Apolipoprotein E polymorphism is related to plasma lipids and apolipoproteins in Mexican adolescents

Previous studies in the Mexican population have failed to show an effect of apolipoprotein E (APOE) polymorphism on the lipid profile. The purpose of the present study was to determine the frequencies of APOE phenotypes, and their influence on lipid and apolipoprotein levels in a random sample of Mexican adolescents living in Mexico City. APOE polymorphism, fasting insulin levels, lipid levels, and apolipoprotein levels were determined in 420 adolescents. We found a high frequency of APOE*3 subjects (89.5%) and a low frequency of APOE*2 (3.0%) and APOE*4 (7.5%) subjects. The APOE*4 subjects (including APOE 4,3 and APOE 4,4) showed the highest concentrations of total cholesterol, low-density lipoprotein cholesterol, and apoB and the lowest high-density lipoprotein cholesterol levels, whereas carriers of the APOE*2 allele (APOE 3,2 and APOE 2,2) had the lowest values for total and low-density lipoprotein cholesterol and the highest concentrations of high-density lipoprotein cholesterol. No significant differences in triglyceride and insulin levels among subjects with different APOE polymorphisms were observed. Unlike previous studies in the Mexican population, our results show that lipid and lipoprotein levels are under the influence of APOE polymorphism. As in whites, APOE*4 may be a cardiovascular risk factor in the Mexican population.     

Congruence of individual responsiveness to dietary cholesterol and to saturated fat in humans

Previous experiments have shown that differences between humans in the response of serum cholesterol to dietary cholesterol are at least partly reproducible and stable over a prolonged period. In this study it was investigated whether enhanced sensitivity to dietary cholesterol and saturated fat go together. The subjects had also participated in three or four experiments dealing with the reproducibility of the effect on blood cholesterol of either adding cholesterol to the diet in normal subjects (NORM-EGG group; n = 23) or of cessation of egg consumption in subjects with a high habitual egg intake (HAB-EGG group; n = 24). In the present experiment the NORM-EGG subjects were fed a mixed natural diet providing 21% of energy as polyunsaturated and 11% as saturated fat (P/S2 ratio, 1.9) for 3 weeks, and one providing 5% of energy as polyunsaturated fat and 23% as saturated fat (P/S ratio, 0.2) for the next 3 weeks. The HAB-EGG group was fed the same diets in reverse order. The serum cholesterol concentrations were higher on the low P/S diet than on the high P/S diet (on average 23% in normal subjects and 16% in habitual egg eaters). The correlation coefficient between each subject's serum cholesterol response to fatty acids and his or her average response to dietary cholesterol in the dietary cholesterol experiments was 0.62 for the normal subjects (P less than 0.01) and 0.15 for the HAB-EGG group. We conclude that modest differences in responsiveness of serum cholesterol to dietary saturated fat do exist in humans, and that, in people of normal cholesterol intake, responsiveness to dietary cholesterol and to saturated fat tend to go together.     

Apolipoprotein E polymorphism in Northern Indian patients with coronary heart disease: Phenotype distribution and relation to serum lipids and lipoproteins

Apolipoprotein E (apo E), a genetic determinant of plasma lipid levels and coronary heart disease (CHD) needs to be investigated in Asian Indians since they have a propensity to develop dyslipidemia and accelerated atherosclerosis. We studied apo E phenotypes and plasma lipid levels in 52 Northern Indian male patients (aged 38–71 years) with angiographically proven CHD, and compared them to 50 healthy blood donors taken as the control group. High levels of Lp(a), (p < 0.05), and a definite trend towards lower levels of HDL-C (p < 0.05), was observed in the CHD patients as compared to the control subjects. The frequency of apo E allele 3 was 0.86 and 0.862, and 4 allele was 0.12 and 0.08 in the patients and controls, respectively. However, a lower frequency of the E2 allele was observed in the patient group (2 = 0.02) as compared to the controls (2 = 0.06) (p = ns). In individuals with apo E3/E3 phenotype, significantly lower HDL-C levels was observed in the CHD patients as compared to the control subjects (p < 0.05). A positive correlation was observed between apo E phenotypes and Lp(a) levels in the CHD subjects as compared to the controls (p < 0.05), the level being significantly high in CHD subjects with at least one E4 allele. To conclude, in this sample of Northern Indian subjects with CHD, there is a significant correlation between apo E3/E3 phenotype and low levels of HDL-C as compared to the control subjects. Further, apo E phenotype is positively correlated with high Lp(a) levels in the CHD subjects having at least one E4 allele. However, these relationships need to be explored in a larger sample of subjects.     

Apolipoprotein J polymorphisms and serum HDL cholesterol levels in African blacks

Apolipoprotein J (apoJ, protein; APOJ, gene) is found in serum associated with high-density lipoprotein (HDL) subfractions, which also contain apolipoprotein A-I (apoA1) and cholesteryl ester transfer protein. ApoJ has been shown to be involved in a variety of physiological functions, including lipid transport. In earlier studies we reported the existence of a common genetic polymorphism (APOJ*1 and APOJ*2 alleles) using isoelectric focusing (IEF) and immunoblotting. In this study we determined the molecular basis of this polymorphism and together with another polymorphism at codon 328 (G-->A) evaluated its relationship with serum HDL cholesterol and apoA1 levels in 767 African blacks stratified by staff level: junior (less affluent, n = 450) and senior (more affluent, n = 317). The molecular analysis of the cathodally shifted APOJ*2 allele on IEF gels revealed an amino acid substitution of asparagine by histidine resulting from a missense mutation (A-->C) at codon 317 in exon 7. The frequency of the APOJ*2 (C) allele of codon 317 in the total sample was 0.267, whereas that of the less common allele A of codon 328 was 0.04. Despite their close proximity, no linkage disequilibrium was observed between the 2 polymorphisms. The impact of the codon 317 polymorphic variation was significant on serum HDL cholesterol (p = 0.003) and HDL3 cholesterol (p = 0.001) in junior staff. The adjusted mean values of these traits were higher in the codon 317 APOJ*2/*2 genotype than in the *1/*1 and *1/*2 genotypes. Overall, the APOJ codon 317 polymorphism explained 10.2% and 8.3% of the phenotypic variation in HDL cholesterol and HDL3 cholesterol, respectively, in junior staff. The codon 328 polymorphism showed a significant effect on HDL2 cholesterol (p = 0.039) and apoA1 (p = 0.007) only in junior women and accounted for 2.5% and 4.2% of the phenotypic variation in HDL2 cholesterol and apoA1, respectively. We also analyzed the combined effects of these genotypes at the 2 polymorphic sites. Significant effects on HDL cholesterol (p = 0.004) and HDL3 cholesterol (p = 0.008) in junior men and on HDL2 cholesterol (p = 0.003) in junior women were observed in the combined genotype data. The 2-locus genotypes explained 6.0% and 5.3% of the residual phenotypic variation of HDL cholesterol and HDL3 cholesterol in junior men and 10.4% of HDL2 cholesterol in junior women. These data indicate that the effect of the APOJ polymorphism on HDL cholesterol levels is modulated by socioeconomic status, as measured by staff level. Given the association of HDL and its subfractions with cardiovascular disease, these polymorphisms may lead to a better understanding of interracial differences in the risk of cardiovascular disease.     

Effects of dietary monounsaturated fatty acids on plasma lipids in humans

In order to test whether monounsaturated fatty acids (MUFA, M) would lower plasma cholesterol and/or triglycerides (TG), 14 young men were studied in a metabolism ward. They were given two experimental diets with the same P/S ratio (P: polyunsaturated; S:saturated fatty acids) but different P + M/S ratios in composition of dietary fatty acids. Six men were in experiment I. In two groups of three, each group was given either the high or the low P + M/S ratio diet for 6 weeks. In experiment II, two groups of four men were subjected to a 3-week cross-over feeding trial (total of 6 weeks). We found in the crossover study that when the dietary P/S ratio was fixed at 1.0, those subjects given a diet with the higher P + M/S ratio of 4.5 showed significantly higher plasma total TG, very low density lipoprotein (VLDL)-TG, low density lipoprotein (LDL)-TG, and LDL-cholesterol than when given a diet with a lower P + M/S ratio of 1.5. Plasma total cholesterol, apoprotein A-I, and apoprotein B-100 were not significantly different between the two dietary periods. Plasma fatty acid patterns showed a significantly higher plasma MUFA level during the period of a higher P + M/S diet. In contrast to some recent reports, our studies indicate that a large amount of dietary MUFA may raise some fractions of plasma lipids in humans.     

Roles of acyl-coenzyme A:cholesterol acyltransferase-1 and -2

Acyl-coenzyme A:cholesterol acyltransferase (ACAT) is an intracellular enzyme that produces cholesteryl esters in various tissues. In mammals, two ACAT genes (ACAT1 and ACAT2) have been identified. Together, these two enzymes are involved in storing cholesteryl esters as lipid droplets, in macrophage foam-cell formation, in absorbing dietary cholesterol, and in supplying cholesteryl esters as part of the core lipid for lipoprotein synthesis and assembly. The key difference in tissue distribution of ACAT1 and ACAT2 between humans, mice and monkeys is that, in adult human liver (including hepatocytes and bile duct cells), the major enzyme is ACAT1, rather than ACAT2. There is compelling evidence implicating a role for ACAT1 in macrophage foam-cell formation, and for ACAT2 in intestinal cholesterol absorption. However, further studies at the biochemical and cell biological levels are needed in order to clarify the functional roles of ACAT1 and ACAT2 in the VLDL or chylomicron synthesis/assembly process.     

Genes, variation of cholesterol and fat intake and serum lipids

Several studies have examined gene-diet interactions in the response of plasma lipid concentrations to changes in dietary fat and/or cholesterol. Among the gene loci examined, APOE has been the most studied, and the current evidence suggests that this locus might be responsible for some of the interindividual variability in dietary response. Other loci, including APOA4, APOA1 and APOB have also been found to account for some of the variability in the fasting and fed states.     

APOA1/C3/A4/A5基因簇的新载脂蛋白基因：APOA5及其研究进展

应用人和鼠的比较基因组学和功能基因组学方法,Pennaccio等和Vliet等分别在APOA1/C3/A4基因簇中发现新的载脂蛋白基因APOA5。人的APOA5基因编码366个氨基酸,与人APOA4、小鼠Apoa5高度同源。APOA5转基因小鼠其甘油三酯（TG）减少至野生型的1/3,而Apoa5基因敲除小鼠其TG却增加4倍。APOA5多态位点SNP3（-1131T>C）和S19W及单倍型APOA5*3有显著升高TG的作用。APOA5调节血浆TG水平的作用与APOC3作用相反,为冠心病等心血管疾病的易感因素。     

Effect of apolipoprotein A-IV genotype and dietary fat on cholesterol absorption in humans

We investigated the effect of the A-IV-2 allele, which encodes a Q360H substitution in apolipoprotein (apo) A-IV, and dietary fat on cholesterol absorption in humans. In three separate studies we compared fractional intestinal cholesterol absorption between groups of subjects heterozygous for the A-IV-2 allele (1/2) and homozygous for the common allele (1/1) receiving high cholesterol ( approximately 800 mg/day) diets with different fatty acid compositions. All subjects had the apoE 3/3 genotype. There was no difference in cholesterol absorption between the two genotype groups receiving a high saturated fat diet (33% of total energy as fat; 18% saturated, 3% polyunsaturated, 12% monounsaturated) or a low fat diet (22% of total energy as fat; 7% saturated, 7% polyunsaturated, 8% monounsaturated) diet. However, on a high polyunsaturated fat diet (32% of total energy as fat; 7% saturated, 13% polyunsaturated, 12% monounsaturated) mean fractional cholesterol absorption was 56. 7% +/- 1.9 in 1/1 subjects versus 47.5% +/- 2.1 in 1/2 subjects (P = 0.004). A post hoc analysis of the effect of the apoA-IV T347S polymorphism across all diets revealed a Q360H x T347S interaction on cholesterol absorption, and suggested that the A-IV-2 allele lowers cholesterol only in subjects with the 347 T/T genotype.We conclude that a complex interaction between apoA-IV genotype and dietary fatty acid composition modulates fractional intestinal cholesterol absorption in humans.     

Apolipoprotein A1 Forms 5/5 and 5/4 Antiparallel Dimers in Human High-density Lipoprotein

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Highlights

• •Zero-length chemical cross-linking of APOA1 peptides in HDL.
• •Cross-links match antiparallel isomers of APOA dimers in molecular modeling.
• •Identical MS/MS spectra of native and synthetic cross-linked peptides.
• •First biochemical evidence of LL5/5 and LL5/4 isomers in human HDL.

     

Apolipoprotein E polymorphism and its association with serum lipid levels in Brazilian children

The influence of apolipoprotein E (APOE) genotypes on plasma lipid levels was determined in 414 Brazilian healthy children of mixed ethnicity, age 5 to 15 years (mean 8.9+/-2.9). The APOE*3 allele was the most frequent (77%), followed by APOE*4 (17%) and APOE*2 (6%). The pattern of lipid differences among genotypes was similar in both boys and girls. We did not detect an increase in cholesterol levels with the presence of the APOE*4 allele. Because a growing body of evidence suggests that the effect of *4 depends on its interaction with diet, the frequency of *4 might be more variable in children than in adults as well as among populations. Children carrying a *2 allele had lower total cholesterol (TC) and LDL-cholesterol levels (138.47+/-24.32 and 77.72+/-19.42, respectively) compared with *3/*3 children (158.33+/-25.28 and 97.05+/-21.82, respectively). Mean TC/HDLC ratio was also lower in children with the APOE*2 allele (3.27+/-0.66 versus 3.64+/-0.76). In this highly admixed population sample, the *2 anti-atherogenic lipid pattern is already detected in children.     

Association between the interleukin-6 promoter polymorphism -174G/C and serum lipoprotein(a) concentrations in humans

Background

Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease. The interleukin-6 (IL-6) receptor antagonist tocilizumab has been shown to lower serum Lp(a) concentrations. We investigated whether the IL-6 single nucleotide polymorphism −174G/C is associated with baseline serum Lp(a) concentrations.

Methodology/Principal Findings

We divided 2321 subjects from the Lipid Analytic Cologne (LIANCO) cohort into 2 groups, the ones with substantially elevated Lp(a), defined as concentrations ≥60 mg/dl (n = 510), and the ones with Lp(a) <60 mg/dl (n = 1811). The association with the genotypes GG (33.7%), GC (50.75%) and CC (15.55%) was investigated. The GC and the CC genotype were associated with a significantly increased odds ratio of having substantially elevated Lp(a) concentrations (OR = 1.3, 95% CI 1.04 to 1.63, P = 0.02 and OR = 1.44, 95% CI 1.06 to 1.93, P = 0.018). These associations remained significant after adjusting for age, sex, smoking behavior, body mass index, serum lipoproteins, hypertension and diabetes. Of these covariates, only LDL cholesterol was significantly and independently associated with elevated Lp(a) concentrations.

Conclusions/Significance

The IL-6 single nucleotide polymorphism −174G/C is associated with increased odds of having elevated Lp(a). Whether this association plays a role in the Lp(a)-lowering effects of IL-6 receptor antagonists remains to be established.