载脂蛋白A5与血脂代谢

载脂蛋白A5是载脂蛋白家族的新成员,对动物实验和人类观察研究发现,其基因多态性及蛋白浓度均与血浆甘油三酯密切相关,其影响血脂的机制主要是通过激活脂蛋白脂酶和抑制载脂蛋白B与载脂蛋白C3的作用。载脂蛋白A5的基因转录受到多种因素的调控。     

载脂蛋白A5研究现状

载脂蛋白A5是载脂蛋白家族的新成员。载脂蛋白A5基因多态性可以影响血浆甘油三酯水平,这种作用可能是通过调节肝脏极低密度脂蛋白的合成和促进极低密度脂蛋白分解来实现的。载脂蛋白A5可能是脂蛋白脂酶的激活剂,其可加强结合在蛋白多糖上的脂蛋白脂酶对极低密度脂蛋白和乳糜微粒的水解作用。载脂蛋白A5基因多态性可能是冠心病新的危险因子。     

载脂蛋白家族新成员——载脂蛋白A5基因研究进展

通过抑制消减杂交技术和生物信息学技术发现并证实了载脂蛋白家族新成员载脂蛋白A5基因的存在，进一步的实验结果证实该基因定位于人11号染色体长臂23区。该基因可能在欠鼠肝脏再生过程中调节肝脏脂质的摄入量，但具体机制不详。转基因动物以及基因敲除动物与对照组动物比较发现，该基因非常显著地影响实验组动物的血浆甘油三酯水平。讨论了在不同地域人群中该基因的多态性以及单倍型与人血浆中甘油三酯水平的关系，介绍了载脂蛋白A5的表达调控机制。     

载脂蛋白AⅤ研究进展

人载脂蛋白AⅤ是一种新发现的载脂蛋白，平均分子质量为38905 Da，由366个氨基酸组成，在血浆中的含量甚微，主要在肝脏中表达。基因定位于11号染色体长臂q23区，与载脂蛋白AI／CⅢ／AⅣ基因簇紧密相联，在人群中存在多个单核苷酸多态性位点，其中5种主要的单核苷酸多态性组成3种单倍型。它们在人群中的分布频率及其对血浆甘油三酯浓度的影响因种族和性别存在差异，载脂蛋白AⅤ也是迄今发现的唯一一个高表达能降低血浆甘油三酯含量的载脂蛋白。它参与血脂的转运与代谢；降低血浆中甘油三酯的浓度；在肝脏再生中起上调作用。有关它的表达调控及其生理、病理功能尚需进一步研究。     

内源性高甘油三酯血症患者载脂蛋白AⅠ基因MspI酶切位点多态性

探讨中国人内源性高甘油三酯血症患者载脂蛋白AⅠ基因MspI酶切位点变异频率及其对血脂、载脂蛋白水平的影响。应用多聚酶链反应对成都地区汉族 2 5 5例正常人和 134例内源性高甘油三酯血症患者apoAⅠ基因启动子 (- 78bp)及内含子I(+83bp)两个MspI限制性片段多态性进行分析。内源性高甘油三酯血症组及对照组载脂蛋白AⅠ基因MspI的多态性以G/G基因型占优势。载脂蛋白AⅠ基因启动子区MspI酶切位点A等位基因频率内源性高甘油三酯血症组显著高于对照组 (0 .35 0比 0 .2 73,P <0 .0 5 ) ,并显著高于欧美的白种人 (0 .30 0vs 0 .12 0～ 0 .191,P <0 .0 1) ,而 +83bpT等位基因则未见差异。在所研究对象中具有A/A基因型者血清甘油三酯水平、甘油三酯 /高密度脂蛋白胆固醇比值及载脂蛋白CⅢ水平较具有G/G及G/A基因型者显著升高 (P <0 .0 5 ) ,血清载脂蛋白CⅡ水平有增加趋势 (P >0 .0 5 )。载脂蛋白AⅠ基因启动子 (- 78bp)MspI酶切位点的突变与中国人内源性高甘油三酯血症有一定关联 ,载脂蛋白AⅠ基因A/A基因型对血清甘油三酯、载脂蛋白CⅡ水平及甘油三酯 /高密度脂蛋白胆固醇比值的升高有一定影响。     

冠心病患者载脂蛋白A5基因多态性与冠状动脉病变程度的相关性

目的分析冠心病患者载脂蛋白A5基因多态性与冠状动脉病变程度的关系。方法采用聚合酶链反应—限制片长多态性技术分别对260例经冠状动脉造影确诊为冠心病的研究对象载脂蛋白A5基因-1131T>C和c.553G>T多态性位点基因型进行检测;其冠状动脉病变程度由病变支数及Gensini积分表示。结果冠心病患者载脂蛋白A5-1131CC基因型人群和c.553T等位基因携带者血清甘油三酯水平明显高于-1131T等位基因携带者和c.553GG基因型人群(P=0.016和0.008);不同冠状动脉病变支数组间载脂蛋白A5基因型分布和不同基因型间Gensini积分的差异无统计学意义(P>0.05);冠状动脉病变支数和Gensini积分与糖尿病发病率呈显著正相关(r=0.141和0.143,P均<0.05),而与血清高密度脂蛋白胆固醇水平则呈显著负相关(r=-0.129和-0.164,P均<0.05)。结论冠心病患者载脂蛋白A5基因-1131T>C和c.553G>T多态性与其血清甘油三酯水平存在一定的相关性,但与冠状动脉病变程度无关。     

载脂蛋白A1/C3/A4/A5基因簇多态性研究进展

血浆三酰甘油水平受基因和环境的双重影响,是脑血管病的重要危险因素之一。人载脂蛋白A1／C3／A4／A5基因簇定位于11号染色体上,对血脂代谢有重要影响。业已证实,APOA1／C3／A4／A5基因簇上的基因突变与血浆三酰甘油水平有关,但研究结果不一。文章将对此基因簇上不同基因多态性位点与血脂代谢及动脉粥样硬化的关系做了综述。     

中国人内源性高甘油三酯血症与载脂蛋白A5基因-1131T>C多态性、S19W多态性的相关性

目的探讨中国人内源性高甘油三酯血症患者载脂蛋白A5基因的-1131T〉C多态性及S19W多态性与血脂水平的关系。方法用聚合酶链反应-限制性片断长度多态性分析，对182名内源性高甘油三酯血症患者和200名血脂正常者的载脂蛋白A5基因启动子上游-1131T〉C单核苷酸多态性、编码区的S19W（c．56C〉G）多态性、空腹血脂及载脂蛋白水平进行分析。结果患者的体质指数、血清总甘油三酯和总胆固醇水平较对照组显著升高，高密度脂蛋白胆固醇水平则显著降低。-1131T／C单核苷酸多态性位点T和C等位基因频率在病例组和对照组分别为52．7％、47．3％和67.0％、33．0％。等位基因频率和基因型频率分布符合Hardy-Weinberg平衡定律。T/C基因多态性等位基因T和C频率在两组问的差异有显著性（P〈0．05）；S19W多态性与内源性高甘油三酯血症发病风险未见明显相关性。结论载脂蛋白A5基因-1131C等位基因与血清甘油三酯的升高相关。     

载脂蛋白E基因多态性与老年冠心病和脑梗死的关系

冠心病和脑梗死,尤其是动脉血栓性脑梗死,二者共同的病理基础和主要发病因素之一是动脉粥样硬化.动脉粥样硬化形成受多种因素的影响,其中脂质沉积发挥重要作用.载脂蛋白E(apoE)是血浆中主要载脂蛋白之一,具有多态性,参与机体脂质代谢及调节胆固醇平衡.有关apoE基因多态性与冠心病和脑梗死的研究较多,结果不一致.我们对老年冠心病和脑梗死的apoE基因多态性进行研究,以探讨apoE基因多态性与老年心脑血管疾病之间的相关关系.     

国人载脂蛋白E基因多态性与冠心病发病之间的相关性

目的 探讨载脂蛋白E基因112bp与158bp位点多态性与血脂水平及冠心病发生之间的关系。方法采用生物化学法分别测量经冠状动脉造影证实的89例冠心病患者及43例正常人空腹血脂水平，应用聚合酶链反应限制片长多态性分析方法对载脂蛋白E基因DNA244bp的5’末端片段进行限制性片段长度多态性分析。结果冠心病组甘油三酯、总胆固醇、低密度脂蛋白、载脂蛋白B及脂蛋白（a）水平均高于对照组（P〈0．05），而载脂蛋白A1水平则低于对照组（P〈0、05）；冠心病组载脂蛋白Eε2基因型频率明显为低（P〈0．001）。结论载脂蛋白E基因多态性特征会明显影响人群中个体的血浆脂质水平，从而增加人群中个体发生冠心病的危险。     

Lipoprotein predictors of the severity of coronary artery disease in men and women

In this study we examined the relationships between levels of several components of plasma lipoproteins and severity of coronary artery disease in 65 men and 42 women who underwent coronary arteriography for suspected coronary disease. Severity of coronary atherosclerosis was scored as the extent of disease seen at arteriography. Univariate analyses of the relationships between the plasma lipoprotein parameters and score for severity of atherosclerosis revealed a marked difference between men and women. In men, the score for severity of atherosclerosis was strongly related to the low-density lipoprotein (LDL) cholesterol and apolipoprotein B concentrations, whereas in women it was related to the triglyceride concentrations in plasma intermediate-density lipoprotein (IDL) and LDL and to the cholesterol and apolipoprotein B concentrations in IDL. The significance of these correlations was not negated by possible confounding factors such as alcohol intake, diabetes, and treatment with thiazides and beta-adrenergic blockers. Stepwise regression analyses of data adjusted for weight and age indicated that 22% of the variation in the score for severity of atherosclerosis could be accounted for by levels of LDL cholesterol in men. No other lipoprotein parameter could account for any further variation. In contrast, cholesterol did not account for any variation in the score for severity of atherosclerosis in women, whereas plasma triglyceride accounted for 16% of the observed variation in this group. No relationships were found between score for severity of atherosclerosis and high-density lipoprotein cholesterol or plasma apolipoprotein A-I concentrations in either group.(ABSTRACT TRUNCATED AT 250 WORDS)     

载脂蛋白A5与甘油三酯代谢及胰岛素抵抗的关系

近年来高甘油三酯(HTG)所致的脂毒性已引起广泛关注,其可引起并加重胰岛素抵抗(IR),使胰岛素的生物学效应降低.而载脂蛋白A5(ApoA5)可降低血浆甘油三酯(TG)水平.目前对于ApoA5与TG的关系仍存在争议,ApoA5调节血脂代谢的机制尚未阐明.明确ApoA5与TG代谢及lR的关系可能会对揭示脂代谢、糖尿病的发...     

Genetic basis of dyslipidemia in disease precipitation of coronary artery disease (CAD) associated type 2 diabetes mellitus (T2DM)

Type 2 diabetes mellitus (T2DM) and its complications are linked to environmental, clinical, and genetic factors. This review analyses the disorders of lipids and their genetics with respect to coronary artery disease (CAD) associated with T2DM. Cell organelles, hepatitis C‐virus infection, reactive oxygen species produced in mitochondria, and defective insulin signaling due to the arrest of G1 phase to S phase transition of β‐cells have significant roles in the precipitation of the diseases. Adiponectin is anti‐inflammatory and anti‐atherosclerotic and improves insulin resistance. Low‐density lipoprotein (LDL) is atherosclerotic, and LDL‐cholesterol in T2DM is associated with high‐cardiovascular risk. Further, LDL cholesterol reduction significantly reduces cardiovascular morbidity and mortality. High‐density lipoprotein (HDL) is also anti‐atherosclerotic due to HDL associated paraoxonase‐1 serum enzyme, which prevents LDL oxidative modifications and the development of CAD. Moreover, elevated apolipoprotein B and apolipoprotein A‐I (ApoB/ApoA‐I) ratio in plasma is also a risk factor for CAD. LDL receptor, adiponectin, and endocannabinoid receptor‐1 genes are independently associated with CAD and T2DM. Polymorphism of Apo E2 (epsilon2) is a positive factor to increase the T2DM risk and Apo E4 (epsilon4) is a negative factor to reduce the disease risk. Taq 1B polymorphism of cholesterol ester transfer protein (CETP) gene contributes to the development of atherosclerosis, whereas haplotypes of APOA5, APOC3, APOC4, and APOC5 genes are in the same cluster and are independently associated with high plasma triglyceride level, CAD and T2DM. In conclusion, because various genes, LDLR, CETP, APOA5, Apo E, Apo B, and Apo A‐I, are associated with the precipitation of CAD associated with T2DM, a personalized diet–gene intervention therapy may be advocated to reduce the disease precipitation. Copyright © 2014 John Wiley & Sons, Ltd.     

Influence of apolipoproteins on the anatomical distribution of arterial disease.

The association of raised triglyceride levels with peripheral arterial disease has indicated that different interactions of environmental, biochemical and genetic risk factors promote atherosclerosis in particular sites. This hypothesis was investigated in patients presenting with atherosclerotic disease in the carotid (n = 23) or peripheral arteries (n = 94) before the age of 50 years; symptomatic coronary artery disease was also present in some patients (n = 35). Patients presenting with carotid disease had the highest levels of cholesterol (mean 7.6 mmol/l, P less than 0.05), apolipoproteins B (mean 1.02 g/l) and CIII (median 22.8 mg/dl, P less than 0.05) but normal levels of apolipoprotein AI. Patients presenting with peripheral arterial disease were the heaviest smokers and this was the only group where hypertriglyceridaemia was observed. Patients with coronary artery disease had the lowest levels of apolipoprotein AI (mean 1.15 g/l, P less than 0.05). Although polymorphic variation in the apolipoprotein genes did not appear to influence the distribution of symptomatic disease, genetic variation at two polymorphic sites in the apolipoprotein AI-CIII-AIV gene cluster was associated with differences in triglyceride levels. The control of the metabolism of triglyceride rich particles by apolipoproteins may predispose to atherosclerosis in specific sites, low levels of apolipoprotein AI selectively promoting coronary artery atherosclerosis and high levels of apolipoprotein CIII selectively promoting carotid artery atherosclerosis.     

The -1131T>C polymorphism in the apolipoprotein A5 gene is related to hypertriglyceridemia in Taiwanese aborigines

The prevalence of hypertriglyceridemia, considered to be an independent risk factor for the development of cardiovascular disease, is high in Taiwanese aborigines. This study was undertaken to examine the effect of the -1131T>C polymorphism in the apolipoprotein A5 gene on serum triglyceride levels in female Taiwanese aborigines. This was a cross-sectional study, and a total of 316 unrelated female Taiwanese aborigines were genotyped at the -1131T>C polymorphism in apolipoprotein A5 using the polymerase chain reaction-restriction fragment length polymorphism method. Serum triglyceride > or = 150 mg/dL was defined as the hypertriglyceridemia group and triglyceride < 150 mg/dL was considered to be the control group. The frequency of the minor C allele was significantly higher in the hypertriglyceridemia group (0.53) than in the control group (0.35) (p < 0.001). The frequency of this rare allele was comparable to that in Japanese and Han Chinese, but was higher than that in Caucasians. In a multiple logistic model adjusted for possible confounders, C allele-containing variants were independently associated with greater risks (CT genotype: OR = 3.28, 95% CI = 1.43-7.56; CC genotype: OR = 5.86, 95% CI = 2.15-15.99) of hypertriglyceridemia than the TT genotype (p < 0.01), notably with the CC homozygote exhibiting the greatest risks. The genotype polymorphisms were also associated with serum triglyceride concentrations in a linear fashion (for trend, p < 0.05). Our results indicate that the -1131T>C polymorphism of the Apo A5 gene influences serum triglyceride levels in female Taiwanese aborigines, and that differences exist in the frequency of the C allele among people of various ethnicities.     

Apolipoprotein A5, a newly identified gene that affects plasma triglyceride levels in humans and mice

Apolipoprotein A5 (APOA5) is a newly described member of the apolipoprotein gene family whose initial discovery arose from comparative sequence analysis of the mammalian APOA1/C3/A4 gene cluster. Functional studies in mice indicated that alteration in the level of APOA5 significantly affected plasma triglyceride concentrations. Mice that overexpressed human APOA5 displayed significantly reduced triglycerides, whereas mice that lacked apoa5 had a large increase in this lipid parameter. Studies in humans have also suggested an important role for APOA5 in determining plasma triglyceride concentrations. In these experiments, polymorphisms in the human gene were found to define several common haplotypes that were associated with significant changes in triglyceride concentrations in multiple populations. Several separate clinical studies have provided consistent and strong support for the effect with 24% of whites, 35% of blacks, and 53% of Hispanics who carry APOA5 haplotypes associated with increased plasma triglyceride levels. In summary, APOA5 represents a newly discovered gene involved in triglyceride metabolism in both humans and mice whose mechanism of action remains to be deciphered.     

Apolipoprotein(a) polymorphism and its association with plasma lipoprotein(a) levels: a north Indian study

Elevated levels of lipoprotein(a) has been regarded as an independent risk factor for coronary, peripheral and cerebral atherosclerosis. The enormous intra-personal variation in the plasma concentration of lipoprotein(a) is almost entirely controlled by the apolipoprotein(a) i.e. gene locus on the chromosome 6q 26-27. The apolipoprotein(a) molecule is highly polymorphic and is known to exist in multiple, genetically determined isoforms. These polymorphisms may be responsible for difference in promoter activity, variable size of apolipoprotein(a) and thereby variation in plasma lipoprotein(a) concentration. We studied the effect of two types of polymorphisms, (i) variation in length of the pentanucleotide repeat in the 5' flanking region starting -1373 bp upstream of AUG codon, and (ii) the Kringle-4 type 2 size polymorphism, on plasma lipoprotein(a) levels in North Indian population. The study group consisted of 88 angiographically assessed male coronary artery disease patients (age range 30-70 years) and 83 age- and sex-matched healthy controls. The pentanucleotide repeat polymorphism was analysed using polymerase chain reaction. In all, 8/11 pentanucleotide repeat isoforms were observed. Using SDS-agarose gel electrophoresis and immunoblotting isoforms having 12-50 Kringle-4 type 2 repeats were detected. Our study indicates a strong association of elevated plasma lipoprotein(a) concentration with coronary artery disease. An inverse correlation was seen between lipoprotein concentration and isoform size for both the pentanucleotide repeat polymorphism and the Kringle-4 type 2 polymorphisms; statistically significant difference (p = 0.001) was, however, observed only for the later.     

Interaction of the G182C polymorphism in the APOA5 gene and fasting plasma glucose on plasma triglycerides in Type 2 diabetic subjects.

AIM: Apolipoprotein AV (APOA5) is an important determinant of plasma triglyceride concentration. This study aimed to investigate the relationship of an amino acid substitution at position 182 (G182C) of the apolipoprotein AV (APOA5) gene with triglyceride concentration in a Taiwanese population. METHODS: This study enrolled two cohorts: non-diabetic subjects (112 males and 89 females) aged 50.3+/-11.0 years (mean+/-sd) and diabetic subjects (106 males and 96 females) aged 62.1+/-10.3 years. The relationship between the G182C polymorphism (rs 2075291) and plasma triglycerides was examined. Demographic and metabolic parameters including age, sex, body mass index, fasting plasma glucose and total cholesterol were also obtained. RESULTS: The G182C polymorphism was a determinant of plasma triglycerides in both non-diabetic (P=0.022) and diabetic (P=0.003) groups, independent of age, gender, fasting plasma glucose, body mass index and total cholesterol. In the diabetic group, this genetic polymorphism interacts significantly (P=0.032) with fasting plasma glucose concentration on plasma triglycerides after adjustment for age, sex, body mass index and total cholesterol. CONCLUSIONS: In conclusion, the G182C polymorphism of the APOA5 gene affects plasma triglycerides in both non-diabetic and diabetic populations. The observed interaction of gene and glycaemic control further indicates a multifactorial nature of clinical phenotypes in subjects with Type 2 diabetes.     

Association between DNA variant sites in the apolipoprotein A5 gene and coronary heart disease in Chinese

The recently discovered apolipoprotein A5 ( APOA5 ) gene has been shown to be important in determining plasma triglyceride levels, a major cardiovascular disease risk factor. We searched for possible associations of the APOA5 gene polymorphisms S19W and -1131T>C with coronary heart disease (CHD) in a Chinese population. A total of 483 Chinese CHD patients and 502 control non-CHD subjects were genotyped by polymerase chain reaction-restriction fragment length polymorphism for these 2 single nucleotide polymorphisms. We found that the minor allele 19W was observed only in CHD patients and not in controls, with allelic frequencies of 0.047 and 0.000, respectively ( P < .000001), and the minor allele -1131C was significantly higher in CHD patients than in controls (0.391 vs 0.299, P < .0001). These results suggest that both the S19W and -1131T>C variations in the APOA5 gene are associated with the CHD and appear to be 2 genetic risk factors for CHD susceptibility in Chinese. Moreover, we found that triglyceride levels were significantly higher in -1131C carriers than in -1131T subjects of the control group and that high-density-lipoprotein cholesterol was decreased in -1131C carriers among CHD patients.