was consistently associated with lower and the epsilon4 allele with higher total and LDL-cholesterol (p<0.001 for all). In adulthood, there was also a significant apoE phenotype-related difference in high-density lipoprotein (HDL)-cholesterol (p=0.007), and the epsilon2 allele was associated with higher and the epsilon4 allele with lower apoA-I and HDL-cholesterol. In addition, apoB increased in the phenotype order E3/2相似文献   

LDL and HDL subclasses and their relationship with Framingham risk score in middle-aged Serbian population

OBJECTIVES: Small, dense LDL particles are associated with an increased risk of coronary heart disease (CHD), and there is growing evidence that small HDL subclasses are less protective than the larger ones. Very limited information is available about the lipoprotein subclasses among populations living in South-East European region, and none for Serbia. DESIGN AND METHODS: We analyzed the distributions of LDL and HDL subclasses and their relationships with Framingham risk scores (FRS) in 229 Serbian middle-aged asymptomatic individuals. By use of non-denaturing gradient gel electrophoresis, we determined the diameters of LDL and HDL subfractions in a single run. RESULTS: Comparing to women, men had smaller LDL and HDL particles (P<0.001, and P<0.05, respectively), higher frequency of LDL B phenotype (P<0.005), and significant reduction of HDL2b in favor of HDL2a subclasses (P<0.05). The observed gender-related differences disappeared after the age of 60. We found a significant association of the small LDL particles with high FRS values (P<0.005). A notable incidence of risk lipoprotein phenotypes (LDL B-9.2%; small-sized HDL-9.9%) was found among subjects that were categorized as "low-risk", requiring no further intervention, according to FRS. CONCLUSION: Measurement of LDL, and possibly HDL particle size could provide further insight into individual CHD risk, and enable them to benefit from targeted preventive measures.     

Analysis of apolipoprotein E genotypes by the Amplification Refractory Mutation System

The Amplification Refractory Mutation System (ARMS) has been successfully applied to the detection of apolipoprotein (apo) E genotypes in human DNA extracted from peripheral blood. By using four allele-specific oligonucleotide primers and one common primer, one can identify the three common alleles of the apo E genetic polymorphism, epsilon 2, epsilon 3, and epsilon 4. The system amplifies two sequences of the apo E gene, one of 181 bp and the other 319 bp. These sequences are amplified when DNA containing a particular allele is incubated with its allele-specific oligonucleotide primer and a common primer. The method is simple, reliable, and nonisotopic and obviates the need for digestion with restriction endonucleases or for hybridization with allele-specific oligonucleotide probes. Genotyping DNA by this method overcomes the problem of post-translational modification of the apo E phenotype encountered with isoelectric focusing of the mature plasma apo E protein.     

Sex and age differences in lipoprotein subclasses measured by nuclear magnetic resonance spectroscopy: the Framingham Study

BACKGROUND: The sex differential in coronary heart disease (CHD) risk, which is not explained by male/female differences in lipid and lipoprotein concentrations, narrows with age. We examined whether this differential CHD risk might, in part, be attributable to the sizes of lipoprotein particles or concentrations of lipoprotein subclasses. METHODS: We analyzed frozen plasma samples from 1574 men and 1692 women from exam cycle 4 (1988-1990) of the Framingham Offspring Study. Nuclear magnetic resonance (NMR) spectroscopy was used to determine the subclass concentrations and mean sizes of VLDL, LDL, and HDL particles. Concentrations of lipids and apolipoproteins were measured by standard chemical methods. RESULTS: In addition to the expected sex differences in concentrations of triglycerides, LDL-cholesterol, and HDL-cholesterol, women also had a lower-risk subclass profile consisting of larger LDL (0.4 nm) and HDL (0.5 nm) particles. The sex difference was most pronounced for HDL, with women having a twofold higher (8 vs 4 micromol/L) concentration of large HDL particles than men. Furthermore, similar to the narrowing of the sex difference in CHD risk with age, the observed male/female difference in HDL particle size also decreased with age. Although lipoprotein particle sizes were highly correlated with lipid and lipoprotein concentrations, the sex differences in the mean sizes of lipoprotein particles persisted (P <0.001) even after adjustment for lipid and lipoprotein concentrations. CONCLUSIONS: Women have a less atherogenic subclass profile than men, even after accounting for differences in lipid concentrations.     

Small dense LDL particles and metabolic syndrome in a sample of middle-aged women. Findings from Progetto Atena

Metabolic Syndrome (MS) is highly prevalent in the general population. Recently, small dense LDL (sd-LDL) particles have been considered a risk marker in MS diagnosis. We analyzed cross-sectionally the association between sd-LDL and MS in a population-based sample of 210 middle-aged southern Italian women; among them 86 participants had MS (prevalence 40.9%). LDL particle separation was performed by Lipoprint System: seven LDL subfractions were obtained and LDL score (% of sd-LDL particles) calculated. Women with the MS diagnosis had significantly higher LDL score as compared to participants without MS diagnosis (median 0 vs. 3.6, p<0.001 by Mann Whitney). The univariate analysis showed a positive and significant association between MS diagnosis (OR 4.80; 95% CI 2.29-10.18; p<0.001 for MS diagnosis) and some MS components Triglycerides (TG), HDL Cholesterol (HDL-C), (OR 14.82; 95% CI 5.24-41.88; p<0.001 for Ln TG); (OR 0.92; 95% CI 0.89-0.95; p<0.001 for HDL-C) and LDL score. Apo B and insulin levels were also positively related to the presence of sd-LDL (OR 31.56; 95% CI 5.58-178.29; p<0.001 for apo B); (OR 1.07; 95% CI 1.00-1.15; p<0.05 for insulin). After controlling for age, insulin and apo B, MS diagnosis (OR 4.0; 95% CI 1.76-9.09; p<0.001 for MS diagnosis) and MS components (TG, HDL-C) (OR 4.41; 95% CI 1.22-15.87; p=0.023 for Ln TG); (OR 0.94; 95% CI 0.89-0.98; p=0.009 for HDL-C) remained significantly associated with high LDL score (upper quintile). Our results suggest that sd-LDL particles could be a valuable marker for diagnosis and severity of the MS. Future prospective epidemiological studies are envisaged to explore the specific contribution of this marker on cardiovascular risk. LDL size measurement could be an useful tool for identifying a subsample patients with prominent lipoprotein abnormality, within the large population with the MS diagnosis, and who are candidates for intensive lipid-lowering interventions.     

北京地区晚发性阿尔兹海默病患者apo E基因多态性与血脂的相关性

目的探讨晚发型阿尔兹海默病(LOAD)患者载脂蛋白E(apo E)基因多态性与血脂水平之间的关系。方法采用基因芯片法检测150例LOAD患者(LOAD组)及150名体检健康者(正常对照组)apo E基因多态性,同时检测总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白胆固醇(LDL-C)、小而密低密度脂蛋白胆固醇(sd-LDL-C)、高密度脂蛋白胆固醇(HDL-C)、载脂蛋白B(apo B)、脂蛋白(a)[Lp(a)]水平。采用多因素非条件Logistic回归分析筛选LOAD的相关危险因素。结果LOAD组E2/3和E3/3基因型频率均低于正常对照组(P<0.05),E3/4和E2/4基因型频率均高于正常对照组(P<0.01)。LOAD组ε3等位基因频率低于正常对照组(P<0.05),ε4等位基因频率高于正常对照组(P<0.01)。与正常对照组比较,LOAD组TC、LDL-C和sd-LDL-C水平明显升高(P<0.01),HDL-C水平明显降低(P<0.01),其他血脂项目差异均无统计学意义(P>0.05)。TC及LDL-C水平在LOAD组ε2、ε3和ε4表型患者中依次升高(P<0.05)。正常对照组ε4表型LDL-C水平明显高于ε2表型(P<0.05)。apo Eε4等位基因和LDL-C升高是LOAD发生的危险因素[比值比(OR)值分别为14.454、5.824,95%可信区间(CI)分别为5.793~16.368、2.582~7.973],HDL-C升高则是LOAD的保护因素(OR=0.020,95%CI为0.006~0.352)。结论apo E基因多态性与脂质代谢密切相关,ε4等位基因可能是LOAD发病的重要遗传因素之一。     

Fractional esterification rate of cholesterol and ratio of triglycerides to HDL-cholesterol are powerful predictors of positive findings on coronary angiography

BACKGROUND: We examined the predictive value of various clinical and biochemical markers for angiographically defined coronary artery disease (aCAD). Specifically, we assessed the value of the ratio of plasma triglyceride (TGs) to HDL-cholesterol (HDL-C) and the fractional esterification rate of cholesterol in plasma depleted of apolipoprotein B (apoB)-containing lipoproteins (FER(HDL)), a functional marker of HDL and LDL particle size. METHODS: Patients (788 men and 320 women) undergoing coronary angiography were classified into groups with positive [aCAD(+)] and negative [aCAD(-)] findings. Patient age, body mass index, waist circumference, blood pressure (BP), medications, drinking, smoking, exercise habits, and plasma total cholesterol (TC), LDL-cholesterol (LDL-C), HDL-unesterified cholesterol, HDL-C, TGs, FER(HDL), apoB, log(TG/HDL-C), and TC/HDL-C were assessed. Lipids and apoproteins were measured by standard laboratory procedures; FER(HDL) was determined by a radioassay. RESULTS: Members of the aCAD(+) group were older and had a higher incidence of smoking and diabetes than those in the aCAD(-) group. The aCAD(+) group also had higher TG, apoB, FER(HDL), and log(TG/HDL-C) and lower HDL-C values. aCAD(+) women had greater waist circumference and higher plasma TC and TC/HDL-C. aCAD(+) men, but not women, had higher plasma LDL-C. In the multivariate logistic model, the significant predictors of the presence of aCAD(+) were FER(HDL), age, smoking, and diabetes. If only laboratory tests were included in the multivariate logistic model, FER(HDL) appeared as the sole predictor of aCAD(+). Log(TG/HDL-C) was an independent predictor when FER(HDL) was omitted from multivariate analysis. CONCLUSIONS: FER(HDL) was the best laboratory predictor of the presence of coronary atherosclerotic lesions.     

Apolipoprotein E polymorphism and serum concentration in Alzheimer's disease in nine European centres: the ApoEurope study. ApoEurope group.

As part of the ApoEurope Project, apolipoprotein E (apo E) common polymorphism and serum concentration were determined in 489 Alzheimer's disease patients and 429 controls. Patients and controls were recruited through nine centres in eight European countries. Age, sex ratios and education levels of both case and control populations were similar, although discrete differences appeared between centres. The prevalence of the epsilon4 allele was higher in Alzheimer's disease than in controls (increased by 140%), while serum apo E concentration was lower by 11.2% (p<0.001). In addition, serum total cholesterol and triglyceride concentrations were lower in Alzheimer's disease (p<0.001), while that of apo Al was not affected. The decrease in serum apo E concentration was not accounted for by the epsilon4 allele, age or gender, suggesting that apo E concentration might represent an additional risk factor for Alzheimer's disease, complementary and independent of the epsilon4 allele. Further analysis will be aimed at determining whether the quantitative link between apo E concentration and Alzheimer's disease occurs through the effect of apo E genotype on lipid parameters or by other mechanisms.     

Serum lipoproteins in the diabetes control and complications trial/epidemiology of diabetes intervention and complications cohort: associations with gender and glycemia

OBJECTIVE: To relate the nuclear magnetic resonance (NMR)-determined lipoprotein profile, conventional lipid and apolipoprotein measures, and in vitro oxidizibility of LDL with gender and glycemia in type 1 diabetes. RESEARCH DESIGN AND METHODS: In the 1997-1999 Diabetes Control and Complications Trial/Epidemiology of Diabetes Intervention and Complications (DCCT/EDIC) cohort, serum from 428 women and 540 men were characterized by conventional lipids, NMR, apolipoprotein levels, and LDL susceptibility to in vitro oxidation. Simple and partial correlation coefficients were calculated for each lipoprotein-related parameter versus gender, with and without covariates (age, diabetes duration, concurrent HbA(1c), DCCT randomization, hypertension, BMI, waist-to-hip ratio, and albuminuria). For concurrent HbA(1c), data were analyzed as above, exchanging gender for HbA(1c). Associations were significant if P < 0.05. RESULTS: Although men and women had similar total and LDL cholesterol and triglycerides, men exhibited the following significant percent differences in NMR profiles versus women: small VLDL 41; IDL -30; medium LDL 39; small LDL 21; large HDL -32; small HDL 35; LDL particle concentration 4; VLDL and HDL diameters -8 and -4, respectively. Small VLDL, small HDL, medium LDL (women only), small LDL (men only), and LDL particle concentration were positively correlated, and HDL size was inversely correlated, with concurrent HbA(1c). NMR profile was unrelated to prior DCCT randomization. Susceptibility of LDL to oxidation was unrelated to gender and glycemia. CONCLUSIONS: Male gender and poor glycemia are associated with a potentially more atherogenic NMR lipoprotein profile. Neither gender nor glycemia influence LDL oxidation in vitro.     

Evaluation of pathways for the cellular uptake of high density lipoprotein cholesterol esters in rabbits.

Cholesterol esters (CE) formed in HDL by lecithin:cholesterol acyltransferase are thought to mediate the return of cholesterol from extrahepatic tissues to the liver for excretion or reutilization. Several pathways may be involved in that process. Tracer kinetics were used to estimate the contributions of the various pathways to cellular uptake of HDL CE in rabbits. Tracers of HDL CE, HDL apo A-I, LDL apo B, and VLDL CE were simultaneously injected intravenously. Plasma decays were followed for 24 h in 4 lipoprotein pools: HDL without apo E, HDL with apo E, LDL, and VLDL. Kinetic analysis of the resulting plasma decay curves revealed that the preponderance of plasma CE (greater than 90%) originated in the HDL fraction. About 70% of HDL CE were cleared from plasma after transfer to LDL and VLDL, 20% were cleared directly from the HDL pool without HDL particle uptake ("selective" uptake), and 10% were cleared in HDL particles (including particles containing apo E). Since rabbits have about four times the plasma cholesterol ester transfer activity of man, and since the transfer pathway must compete with the selective uptake pathway, these results make it likely that selective uptake plays a substantial role in humans in the clearance of HDL CE.     

Relationship between plasma HDL subclasses distribution and apoA-I gene polymorphisms

BACKGROUND: It is generally accepted that apolipoprotein (apo) A-I is the dominant structural apolipoprotein of HDL particles and different HDL subclasses have distinct but interrelated metabolic functions. HDL is known to directly affect the atherogenic process hence changes in HDL subclasses distribution may be related to the incidence and prevalence of atherosclerosis. METHODS: The ApoA-I contents (mg/l) of plasma HDL subclasses were determined by 2-dimensional gel electrophoresis coupled with immunodetection and apoA-I genotypes were assayed by PCR-RFLP in 307 Chinese subjects (169 males, 138 females). RESULTS: The G/G and C/C genotypes were the most frequent at -78 bp and +83 bp of apoA-I gene, respectively. There were no significant differences in the frequencies of rare A allele at -78 bp and rare T allele at +83 bp between males and females. Compared with the G/G carriers, G/A and A/A carriers had significantly higher plasma concentrations of TG, apoC-II, apoC-III, apoA-I contents of prebeta(1)-HDL, HDL(3a) and TG/HDL-C ratio. And in addition, A/A carriers had significantly lower apoA-I contents of HDL(2a) and HDL(2b). Females had increased plasma concentrations of apoA-I, HDL-C, apoA-I contents of HDL(2a) and HDL(2b) while decreased apoA-I contents of prebeta(1)-HDL, HDL(3b) and TG/HDL-C ratio as compared to males carrying the same genotype. No significant differences were demonstrated on the concentrations of plasma lipids, lipoproteins, apolipoproteins and apoA-I contents of plasma HDL subclasses between the C/C and C/T subjects. CONCLUSION: The G/A polymorphism at -78 bp of apoA-I gene was associated with changes of HDL subclasses distribution. There was a general shift towards smaller-sized HDL, which, in turn, indicated that reverse cholesterol transport (RCT) might be weakened and HDL maturation might be abnormal in the subjects with G/A mutation.     

Severe type III hyperlipoproteinemia associated with unusual apolipoprotein E1 phenotype and & epsilon;1/lsquo;null genotype‡

A 60-year-old white male (KH) was diagnosed to suffer from severe type III hyperlipoproteinemia (HLP) and premature cardiovascular disease. Biochemical analysis revealed an unusual apolipoprotein (apo) E phenotype and genotype. All clinical characteristics of type III HLP were present in the patient. His very low density lipoprotein (VLDL) cholesterol to plasma triglyceride (TG) ratio was elevated at 0.97 without therapy which is unusually high (normal ratio about 0.18). By contrast his plasma apo E level was only moderately elevated (6.8 mg dl-1). The patient's apo E migrated in the apo E1 position on isoelectric focusing gels. Chemical modification with cysteamine and treatment with neuraminidase confirmed the presence of two cysteine residues in the patient's apo E and a normal sialylation pattern. Pedigree analysis suggested that the patient was a compound heterozygote with one apo epsilon 1 allele and another allele whose product did not appear in the plasma compartment ('null' allele). Direct sequencing of polymerase chain reaction (PCR) amplified segments of the apo E gene as well as restriction fragment length polymorphism (RFLP) analysis with the endonuclease Taq I identified an adenosine for guanosine (G-->A) exchange in the second base of codon 127 that is predictive for an Asp for Gly substitution in the encoded apo E amino acid sequence. This mutation is the structural basis for the apo E1 isoform identified upon isoelectric focusing. Five other family members are also carriers of the mutant apo epsilon 1 allele. Two of those were hyperlipidemic and exhibited biochemical characteristics of type III HLP. A second mutation, a deletion of a G in codon 31, is predictive for a reading frameshift that encodes for a premature stop in codon 60. Our inability to identify the product of a second apo E allele in the plasma of the patient and two other members of the KH family corresponds with the heterozygous presence of this mutation in the affected individuals. Both relatives (like the index case) had an increased VLDL cholesterol to plasma TG ratio, which indicates the presence of cholesterol-enriched VLDL particles. We propose that the single base deletion in the apo E gene which is the cause of a non-functional 'null' allele in addition to a probably dominant apo E1 (Gly127-->Asp, Arg158-->Cys) variant of late or incomplete penetrance are the primary genetic defects in this kindred leading to severe dysbetalipoproteinemia.     

Low-density-lipoprotein peak particle size in a Mediterranean population

BACKGROUND: The predominance of small, dense low-density lipoprotein (LDL) particles ('LDL phenotype B') has been associated with a three-fold increased risk of myocardial infarction, but the feasibility of the identification of small, dense LDL as independent predictors of coronary artery disease risk in population studies remains questioned. Design We evaluated the LDL peak particle size and its relation with other established risk factors for coronary heart disease in a group of 156 randomized subjects living on the Mediterranean island of Ustica (71 males and 85 women, range of age 20-69 years), representing approximately 30% of the total population. RESULTS: The prevalence of LDL phenotype B subjects was low (approximately 15% in both men and women) and there was a clear trend for both genders in reducing the LDL peak particle size with age. Moreover, LDL phenotype B subjects had higher BMI values, prevalence of diabetes and plasma triglyceride (TG) levels and lower plasma HDL-C concentrations in comparison with LDL phenotype A individuals; in a multivariate analysis, plasma TG levels were the only variable independently associated with LDL peak particle size. CONCLUSIONS: In this population, which appears to be somewhat protected by premature coronary artery disease, a low prevalence of the LDL pattern B was found in both men and women, and plasma TG could have a key role in regulating the LDL peak particle size. The follow up, still ongoing, will provide useful information on the predictive role of LDL peak particle size on cardiovascular risk, at least in a low-risk population.