Common genetic variation in the ATP-binding cassette transporter A1, plasma lipids, and risk of coronary heart disease

The ATP-binding cassette transporter A-1 (ABCA1) regulates cholesterol efflux from cells and is involved in high-density lipoprotein (HDL) metabolism and atherogenesis. We investigated whether common ABCA1 variants, previously reported to have phenotypic effects in humans, were associated with plasma lipids and CHD in a prospective study of coronary heart disease (CHD) in healthy women. Three polymorphisms in the promoter region (-565C/T, -191G/C, and -17C/G) and two in the coding region (I883M and R1587K) were genotyped in the Nurses' Health Study. During 8 years of follow-up, 249 incident cases of CHD were identified and matched to controls (1:2) on age and smoking. The I883M variant was associated with higher HDL-cholesterol levels among younger women. Nearly complete linkage disequilibrium was observed between -565C/T and -191G/C and their less common alleles predicted a lower risk of CHD (odds ratio of CHD per -191C allele: 0.8; 95% CI, 0.6-1.0). Neither the -17C/G SNP nor the 2 the coding polymorphisms were associated with risk of CHD. The -565C/T and the -191G/C variants were inversely associated with risk of CHD among healthy women, without pronounced effects on plasma lipids.     

三磷酸腺苷结合盒转运子A1基因多态性与冠心病及缺血性脑卒中的关系研究

目的探讨三磷酸腺苷结合盒转运子A1(ATP-binding cassette transporter A1,ABCA1)基因多态性与广西汉族人群冠心病(CHD)及缺血性脑卒中(IS)易感的相关性。方法选择住院患者1134例,根据诊断分为CHD组565例、IS组569例,同时选择年龄、性别匹配的健康人群541例作为对照组,进行临床资料分析,采用聚合酶链反应-限制性片段长度多态性检测ABCA1基因的单核苷酸多态性(SNP)位点rs2066715和rs2740483的基因分型,探讨其与CHD及IS易感的相关性。结果 3组rs2066715基因型及等位基因频率差异无统计学意义(P>0.05),该SNP与CHD及IS的易感无相关性(P>0.05);与对照组比较,CHD组和IS组rs2740483等位基因和基因型频率分布差异均有统计学意义(P<0.05,P<0.01);该SNP与CHD及IS的易感有相关性(P<0.05)。结论 ABCA1rs2740483与广西汉族CHD和IS易感相关,携带野生型等位基因的个体有更高的罹患风险。     

新疆维吾尔族ATP结合盒转运子A1基因R219K多态性与冠心病的关系

目的：探讨ATP结合盒转运子A1基因（ATP binding cassette transporter1,ABCA1）R219K多态性在新疆维吾尔族人群中的分布及其与冠心病（CHD）的关系。方法：采用病例对照研究。用聚合酶链式反应-限制性片段长度多态性（PCR～RFLP）方法测定ABCA1基因多态性。结果：新疆维吾尔族ABCA1基因的多态性位点存在RR、RK、KK型三种基因型。冠心病组KK型基因频率、K等位基因频率低于对照组（P〈0．05～〈0．01）。K等位基因与冠心病的患病风险呈负相关．OR值为0．640（95％CI0．459-0．893）,该等位基因可能为冠心病的保护因素。K等位基因携带者的高密度脂蛋白-胆固醇（HDL-C）水平高于RR基因型（P〈0．05）。多因素Logistic回归分析显示．性别、血清总胆固醇、吸烟、高血压、糖尿病为研究对象发生冠心病的独立危险因素。结论：研究显示K等位基因可能通过作用于血脂间接影响新疆维吾尔族冠心病的患病风险．但不是其免于发生冠心病的独立保护因素。     

Common variants in the gene encoding ATP-binding cassette transporter 1 in men with low HDL cholesterol levels and coronary heart disease

HDL cholesterol (HDL-C) deficiency is the most common lipid abnormality observed in patients with premature coronary heart disease (CHD). Recently, our laboratory and others demonstrated that mutations in the ATP-binding cassette transporter 1 (ABCA1) gene are responsible for Tangier disease, a rare genetic disorder characterized by severely diminished plasma HDL-C concentrations and a predisposition for CHD. To address the question of whether common variants within the coding sequence of ABCA1 may affect plasma HDL-C levels and CHD risk in the general population, we determined the frequencies of three common ABCA1 variants (G596A, A2589G and G3456C) in men participating in the Veterans Affairs Cooperative HDL Cholesterol Intervention Trial (VA-HIT), a study designed to examine the benefits of HDL raising in men having low HDL-C (< or =40 mg/dl) and established CHD, as well as in CHD-free men from the Framingham Offspring Study (FOS). Allele frequencies (%) in VA-HIT were 31, 16, and 4 for the G596A, A2589G, and G3456C variants, respectively, versus 27, 12, and 2 in FOS (P<0.03). None of the variants were significantly associated with plasma HDL-C concentrations in either population; however, in VA-HIT, the G3456C variant was associated with a significantly increased risk for CHD end points, suggesting a role for this variant in the premature CHD observed in this population.     

ATP结合盒转运蛋白A1研究进展

动脉粥样硬化是心脑血管疾病的重要基础病理改变,而胆固醇在巨噬细胞内聚集和泡沫细胞形成是动脉粥样硬化的始动环节。ATP结合盒转运蛋白Al（ABCAl）是一种重要的胆固醇流出调节蛋白,能介导细胞内胆固醇逆向转运到细胞外,使之与载脂蛋白A-Ⅰ结合并包装形成高密度脂蛋白（HDL）的膜转运蛋白。因此,ABCAl是调节血浆HDL及细胞内胆固醇水平的重要膜蛋白,ABCAl的表达水平与动脉粥样硬化的发生关系密切。同时,细胞内脂质、核受体PPAR、LXR、RXR和细胞因子等对ABCAl蛋白表达具有凋控作用。本文将ABCAl研究进展作一综述。     

膜转运蛋白三磷酸腺苷结合盒转运体A1的表达调控与信号传导

<正>动脉硬化性心血管疾病(atherosclerotic cardiovascular disease,CVD)是最常见的死亡原因。高密度脂蛋白(High density lipoprotein,HDL)主要通过转运动脉巨噬细胞多余的胆固醇到肝脏代谢来预防CVD。这个途径的第1步称为胆固醇逆转运,由整合膜蛋白——三磷酸腺苷结合盒转运体A1(ATP-binding cassette transporter A1,ABCA1)介导。ABCA1转运细胞的胆固醇和磷脂到乏脂载脂蛋白     

ATP结合盒转运子A1基因R219K多态性与冠心病的关系

目的:检测冠心病患者及健康对照者ATP结合盒转运子A1(ABCA1)R219K基因多态性,探讨其与中国人冠心病以及血脂水平的关系。方法:选择234例冠心病患者(冠心病组)和198例正常对照者(对照组)为研究对象,用聚合酶链式反应-限制性片段长度多态性方法研究R219K基因多态性与冠心病和血脂水平的关系。结果:与对照组比较,冠心病组RR基因型频率(46·2%)明显高于对照组(33·8%)(P<0·05),而KK型频率(8·9%)显著低于对照组(15·2%)(P<0·05);与RR型患者相比,KK基因型患者血浆高密度脂蛋白(HDL)水平较高。基因型与血脂水平Logistic回归分析结果表明,三酰甘油、HDL、载脂蛋白A1与基因型相关。结论:ABCA1基因R219K变异可能具有动脉硬化保护作用。     

组织蛋白酶S基因启动子区-25G／A多态不是中国人群中冠心病的预测因子

目的这项研究的目的旨在观察中国人群中，组织蛋白酶S（CTSS）基因-25G／A多态分布及其多态性与冠心病（CAD）危险性之间的关联。方法CTSS基因-25G／A多态性由多聚酶链式反应PCR及限制性内切酶降解方法获得。经冠脉造影检查明确的共659名冠心病患者（冠脉狭窄≥50％）及352名非冠心病患者（对照组）纳入这项研究。结果所有研究对象中的等位基因G和A的频率分别为0．630及0．370。在病例组及对照组之间未发现其CTSS-25G／A多态性频率（G：0．626vs．0．633，P〉0．05；A：0．374vs．0．367，P〉0．05）及基因型分布（G：83．4VS．85．3，P〉0．05；A：58．0vs．58．5，P〉0．05）存在显著性差异。使用逻辑回归对其他危险因素校正后，CTSS基因型与冠脉狭窄严重程度之间亦未发现存在关联（P〉0．05）。结论在中国人群中，基因型AA较基因型GG和GA更为少见。对照组及冠心病组之间的等位基因频率及基因型分布均无显著性差异。CTSS-25G／A多态性与冠状动脉狭窄的发生率及严重程度不相关。     

新发现的中国人ATP结合盒转运子A1基因M233V 单核苷酸多态性及其家系调查

目的对112例中国冠心病患者行ATP结合盒转运子A1（ABCA1）基因筛选以发现新的单核苷酸多态性（SNP）,并对先证者家系进行调查确定其意义。方法用聚合酶链反应（PCR）．单链构象多态性分析（SSCP）-DNA测序及限制性酶切发现ABCA1基因新的SNP,进一步对先证者家系的16位成员进行血脂检查、基因组DNA提取及限制性酶切分析。结果N233V是一个新发现的ABCA1基因SNP,此位点在外显子7,cDNA位置为A1092G,并导致233位氨基酸由甲硫氨酸转变为缬氨酸（N233V）。16位家族成员中发现5例存在N233V SNP位点改变,且均为AG型改变。结论中国人中存在新发现的ABCA1基因N233V SNP,家系调查显示N233V SNP中AA型分布频率最高,AG型次之,AG型SNP的发生具有家族倾向性。     

三磷酸腺苷结合盒转运体A1的组织特异性功能与动脉粥样硬化

动脉粥样硬化是一种脂质沉积引发的慢性血管炎症。动脉粥样硬化的发生发展与细胞胆固醇稳态的破坏密切相关。三磷酸腺苷结合盒转运体A1(ABCA1)介导了细胞胆固醇流出至载脂蛋白AⅠ、preβ高密度脂蛋白(HDL)和HDL₃。当该通路胆固醇流出障碍可致细胞内胆固醇沉积。更重要的是,ABCA1的功能障碍还影响着动脉粥样硬化斑块的生长及临床冠心病的发生。最近研究显示ABCA1对动脉粥样硬化的调控作用具有组织特异性。本文介绍了胆固醇逆向转运与动脉粥样硬化的相关性,并着重讨论了ABCA1的组织特异性功能及其调控动脉粥样硬化的作用和机制。     

A common Ile 823 Met variant of ATP-binding cassette transporter A1 gene (ABCA1) alters high density lipoprotein cholesterol level in Japanese population

Recently, variants in ATP-binding cassette transporter A1 (ABCA1) were demonstrated to be associated with increased level of high density lipoprotein cholesterol (HDL-C) and decreased risk of coronary artery disease (CAD) in Caucasians. However, this is not universally applicable due to the ethnic or environmental differences. In this context, to clarify the effect of ABCA1 in Japanese, we evaluated the phenotypic effects of I/M 823 and R/K 219 variants on the plasma level of HDL-C in 410 patients recruited in our hospital. Subjects with M 823 allele had significantly higher level of HDL-C than those without M823 allele (49.0+/-15.1 vs. 44.9+/-11.5 mg/dl, respectively, P<0.05). This statistical significance did not change even after multiple regression analysis. In contrast, there was no difference in HDL-C level among the genotypes in R/K 219 polymorphism. Further, in our study population an inverse relationship was shown to exist between HDL-C level and incidence of CAD. However, no positive association was observed between those variants and susceptibility to CAD. In this study, we provide evidence that I/M 823 variant, not R/K 219 variant, in ABCA1 is one of the determinants of HDL-C level, suggesting the importance of this gene on lipid metabolism in Japanese.     

Insulin down-regulates specific activity of ATP-binding cassette transporter A1 for high density lipoprotein biogenesis through its specific phosphorylation

Insulin resistance/hyperinsulinism is one of the major risks for atherosclerotic vascular diseases and low HDL may be involved in pathogenesis. We examined direct effects of insulin on HDL biosynthesis focusing on the activity of ATP-binding cassette transporter A1 (ABCA1) in culture cells and in experimental animals. Insulin impairs HDL biosynthesis through modulation of ABCA1 activity by two different mechanisms. Insulin enhances degradation of ABCA1. However, even after this effect was cancelled by blocking its specific signal, insulin still reduces HDL biogenesis. This effect was found due to phosphorylation of ABCA1 that leads to decrease of its specific activity. We identified a novel insulin-specific phosphorylation site Tyr1206 of ABCA1 to regulate its specific activity. The observation in a rat model of insulin resistance was consistent with these results. The findings demonstrate a new mechanism for regulation of ABCA1 activity and provide new insights into the link between development of atherosclerosis, and insulin resistance/hyperinsulinism.     

Estrogen replacement therapy is underutilized among postmenopausal women at high risk for coronary heart disease

Observational studies have found that estrogen replacement therapy (ERT) reduces the risk of coronary heart disease (CHD) in postmenopausal women. To determine the frequency of current use of ERT in an economically and racially diverse group of women at high risk for CHD, we examined the medical records of 393 women older than 40 who were admitted to the University of South Alabama Medical Center with symptoms suggestive of angina. Women in the study group were classified as African American or European American and data were examined for significant differences. Use of ERT was lower in African American women (11 of 111, 9.9%) than in European American women (26 of 152, 17.1%, odds ratio 1.9). Compared with the reported utilization of ERT in middle-class European American women, ERT is underutilized in this economically diverse group of women at high risk for coronary heart disease. In our population, European American women were twice as likely to be receiving ERT as African American women.