5' ins/del and 3' VNTR polymorphisms in the apolipoprotein B gene in relation to lipids and coronary artery disease.

BACKGROUND: Studies that considered apolipoprotein B (APOB) gene polymorphisms as risk factors for coronary artery disease (CAD) have reported conflicting results. We sought to analyze the association between 5' ins/del and 3' VNTR polymorphisms of APOB, lipid parameters and CAD risk. METHODS: We recruited 251 patients with CAD, documented by coronary angiography, and 94 controls. Genotyping was performed by PCR. Lipids and apolipoproteins were measured. RESULTS: 5' ins/del (ins/ins, ins/del, del/del) and 3' VNTR (LL, SS, LS) polymorphism frequencies were significantly (p<0.05) different between controls and CAD patients. LL and del/del were significantly associated with higher levels of apolipoprotein B (apoB), total cholesterol/high-density lipoprotein cholesterol ratio and apoB/apoA-I ratio (p<0.05) and with increased risk of CAD. The odds ratio for significant coronary stenosis associated with del/del was 3.2 (95% CI 1.6-36.42) (p=0.032) and with LL was 2.2 (95% CI 1.1-5.1) (p=0.042). CONCLUSIONS: The two polymorphisms exert an impact on lipid levels and contribute to the susceptibility to the development of CAD.     

昆明地区汉族人群载脂蛋白E基因多态性频率分布及与高脂血症患者关系的研究

目的探讨ApoE112/158基因中,E3/E3、E2/E3、E2/E4、E3/E4、E4/E4、E2/E2基因型及等位基因频率及其与原发性高脂血症患者的相关性。方法采用病例-对照相关性研究策略,选择昆明地区汉族作为研究对象,对91例高脂血症患者及76例健康对照者进行了上述基因多态性检测。结果 (1)76例健康者中E3/E3、E2/E3、E2/E4、E3/E4、E2/E2基因型频率分别是0.263、0.421、0.237、0.066、0.013,未检出E4/E4基因型;E2、E3和E4等位基因频率分别是0.342、0.506、0.152。(2)91例高脂血症患者中,E3/E3等位基因频率高于对照组,差异有显著性意义(P0.001),Odd Ratio为7.392(95%CI:3.710～14.699)。E2/E3等位基因频率低于对照组,差异有极显著性意义(P0.001),Odd Ratio为0.209(95%CI:0.098～0.446)。而E2/E4、E3/E4基因型频率与对照组比较,差异无显著性意义(P0.05)。结论昆明地区汉族健康人群ApoE112/158基因多态性有地区特征。该地区汉族高脂血症患者中的E3/E3基因型与高脂血症的易感性相关,而E2/E3基因型与高脂血症发病保护性可能相关。     

昆明地区汉族人群载脂蛋白E基因多态性频率分布及与高脂血症患者关系的研究

目的探讨ApoE112/158基因中,E3/E3、E2/E3、E2/E4、E3/E4、E4/E4、E2/E2基因型及等位基因频率及其与原发性高脂血症患者的相关性。方法采用病例-对照相关性研究策略,选择昆明地区汉族作为研究对象,对91例高脂血症患者及76例健康对照者进行了上述基因多态性检测。结果 （1）76例健康者中E3/E3、E2/E3、E2/E4、E3/E4、E2/E2基因型频率分别是0.263、0.421、0.237、0.066、0.013,未检出E4/E4基因型;E2、E3和E4等位基因频率分别是0.342、0.506、0.152。（2）91例高脂血症患者中,E3/E3等位基因频率高于对照组,差异有显著性意义（P〈0.001）,Odd Ratio为7.392（95%CI：3.710～14.699）。E2/E3等位基因频率低于对照组,差异有极显著性意义（P〈0.001）,Odd Ratio为0.209（95%CI：0.098～0.446）。而E2/E4、E3/E4基因型频率与对照组比较,差异无显著性意义（P〉0.05）。结论昆明地区汉族健康人群ApoE112/158基因多态性有地区特征。该地区汉族高脂血症患者中的E3/E3基因型与高脂血症的易感性相关,而E2/E3基因型与高脂血症发病保护性可能相关。     

粤北地区瑶族人群载脂蛋白B基因多态性与血脂的关系

目的探讨粤北地区瑶族人群ApoB基因多态性与血脂的关系。方法应用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）技术对粤北地区瑶族高脂血症患者和健康个体各250例的ApoB进行基因分型,并检测其血脂水平。结果 X＋X-、E＋E-基因型个体中TC、LDL-C水平高于X-X-、E＋E＋纯合型（P〈0.05）,X＋X-、E＋E-基因型个体中TG水平明显高于X-X-、E＋E＋纯合型（P〈0.01）;携带X＋等位基因的个体患高脂血症的风险高于携带X-等位基因者（OR=1.957,95%CI：1.214~3.154）;携带E-等位基因的个体患高脂血症的风险高于携带E＋等位基因者（OR=1.466,95%CI：0.889~2.416）。结论瑶族人群ApoB基因XbaⅠ和EcoRⅠ位点基因多态性与血脂水平有关,X＋和E-等位基因可能是血脂增高的遗传危险因素。     

Serum lipid and apolipoprotein profiles in newborns and six-year-old children: the Tallinn Young Family Study

Seventy children aged 6 years (34 boys, 36 girls) were studied for cardiovascular risk factors. Among the children 40 had also been investigated at birth. The aim of the study was to determine changes in serum lipoprotein parameters from birth up to preschool age and to assess the role of some relevant factors that might affect the process. An obvious association was found between serum apolipoprotein (apo) B levels, the apoB/apoA-I ratio and lipoprotein(a) (Lp(a)) levels at birth and at 6 years of age (r = 0.43; p<0.05, r = 0.73; p<0.0001 and r = 0.81; p<0.0001, respectively). Thirty percent of children who were in the top quartile by apoB or total cholesterol levels and 66.7% of those in this quartile by apoB/apoA-I ratio at birth remained in the top quartiles also in the follow-up study. The significantly higher apoB/apoA-I ratio in newborns and the apoB/apoA-I and apoB values in the 6-year-old children were observed in the carrier apoE4 isoform as compared to E3 homozygotes. A significant influence of apoE polymorphism on serum apoB/apoA-I ratio and apoB level in preschool children was confirmed by ANOVA one-way analysis of variance. In a multiple regression analysis from all the studied factors, the independent determinants of apoB level in preschool age were apoE phenotype, gestational age and Apgar score in the first minute of life. Thus, tracking of serum Lp(a), apoB, apoB/apoA-I ratio and total cholesterol levels from birth up to 6 years of age was demonstrated. The association between apoE polymorphism and serum lipoprotein parameters became more obvious after the first 6 years of life.     

Major gene effects on apolipoprotein B concentrations in families of adolescents--results from a community-based study in Taiwan

BACKGROUND: Apolipoprotein (Apo) B is considered as a risk factor for atherosclerosis. Previous reports of segregation analyses on the mode of inheritance of Apo B were inconsistent because of heterogeneity in study population or elderly adult diseased probands. We performed complex segregation analysis of Apo B levels in the families of adolescents, systematically ascertained from junior high school students in a rural community in Taiwan. RESULTS: There is a sex-specific influence in the variation of apo B levels. The mother-daughter (0.216), sister-sister (0.181), sister-brother (0.179) correlations were higher than father-son (0.206), brother-brother (0.002) or cross-sex correlations for the variation in Apo B levels. By the variance component model, the heritability estimate was 26.3+/-6.7% (P<.0001) in Apo B levels. Commingling analysis indicated that a 2-component distribution was needed to account for Apo B variation. Segregation analysis using regressive models revealed that the best-fit model of Apo B was the model of major gene effect plus familial correlation. The gene frequency controlling high Apo B was 0.17, and 3 means of genotypes were 56.3, 54,2, and 117.2 mg/dl. CONCLUSION: Variations of Apo B levels in the normal range among adolescent families are controlled by major gene, and further identification of this gene locus will be mandatory.     

汉族人载脂蛋白B基因EcoRⅠMspⅠ多态性与冠心病的关系研究

目的 探讨我国北方地区汉族人载脂蛋白B(apoB)基因EcoRⅠ、MspⅠ多态性与冠心病的关系。方法 应用聚合酶链反应限制性片段长度多态性(PCR—RFLP)技术，检测了120名对照组和137例冠心病组apoB基因EcoRⅠ、MspⅠ多态性基因型和等位基因频率分布。研究了apoB基因多态性对血脂、脂蛋白和载脂蛋白水平的影响。结果 冠心病组与对照组apoB基因EcoRⅠ、MspⅠ多态性基因型和等位基因频率分布差异无显著性，且与性别、家族史、吸烟史、体重指数及冠脉病变程度无明显关系。两组间罕见的E—和M—等位基因存在连锁不平衡。冠心病组中E—等位基因携带者血清血清总胆固醉(TC)、低密度脂蛋白(LDL-C)明显高于仅含E 等位基因者。M—等位基因与各项血脂水平无明显相关性。结论 apoB基因EcoRⅠ、MspⅠ多态性对人群血脂水平有一定影响，但不是我国北方地区汉族人冠心病发生的独立危险因素。     

Abnormalities in apolipoprotein and lipid levels in an HIV-infected Brazilian population under different treatment profiles: the relevance of apolipoprotein E genotypes and immunological status.

HIV infection is associated with disturbances in lipid metabolism due to a host's response mechanism and the current antiretroviral therapy. The pathological appearance and progression of atherosclerosis is dependent on the presence of injurious agents in the vascular endothelium and variations in different subsets of candidate genes. Therefore, the Hha I polymorphism in the apolipoprotein E gene was evaluated in addition to triglycerides, total cholesterol, very low-density lipoprotein (VLDL), LDL, high-density lipoprotein (HDL), and apolipoprotein (apo) Al, B and E levels in 86 Brazilian HIV-infected patients and 29 healthy controls. The allele frequency for apoE in the HIV-infected group and controls was in agreement with data on the Brazilian population. Dyslipidemia was observed in the HIV group and verified by increased levels of triglycerides, VLDL and apoE, and decreased levels of HDL and apoAl. The greatest abnormalities in these biochemical variables were shown in the HIV-infected individuals whose immune function was more compromised. The effect of the genetic variation at the APOE gene on biochemical variables was more pronounced in the HIV-infected individuals who carried the apoE2/3 genotype. The highly active anti-retroviral therapy (HAART)-receiving group presented increased levels of total cholesterol and apoE. Dyslipidemia was a predictable consequence of HIV infection and the protease inhibitors intensified the increase in apoE values.     

Variants in the SLCO1B3 gene: interethnic distribution and association with paclitaxel pharmacokinetics

To explore retrospectively the relationships between paclitaxel pharmacokinetics and three known, non-synonymous single-nucleotide polymorphisms (SNPs) in SLCO1B3, the gene encoding organic anion transporting polypeptide (OATP)1B3. Accumulation of [(3)H]paclitaxel was studied in Xenopus laevis oocytes injected with cRNA of Oatp1b2, OATP1A2, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, and NTCP. The 334T>G (Ser112Ala), 699G>A (Met233Ile), and 1564G>T (Gly522Cys) loci of SLCO1B3 were screened in 475 individuals from five ethnic groups and 90 European Caucasian cancer patients treated with paclitaxel. Only OATP1B3 was capable of transporting paclitaxel to a significant extent (P=0.003). The 334T>G and 699G>A SNPs were less common in the African-American and Ghanaian populations (P<0.000001). Paclitaxel pharmacokinetics were not associated with the studied SNPs or haplotypes (P>0.3). The studied SNPs in SLCO1B3 appear to play a limited role in the disposition of paclitaxel, although their clinical significance in other ethnic populations remains to be investigated.     

Apolipoprotein B gene polymorphisms: prevalence and impact on serum lipid concentrations in hypercholesterolemic individuals from Brazil

Genetic polymorphisms at the apolipoprotein B (apo B) have been associated with elevated plasma concentrations of low-density lipoprotein (LDL) cholesterol, atherosclerosis and increased risk for coronary artery disease (CAD). In the present study, four apo B gene polymorphisms (MspI, XbaI, Ins/Del and 3'HVR) have been investigated to determine their frequencies and influence on the lipid profile of 177 hypercholesterolemic white Brazilian subjects (HG) and 100 control individuals (CG). The genotype distribution and allele frequency of MspI, XbaI and Ins/Del polymorphisms of apo B gene were similar between HG and CG groups. The frequency of the alleles smaller than 43 repeats (< or =43) of 3'HVR polymorphism in the HG group was higher when compared to controls (16.4 vs. 8.5%, P<0.05). Moreover, these alleles were associated with higher total cholesterol concentrations in serum of hypercholesterolemic individuals (P<0.05). In addition, an association between Ins/Del and 3'HVR polymorphism was observed. The alleles < or =43 and Del were more frequent in the HG when compared to the CG individuals (P<0.05). We concluded that 3'HVR polymorphism at the apo B gene may be an important genetic marker to evaluate atherosclerotic disease risk.     

Analysis of the apolipoprotein B gene and messenger ribonucleic acid in abetalipoproteinemia.

The apolipoprotein B-100 (apoB-100) gene in leukocytes and the apoB-100 messenger RNA (mRNA) and translated apolipoprotein in the livers from normal and abetalipoproteinemic individuals were evaluated. Four complementary DNA probes for apoB-100 covering the 5', middle, and 3' regions of the apoB-100 mRNA were utilized and Southern blot analysis indicated that the apoB-100 gene is present in abetalipoproteinemia without major insertions or deletions. Polyadenylated hepatic apoB-100 mRNA from two abetalipoproteinemic patients was normal in size, and the concentration of apoB-100 mRNA was increased sixfold compared with control hepatic apoB-100 mRNA levels. ApoB-100 was detected in hepatocytes of abetalipoproteinemic patients by immunohistochemical techniques. These results indicate that the biochemical defect in abetalipoproteinemic patients studied is most consistent with a posttranslational defect in apoB-100 processing or secretion with an up-regulation of the apoB-100 mRNA.     

Polymorphism of the apolipoprotein A-IV gene and its significance in lipid metabolism and coronary heart disease in a Japanese population

Apolipoprotein A-IV (apo A-IV) is involved in the metabolism of both triglycerides and high-density lipoproteins (HDLs). Apo A-IV has been suggested as participating in several stages of reverse cholesterol transport. Uncertainty about the exact biochemical function of apo A-IV has made the use of genetic apo A-IV polymorphism (variants) attractive in evaluating its physiological role. To date, although some reports indicate that DNA polymorphisms at this locus play an important role in the metabolism of lipids and lipoproteins in western (Caucasian) populations, no similar comprehensive analysis has been performed in a distinct Japanese population. Using DNA sequencing and a restriction fragment length polymorphism (RFLP) study with polymerase chain reaction (PCR), the following allele frequencies were established: (a) codon ?8 (G→A, non-synonymous) allele 2=0 (n=105); (b) codon 9 (A→G, synonymous) allele 2=0.388 (n=152); (c) codon 347 (A→T, non-synonymous) allele 2=0 (n=900); (d) codon 360 (T→G, non-synonymous) allele 2=0 (n=800); (e) VNTR exon 3 [(CTGT)₃ and (CTGT)₄] (CTGT)₃=0.262 (n=105); and (f ) MspI (newly detected polymorphic site) polymorphism (C C/T GG) within intron 2, allele 2=0.096 (n=193). The frequencies of these polymorphisms, except for that of the newly identified MspI site, are completely different from those reported in western populations. Among the 900 subjects examined, we found one ACT (Thr) to ACG (Thr) synonymous mutation at codon 347, which does not change the primary structure of apo A-IV. The apo A-IV allele frequency in patients (166 men and 56 women) with angiographically proven coronary heart disease (CHD) was also studied [codon 9 allele 2=0.329 (n=217); VNTR exon 3 (CTGT)₃=0.262 (n=84); MspI within intron 2, allele 2=0.092 (n=222)]. Furthermore, we evaluated serum lipid and lipoprotein levels quantitatively in control subjects and Japanese CHD patients. These polymorphisms did not show any consistent and significant association with lipid and lipoprotein parameters. In addition, no gender-specific effects of apo A-IV polymorphisms on lipid parameters adjusted for confounding factors were observed in either CHD patients or control subjects. Our results indicate that the apo A-IV gene is not a major determinant of the risk for CHD in Japanese.     

Immunoquantification of total apolipoprotein B in serum by nephelometry: influence of lipase treatment and detergents

The immunoquantification of total apolipoprotein B in human serum has been evaluated by rate and equilibrium nephelometry. The presence of triglyceride-rich lipoproteins spoiled all immunochemical assays and yielded too-high values for apolipoprotein B. The use of detergents improved the results substantially, but results were inaccurate at high triglyceride concentrations. Of many detergents investigated, only Thesit, Kryo Ebo, and Apovax were useful, decreasing the light-scatter signals almost linearly with increasing detergent concentrations. The regression lines, however, were not parallel among the different apo B-containing lipoproteins. Incubating sera or apo B-containing lipoproteins with bovine milk lipoprotein lipase or bacterial triacylglycerol lipase, at concentrations of 100 kU/L, hydrolyzed all of the triglycerides and most of the phosphatidylcholine within 18 h at 37 degrees C Lipase-pretreatment of samples gave optimal correlation between apo B values as determined by nephelometry with those obtained gravimetrically. We also assessed the influence of sample storage, freezing, and thawing on the nephelometric apo B assays.     

Apolipoprotein A-I, apolipoprotein B, and apolipoprotein B/apolipoprotein A-I ratio: reference intervals compared with values in different pathophysiological conditions from the FINRISK 2007 study

BackgroundIn addition to traditional measurements of serum lipid levels, apolipoprotein A-I (apoA-I), apolipoprotein B (apoB), and apoB/apoA-I ratio may add more value to risk assessment guidelines for cardiovascular disease.MethodsWe calculated reference intervals for apoA-I, apoB, and apoB/apoA-I ratio using a reference sample (n = 2828) from the FINRISK 2007 study.ResultsThe reference intervals for apoA-I were 1.1–2.0 g/l for men and 1.2–2.3 g/l for women. The corresponding reference intervals for apoB were 0.6–1.5 g/l and 0.6–1.3 g/l. The reference intervals for apoB/apoA-I ratio were 0.3–1.0 for men and 0.3–0.8 for women. Compared with the healthy reference group, obese men had the lowest ApoA-I, the highest apoB, and the highest apoB/apoA-I ratio. Men with CVD and cholesterol-lowering medication, or diabetes had lower apoB levels and apoB/apoA-1 ratio than the reference group but the opposite was true for women. The therapeutic goal for low-risk individuals for apoB was 0.9 g/l coinciding with LDL-C concentration of 3.0 mmol/l.ConclusionsReference intervals for apoA-I, apoB, and the apoB/apoA-I ratio and their cutoff values may be useful for the risk evaluation and follow-up of treatment among individuals having CVD or other metabolic disorders.     

apo(a)PNR基因多态性在汉族人群中的表达与冠心病的关系(英文)

目的:通过检测冠心病患者和正常人群apo(a)PNR基因型及血脂水平的变化,研究载脂蛋白(a)犤apo(a)犦五核苷酸重复序列(PNR)基因多态性与冠心病(CHD)及其血脂水平的关系。方法:采用聚合酶链反应结合高压变性聚丙烯酰胺凝胶电泳,分析了153例健康志愿者及88例冠心病患者(武汉大学中南医院,武汉大学亚太医院1998～1999住院患者)的apo(a)PNR基因型,同时检测基因型与血清脂质。脂蛋白和载脂蛋白水平之间的关系。结果:CHD组apo(a)PNR(TTTTA)5/8基因型频率(0.181)和(TTTTA)5等位基因频率(0.107)分别显著高于对照组(0.039,χ2=13.779,P<0.01;0.026,χ2=6.39,P<0.05);(TTTTA)5/8基因型者血清LP(a)水平高于(TTTTA)8/8,(TTTTA)8/9基因型者。结论:apo(a)PNR基因多态性与Lp(a)水平密切相关,apo(a)PNR(TTTTA)5等位基因可能是中国汉族人群冠心病的危险因子之一。此结论可为冠心病的康复、预防提供理论依据。     

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.     

Influence of intravenous n-3 lipid supplementation on fatty acid profiles and lipid mediator generation in a patient with severe ulcerative colitis

Abstract. N-3 fatty acids were supplied to a 36-year-old female patient suffering from ulcerative colitis and severe steroid side-effects, in a sequence of parenteral and enteral administration. During a moderately active period of disease, 200 ml d^-1 fish oil-derived lipid emulsion (eicosapentaenoic acid [EPA], 4–2 g; docosahexaenoic acid [DHA], 4.2 g) was infused for 9 days, in parallel with rapid tapering of the steroid dose. Disease activity declined rapidly, and the patient was subsequently provided with 16 fish oil capsules per day (EPA, 2.9 g; DHA, 1.9 g) for 2 months. At the end of this period of therapy, severe colitis recurred with intestinal and extraintestinal manifestations. The n-3 lipid emulsion was then used for intravenous alimentation (29 days, maximum dose 300 ml per day); during this time, marked improvement of the inflammatory bowel disease was noted. During both periods of parenteral n-3 lipid administration, total plasma EPA and DHA contents increased several-fold, surpassing that of arachidonic acid; this plasma n-3 fatty acid enrichment was only maintained to a minor extent during the intermediate period of dietary fish oil supplementation. The intravenously administered EPA-containing triglycerides were rapidly hydrolyzed, as evidenced by the appearance of substantial quantities of EPA in the plasma free fatty acid fraction. Platelet and neutrophil total membrane content of EPA and DHA as well as n-3 fatty acid/AA membrane ratios similarly increased during the periods of intravenous n-3 lipid administration and declined during oral fish oil uptake. In contrast, erythrocyte membrane enrichment in EPA and DHA occurred only after the prolonged (2 month) period of dietary n-3 lipid supplementation. Ex vivo stimulation of neutrophils with A23187 showed progressive increase in 5-series leukotriene- and 5-HEPE-generation during both periods of n-3 lipid infusion, in parallel with the rise of plasma EPA contents. Maximum 5-series/4-series leukotriene ratios surpassed 0.25. Similarly, ratios of thromboxane B₃/B₂ liberated from ex vivo stimulated platelets surpassed 0.4 during ongoing n-3 lipid infusion. The profound changes in fatty acid profiles and lipid mediator generation may be related to the reduction in colitis activity observed during the periods of intravenous n-3 lipid supplementation.