Polymorphisms in CYP-7A1, not APOE,influence the change in plasma lipids in response to population dietary change in an 8 year follow-up; results from the Czech MONICA study

OBJECTIVES: To evaluate the influence of variation in the genes for apolipoprotein E (APOE; epsilon2, epsilon3, epsilon4) and cholesterol-7alpha hydroxylase (CYP-7A1; -204A-->C) on plasma lipid level changes. DESIGN AND METHODS: 131 males for whom dietary composition markedly changed and total cholesterol decreased (from 6.21 +/- 1.31 mmol/L in 1988 - 5.43 +/- 1.06 mmol/L in 1996) over an 8 yr follow-up study. Polymorphisms were investigated using PCR. RESULTS: APOE genotype influenced plasma total and LDL cholesterol, with carriers of the epsilon4 having the highest and epsilon2 carriers the lowest levels, this reached borderline significance for cholesterol in 1988 (p = 0.06) and strongly affected the 1996 levels of LDL cholesterol (p = 0.008). However, APOE did not influence the change in these measures over time. In contrast, the CYP-7A1 -204A-->C polymorphism did not affect lipid measures per se but was strongly associated with a decrease in plasma total cholesterol [AA -0.38 (+/- 0.20) mmol/L, AC -0.65 +/- (0.08), CC -1.33 (+/- 0.3) mmol/L, p = 0.01] over the 8 yr time period. CONCLUSIONS: Variation in the CYP-7A1 gene may play an important role in an individual's sensitivity to dietary composition.     

Gender-related effect of apo E polymorphism on lipoprotein particle sizes in the middle-aged subjects

OBJECTIVES: We determined the frequencies of apolipoprotein E (apo E) alleles and examined the effect of apo E polymorphism on lipoprotein particle sizes in Serbian healthy, middle-aged individuals. DESIGN AND METHODS: We performed apo E phenotype by immunobloting method in 183 men and 143 women (mean years: 56.3+/-10.60 and 54.9+/-10.31, respectively). Plasma lipid and apolipoprotein levels were measured by routine laboratory methods. LDL and HDL particle sizes were determined by nondenaturing polyacrylamide gradient (3-31%) gel electrophoresis. RESULTS: The apo E allele frequencies were epsilon2--4.9%, epsilon3--86.5%, and epsilon4--8.6%. Men with epsilon4 allele had lower HDL-C and Apo AI concentrations than epsilon3 men. The epsilon2 allele men had the smallest LDL particles, highest percent of subjects with LDL phenotype B and highest TG/HDL-C ratio. Women with epsilon2 allele had lowest concentration of apo B. The epsilon4 allele women had smallest HDL particles and highest percent of the subjects with small-sized HDL phenotype. CONCLUSIONS: This study showed gender-related effect of apo E polymorphism on lipoprotein particle size. In men, possession of the epsilon2 allele is associated with small LDL particles, whereas in women, epsilon4 allele is associated with small HDL particles. Differences in gender-related influence of apo E polymorphism on LDL and HDL particle sizes could be clinically useful in strategy for reduction of coronary disease risk in middle-aged men and women.     

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.     

Relationship of genetic variation in genes encoding apolipoprotein A-IV, scavenger receptor BI, HMG-CoA reductase, CETP and apolipoprotein E with cholesterol metabolism and the response to plant stanol ester consumption

BACKGROUND: Differences in genetic constitution may affect cholesterol metabolism and responses to diet. Identification of common variations in genes related to dietary responsiveness is therefore an attractive goal to be able to prescribe individually tailored diets for the treatment of dyslipidaemia. MATERIALS AND METHODS: We have examined relationships between serum lipids and lipoproteins, cholesterol-standardized campesterol and lathosterol concentrations with genetic variation, and the presence of a gene-diet interaction between plant stanol ester consumption. Candidate genes were apolipoprotein A-IV (apoA-IV), scavenger receptor-BI (SR-BI), cholesterol ester transfer protein (CETP), 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, and apolipoprotein E (apoE). These relations were examined in 112 nonhypercholesterolaemic subjects, of whom 70 consumed 3.8-4.0 g plant stanol esters a day for 8 weeks. RESULTS: At baseline, high-density lipoprotein (HDL) concentrations of 1.56 +/- 0.36 mmol L(-1) in SR-BI-2 allele carriers tended to be lower compared to the 1.72 +/- 0.42 mmol L(-1) in SR-BI-1/1 subjects (P = 0.069). Cholesterol standardized lathosterol concentrations were also lower in the SR-BI-2 allele carriers (P = 0.002). Furthermore, low-density lipoprotein (LDL) cholesterol concentrations in apoE2 subjects, were lower compared to the LDL cholesterol concentration in apoE3 group (P = 0.002) and apoE4 subjects (P < 0.001). No significant differences between the polymorphisms and dietary responsiveness to plant stanol ester consumption could be found, which indicates that it is unlikely that one of the single polymorphisms analysed in this study is a major factor in explaining the variation in serum LDL cholesterol responses. CONCLUSION: These findings suggest that all subjects who want to lower their cholesterol concentration, will benefit from plant stanol ester consumption, irrespective of their apoA-IV, SR-BI, HMG-CoA reductase, CETP, or apoE genotype.     

Cholesterol-rich diet induced changes in plasma lipids in relation to apolipoprotein E phenotype in healthy students.

The hypothesis that apolipoprotein E (apoE) polymorphism modulates an individual's response to cholesterol-rich diet was tested in 36 healthy normolipidaemic students with apoE phenotypes E3/2 (n = 9), E3/3 (n = 11), E4/3 (n = 13) and E4/4 (n = 3). The subjects were instructed to eat their usual diets, omitting eggs, for three weeks (baseline). This was followed by a diet high in cholesterol (750 mg/day, from egg yolks) for three weeks (intervention) after which they returned to their normal diet (without eggs for three weeks). Concentrations of plasma lipids and apolipoprotein B, and the composition of total fatty acids were monitored. At baseline, there were no statistically significant differences in lipid concentrations between the phenotype groups. The cholesterol-rich diet induced significant increases in total cholesterol, LDL cholesterol, and apoB in all apoE groups (P less than 0.001). The magnitudes of these increases were similar in groups E3/2, E3/3, and E4/3, in which total cholesterol concentration rose by 13%, 18%, and 12%, respectively. Stronger responses were observed in the small group of E4/4 subjects, in whom the increases in total cholesterol, LDL cholesterol, and apoB were 2.3-fold (P = 0.054), 2.25-fold (P = 0.02) and 2.3-fold (P = 0.004), respectively, compared with all the other phenotypes studied.     

Effect of apolipoprotein E4 allele on plasma LDL cholesterol response to diet therapy in type 2 diabetic patients

OBJECTIVE: The aim of this study was to investigate the effect of apolipoprotein (apo)E4 allele on plasma LDL cholesterol response to calorie-restricted diet therapy in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: Twenty-four diabetic patients with the apoE3/3 genotype and 11 diabetic patients with the apoE4/3 genotype were recruited. Participants were hospitalized for calorie-restricted diet therapy (25.0 kcal. kg body wt(-1). day(-1)) for 14 days. Body weight, fasting plasma glucose (FPG) levels, and plasma lipid levels on hospital days 1 and 14 were compared between the two apoE genotype groups. RESULTS: There were no significant differences in baseline FPG levels, HbA(1c) levels, BMI, and plasma levels of total cholesterol, triglyceride, and HDL cholesterol between the two apoE genotype groups, but baseline plasma levels of LDL cholesterol were significantly higher in the apoE4/3 group than in the apoE3/3 group. Body weight decreased slightly and FPG levels decreased significantly after diet therapy in both apoE genotype groups. In the apoE3/3 group, only plasma levels of triglyceride decreased significantly after diet therapy, whereas in the apoE4/3 group, plasma levels of triglyceride, total cholesterol, and LDL cholesterol decreased significantly after diet therapy. The decrease (percentage of change) in total cholesterol (-16.3 vs. -6.6%) and LDL cholesterol (-15.6 vs. -0.7%) after diet therapy was significantly greater in the apoE4/3 group than in the apoE3/3 group. CONCLUSIONS: Calorie-restricted diet therapy is more effective in reducing plasma LDL cholesterol in type 2 diabetic patients with the apoE4 allele.     

Apolipoprotein E polymorphism--a risk factor for metabolic syndrome.

BACKGROUND: Metabolic syndrome is closely related to several disturbances in lipid and lipoprotein metabolism. The aim of this study was to determine the association between apolipoprotein E (apoE) genotypes and the risk of metabolic syndrome and/or coronary heart disease complications. METHODS: The study included 279 subjects divided into three groups: 1) control subjects, 2) metabolic syndrome patients, and 3) obese patients with coronary heart disease. All subjects were characterized by body mass index, and plasma levels of glucose, triglycerides, cholesterol, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). ApoE genotypes were identified by PCR-restriction fragment length polymorphism using genomic DNA. RESULTS: Statistical analysis of plasma parameters showed that subjects in groups 2 and 3 had higher levels of triglycerides and lower levels of HDL-C compared to group 1. The frequencies of apoE genotypes determined in this Romanian population (65% for E3/3, 19.6% for E4/3, 9.5% for E3/2, 4.1% for E2/2, 0.6% for E4/4, 1.3% for E4/2) were in agreement with those reported for other Caucasian populations. The distribution of apoE alleles indicated a higher frequency of epsilon4 in groups 2 and 3. There was a higher frequency of the apoE4/3 genotype in groups 2 and 3, which was significantly correlated with higher levels of triglycerides and lower levels of HDL-C. CONCLUSIONS: Correlations of apoE genotypes with these markers indicate that the epsilon4 allele is an independent risk factor for metabolic syndrome.     

Apolipoprotein E2/E2 genotype in combination with mutations in the LDL receptor gene causes type III hyperlipoproteinemia.

The primary genetic cause of type III hyperlipoproteinemia is the homozygous presence of the apolipoprotein E2 allele. However, only approximately 1% of subjects with the apolipoprotein E2/E2 genotype develop type III hyperlipoproteinemia. Other factors are therefore necessary to express type III hyperlipoproteinemia. Two individuals were identified as having type III hyperlipoproteinemia (triglyceride to very low-density lipoprotein (VLDL) cholesterol ratio >0.3). However, in contrast to unchanged or slightly decreased low-density lipoprotein (LDL)-cholesterol levels typically observed in type III patients, elevated LDL-cholesterol levels were observed. The expected apolipoprotein E2/E2 isoform was confirmed by genetic analysis. To explain the elevated LDL-cholesterol level, single strand conformation polymorphism analysis was performed to screen for mutations in the LDL receptor gene. In both individuals, mutations causing an impaired LDL receptor function (2 bp insertion in exon 3 and Glu119 --> Gly mutation in exon 4) were identified. In six more unrelated individuals, these mutations combined with the common apolipoprotein E3/E3 genotype, resulted in an isolated, severe LDL-cholesterol elevation. Our results indicate that the level of LDL receptors plays an important role in remnant clearance, and that the combination of the binding-defective apolipoprotein E2 with a defective LDL receptor precipitate type III hyperlipoproteinemia.     

血管性痴呆患者与载脂蛋白E基因多态性关系的配对分组实验

背景载脂蛋白E是血浆主要载脂蛋白之一,具有多形性,参与机体脂质代谢及调节胆固醇平衡,同时参与神经系统的正常生长和损伤后的修复过程.目的对血管性痴呆患者的载脂蛋白E基因多态性进行分析,并与脑梗死、健康者进行对照,探讨载脂蛋白E基因多态性与血管性痴呆的关系.设计病例-对照实验.单位解放军济南军区总医院神经内科.对象选择2001-08/2003-10解放军济南军区总医院门诊或住院的脑血管病患者以及健康查体者,包括35例血管性痴呆患者,36例脑梗死患者,以及40例健康者.方法全部受检者禁食12 h后,采取肘静脉血4 mL,应用聚合酶链反应-限制性片段长度多态性技术,检测35例血管性痴呆患者、36例脑梗死患者以及40例健康人的载脂蛋白E基因型,同时检测其血脂及载脂蛋白的含量.主要观察指标①所有被检者的载脂蛋白E等位基因频率.②不同载脂蛋白E等位基因的血管性痴呆患者三酰甘油、总胆固醇、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇和载脂蛋白A以及载脂蛋白B水平.结果35例血管性痴呆患者、36例脑梗死患者以及40例健康对照者血样均进入结果分析.①血管性痴呆组和脑梗死组患者ε 4频率均高于对照组(22.86%,22.22%,7.5%,P＜0.01),ε3频率均低于对照组(70%,69.45%,86.25%,P＜0.05),而两组患者间各等位基因频率基本一致(P＞0.05).②血管性痴呆患者载脂蛋白Eε4等位基因携带者三酰甘油、低密度脂蛋白胆固醇、载脂蛋白B水平均较载脂蛋白E ε2,ε3携带者高[(5.85±1.03),(4.73±0.29),(4.96±0.87)mmol/L;(3.91±0.87),(3.12±0.65),(3.06±0.33)mmol/L;(1.34±0.21),(1.00±0.28),(0.94±0.32)g/L,(P＜0.05)].结论载脂蛋白E基因多态性与血管性痴呆的发病有关,ε4基因可能为该病的危险因子,且可能与其在脑梗死中的作用相似.     

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   

Regional differences in apolipoprotein E polymorphism in Finland

Apolipoprotein E (apoE) polymorphism is a genetic determinant of plasma lipid levels and of coronary heart disease risk. We determined apoE phenotypes and plasma lipid levels in 1564 subjects aged three to 18 years, living in five geographical areas of Finland in 1980. ApoE phenotyping was performed directly from plasma by isoelectric focusing and immunoblotting. The serum concentrations of total cholesterol, low density lipoprotein cholesterol and apolipoprotein B varied with apoE phenotype, and there were increases in all three variables (all P less than 0.001) of the order of E2/2 less than E3/2 less than E4/2 less than E3/3 less than E4/3 less than E4/4. These differences were present in all five areas. The mean levels of high density lipoprotein cholesterol, apolipoprotein A-I and triglyceride in the subjects did not differ between the apoE phenotypes or between their areas of residence. The apoE phenotype dependency of serum total and LDL cholesterol remained significant in all five areas during the six year follow-up from 1980 to 1986, when the mean level of serum total cholesterol fell by 5.8% in east (P less than 0.05) and by 4.4% in west Finland (P less than 0.05); the fall was steeper (P less than 0.01) in the east than the west. In all subjects, particularly those in west Finland, the size of the falls of serum total and LDL cholesterol concentrations depended on the apoE phenotype in the order of E3/2 less than E3/3 less than E4/3, but this effect was not seen in the east.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Differences between men and women in the response of serum cholesterol to dietary changes

BACKGROUND: Hypercholesterolaemia is initially treated by diet. However, most studies of diet and cholesterol response have been carried out in men, and it is not known whether women react to diet to the same extent as men do. We therefore studied sex differences in the response of serum cholesterol and lipoproteins to diet. MATERIALS AND METHODS: We measured the responses of serum cholesterol to a decrease in dietary saturated fat in seven trials involving 126 men and 147 women, to a decrease in dietary trans fat in two trials (48 men and 57 women) and to a decrease in dietary cholesterol in eight trials (74 men and 70 women). We also measured responses to the coffee diterpene cafestol, which occurs in unfiltered coffee, in nine trials (72 men and 61 women). All subjects were lean and healthy. RESULTS: The response of total cholesterol (+/- standard deviation) to a decrease in the intake of saturated fat was greater in men (-0.62 +/- 0.39 mmol L-1) than in women (-0.48 +/- 0.39 mmol L-1; 95% confidence interval, 0.04-0.23 mmol L-1). The response of total cholesterol to a decrease in the intake of cafestol was also larger in men (-1.01 +/- 0.49 mmol L-1) than in women (-0.80 +/- 0.49 mmol L-1; 95% confidence interval, 0. 04-0.39 mmol L-1). Responses to trans fat and to dietary cholesterol did not differ between men and women. CONCLUSION: Men have larger responses of total and low-density lipoprotein cholesterol to saturated fat and cafestol than women do.     

Improvement of myocardial blood flow by lipid-lowering therapy with pravastatin is modulated by apolipoprotein E genotype

OBJECTIVE: Apolipoprotein E (apoE) polymorphism affects the risk of advanced coronary artery disease, but its role in early atherosclerosis remains unknown. We used positron emission tomography (PET) to study whether coronary reactivity or its response to pravastatin is related to the apoE genotype. MATERIAL AND METHODS: Samples from 44 mildly hypercholesterolaemic men (aged 35 +/- 4 years) of an earlier trial were re-analysed according to apoE genotype. Subjects were randomized to receive either 40 mg/day pravastatin or placebo for 6 months. To assess coronary reactivity, myocardial blood flow was measured by PET at rest and during adenosine infusion. PET studies and lipid analyses were done at baseline and after 6 months of therapy. RESULTS: There were no differences between apoE epsilon3/3 and epsilon4/3 genotypes in basal or adenosine-stimulated flow or in coronary flow reserve (CFR) at baseline. There was a significant apoE genotype-by-treatment group interaction regarding the change in adenosine-stimulated flow (ANCOVA; p = 0.018) and CFR (p = 0.020) at the end of the study. In the pravastatin group, the adenosine-stimulated flow increased by 32.5 % in subjects with epsilon3/3 (n = 9), but decreased non-significantly (-14.4 %) in subjects with epsilon4/3 (n = 9) (p = 0.0009). The corresponding changes in CFR were +17.8 % for epsilon3/3 and (-11.9 % for epsilon4/3 (p = 0.05). There were no significant changes from the baseline values in placebo recipients. After pravastatin treatment, both genotype groups showed a similar decrease in serum total and low-density lipoprotein cholesterol (p<0.0001 for both). CONCLUSIONS: Coronary function improves by 6 months of pravastatin in subjects with the apoE epsilon3/3 genotype, but not in those with the epsilon4/3.     

Serum zinc, copper, insulin and lipids in Alzheimer''s disease epsilon 4 apolipoprotein E allele carriers*

BACKGROUND: Copper (Cu) and zinc (Zn) have been implicated in the development of Alzheimer's disease (AD) and, in this regard, Cu and Zn serum concentrations have been analysed but with inconclusive results. Serum insulin, glucose and cholesterol concentrations have been related to the apolipoprotein E genotype in non-AD populations. DESIGN: In this study, we have analysed the relationship between serum Cu, Zn, insulin, glucose and lipid parameters (cholesterol, triglycerides, apoA and apoB apolipoproteins) in AD and AD epsilon 4 apolipoprotein E carriers by multivariate analysis using logistic regression, including the variables that showed a significance of P < 0.05 in the bivariate analysis. RESULTS: The results obtained show that epsilon 4 apoE allele is an independent AD risk factor (OR = 6. 67, 95% CI = 2.59-17.16). In AD epsilon 4 apoE allele carriers, we found significantly higher Zn, Cu and insulin serum concentrations. Non-demented control subjects with at least one epsilon 4 apoE allele had the lowest serum insulin concentrations. There was no significant association between epsilon 4 apolipoprotein E allele and lipid parameters in the sample studied. CONCLUSIONS: In AD we have found a significant association between higher serum Zn, Cu and insulin concentrations and the presence of an epsilon 4 apoE allele, but only greater serum Zn concentration appears to be an independent risk factor associated with the development of AD.     

Apolipoprotein E gene polymorphism frequencies in a sample of healthy Hungarians.

Apolipoprotein E (apo E) has been found to play an important role in lipid metabolism and has been associated with cardiovascular and neurodegenerative conditions. Hungarians have some of the highest rates of cardiovascular morbidity and mortality in the world. This study examines the distribution of apo E alleles and genotypes in a population of healthy ethnic Hungarian blood donors (n = 302). Male (n = 152) and female (n = 150) subjects ranging from 18 to 62 years of age (mean 37.0) were involved. To determine the frequency of apo E alleles, polymerase chain reaction followed by restriction length polymorphism was applied. The analyses of data showed that apo E allele epsilon3 had the greatest frequency in this group (0.807), followed by apo epsilon2 (0.104) and apo epsilon4 (0.087). The highest genotype frequency was found to be epsilon3/3 at 65.2% (n = 197) followed by genotype epsilon3/4 at 15.9% (n = 48), genotype epsilon2/3 at 15.2% (n = 46), genotype epsilon2/2 at 2.3% (n = 7), genotype epsilon2/4 at 1.0% (n = 3) and genotype epsilon4/4 at 0.4% (n = 1). The apo E frequencies found in this study appear to differ from an earlier study of blood donors, where the results are based on apo E phenotyping.     

Association of high sensitive C-reactive protein with apolipoprotein E polymorphism in children and young adults: the Cardiovascular Risk in Young Finns Study.

BACKGROUND: A relation between apolipoprotein E (APOE) genotypes and high sensitive C-reactive protein (hsCRP) has been observed in some studies with elderly subjects and different patient groups. We studied whether serum hsCRP levels are linked with common APOE (epsilon 2, epsilon 3, epsilon 4) polymorphism already in children and young adults. METHODS: The study cohort included 1221 subjects participating in the Cardiovascular Risk in Young Finns Study at age 3-18 years at baseline in 1980. These subjects were reexamined at the 21-year follow-up at age 24-39 years in 2001. APOE phenotypes were examined in 1986, serum hsCRP was measured from fresh samples in 2001 and baseline hsCRP (in 1980) was measured from frozen samples in 2005. RESULTS: Serum hsCRP was significantly associated with APOE phenotypes in children and young adults using multivariate analysis adjusted for age, body mass index, smoking, total cholesterol and low-density lipoprotein cholesterol. Male epsilon 4 carriers had significantly lower hsCRP levels both in childhood (p=0.003) and in adulthood (p=0.013). hsCRP increased in both phenotype classes (epsilon 4+ and epsilon 4-) during the 21-year follow-up. Female epsilon 4 carriers had lower hsCRP levels in childhood (p=0.032) but not in adulthood (p=0.995). An interaction effect between time and APOE phenotype (p=0.045) in relation to hsCRP was observed in females during the 21-year follow-up. CONCLUSIONS: Common APOE polymorphism affects the level of circulating hsCRP already in children and young adults. Male APOE epsilon 4 carriers have consistently lower hsCRP levels. In females, APOE epsilon 4 carriers had lower hsCRP levels in childhood but not in adulthood.     

Apolipoprotein E3Basel: new insights into a highly conserved protein region

BACKGROUND: Apolipoprotein E is important for the receptor-mediated uptake of triglyceride-rich lipoproteins. Mutations in the gene encoding apolipoprotein E may cause a reduced uptake of these lipoproteins. Particular apolipoprotein E mutations have been also found to be associated with nephrologic, neurologic, and even ophthalmologic diseases. Hence, a continuously expanding role in biology is being attributed to this protein. DESIGN: Randomly selected volunteers from of a large Swiss cohort were genotyped for the common apolipoprotein E isoforms (apolipoprotein E2, apolipoprotein E3, apolipoprotein E4). RESULTS: In one of the volunteers, a novel C-to-T mutation causing an alanine-to-valine substitution (A106V, designated apolipoprotein E3Basel) was discovered. Alanine at residue 106 is highly conserved between mammalian species and is located in the immediate vicinity of the 112C/R polymorphism (apolipoprotein E4). Recombinant apolipoprotein E3Basel, expressed in the baculovirus system, displayed no detectable reduction in its low density lipoprotein (LDL) receptor- and heparin-binding activities. Despite normal binding functions, apolipoprotein E3Basel might cause modifications in the lipoprotein pattern. In the index case, plasma triglycerides were elevated and in two further apolipoprotein E3Basel-carriers, cholesterol, phospholipid, apolipoprotein CIII levels, LDL-cholesterol/apoB-100- and VLDL-triglyceride/VLDL-cholesterol-ratios were higher compared with apolipoprotein E3Basel-noncarriers when pair-matched for age and gender. One of the four apolipoprotein E3Basel-carriers from the index family had a personal history of Alzheimer's disease. CONCLUSIONS: Alanine at amino acid position 106 is highly conserved but not crucial in the receptor-mediated uptake of lipoprotein particles. Nevertheless, amino acid position 106 might be involved in the apolipoprotein E-dependent regulation of the lipoprotein lipase that hydrolyzes triglycerides and in the development of Alzheimer's disease.