ALOX5AP基因T(-1340)G多态性与中国北方汉族人群冠状动脉粥样硬化性心脏病发病的关联

目的:探讨编码5-脂氧合酶激活蛋白FLAP的基因ALOX5APT(-1340)G多态性与中国北方汉族人群冠心病发病的相关关系.方法:选自2006-01/2007-09在解放军沈阳军区总医院行选择性冠状动脉造影者共680例.根据造影结果分为冠心病组336例均为选择性冠状动脉造影阳性,对照组344例为造影阴性或动脉管腔狭窄<50%且临床上无相关心肌缺血证据者.在随机选择的无亲缘关系的48名中国北方汉族个体中,采用聚合酶链反应-重测序法对ALOX5AP基因进行单核苷酸多态的筛查,共发现7个多态.冠心病组和对照组受试者采用聚合酶链反应-限制性片段长度多态性方法检测ALOX5AP基因T(-1340)G多态性位点在两组间的基因型和等位基因分布.结果:ALOX5AP基因T(-1340)G3种基因型(TT型,TG型和GG型)在冠心病组分布频率分别为26.79%,51.79%和21.43%,在对照组分别为33.72%,47.38%和18.90%,两组间的基因型分布皆符合Hardy-Weinberg平衡定律,3种基因型在两组间的分布差异无显著性意义(x~2=3.90,P>0.05).G等位基因在两组间的分布频率为47.32%和42.59%,差异无显著性意义(x~2=3.08,P>0.05).按性别分层进行亚组分析,发现ALOX5AP T(-1340)G多态的基因型和等位基因频率在冠心病组和对照组间的比较差异无显著性意义.结论:5-脂氧合酶激活蛋白基因ALOX5AP T(-1340)G多态性与中国北方汉族人群冠心病发病可能无相关关系.     

五脂氧化酶激活蛋白基因多态性及冠心病易患风险

目的：探讨五脂氧化酶激活蛋白基因（-5lipoxygenase activating protein gene,ALOX5AP）突变与冠心病的关系。方法：采用高分辨率溶解曲线法（high resolution melting,HRM）分析150例冠心病患者和280例健康对照者ALOX5AP基因的单核苷酸多态性（SNPs）。结果：ALOX5AP的A22879C位点的CC基因型增加了冠心病3.691倍患病风险;T8733A位点的AA基因型增加了冠心病2.718倍患病风险;T8733A位点的TA杂合基因型增加了冠心病2.962倍患病风险。结论：ALOX5AP的A22879C位点和T8733A位点多态性是冠心病的易患风险因素。     

人类腺病毒5型早期区域1 A激活基因阻遏子rs3753921多态性与中国北方汉族人群冠心病发病的关联研究

目的 探讨人类腺病毒5型早期区域1A激活基因阻遏子(cellular repressor of E1A-stimulated genes,CREG)基因rs3753921单核苷酸多态与中国北方汉族人群冠心病发病的相关关系.方法 对经冠状动脉造影证实的338例冠心病患者和287例健康对照者,采用聚合酶链反应-重测序法检测CREG基因rs3753921单核苷酸多态位点在两组间的基因型和等位基因分布.结果 CREG基因rs3753921单核苷酸多态3种基因型(TT型,CT型和CC型)在冠心病组分布频率分别为65.7%,30.2%和4.1%,在对照组分别为59.2%,35.5%和5.2%,两组间的基因型分布皆符合Hardy-Weinberg平衡定律,3种基因型在两组间的分布差异无统计学意义(P>0.05).C等位基因在冠心病组和对照组间的分布频率分别为19.2%和23.0%.差异亦无统计学意义(P>0.05).按性别及年龄分层进行亚组分析,CREG基因rs3753921单核苷酸多态的基因型和等位基因频率在冠心病组和对照组间差异无统计学意义.结论 CREG基因rs3753921单核苷酸多态性与中国北方汉族人群冠心病发病可能无相关关系.     

PPAR-γ基因C161T多态性与大动脉粥样硬化性缺血性卒中的相关性

目的:探讨广东汉族人群PPAR-γ基因单核苷酸多态(SNP)位点C161T与大动脉粥样硬化性缺血性卒中(LAA)关系。方法:采用聚合酶链式反应(PCR)-限制性片段长度多态性(RFLP)方法,对149例LAA患者(LAA组)和125例健康者(对照组)的PPAR-γ基因SNP位点C161T进行基因分型,比较两组基因型的频率。结果:LAA组PPAR-γ基因C161T多态性检测结果为野生型等位基因CC型111例(74.5%),变异型等位基因CT+TT型38例(25.5%);对照组PPARγ基因C161T多态性检测结果为野生型等位基因CC型79例(63.2%),变异型等位基因CT+TT基因型46例(36.8%),两组基因型频率有显著性差异(P0.05)。结论 :广东汉族人群PPAR-γ基因SNP位点C161T可能与LAA患者的发病有关。     

AMI患者ALOX5AP基因SG13S114位点SNP与ARPs的关系

目的研究心肌梗死(AMI)患者ALOX5AP基因SG13S114位点单核苷酸基因多态性(SNP)与急性时相反应蛋白(ARPs)的关系.方法分别采用限制性长度多态性聚合酶链反应(RLFP)方法,免疫比浊法研究ALOX5APSG13Sll4A/T的SNP及ARPs包括纤维蛋白原(fbg),高敏C反应蛋白(hs-CRP)的关系.结果心肌梗死组与冠心病组患者外周血基因组ALOX5AP基因SG13S114位点SNP分布T/T,T/A,A/A具有显著性差异(P<0.05;ALOX5AP基因SG13S114A/A型的AMI患者中FBg和hs-CRP显著高于对照组.结论 ALOX5AP基因SG13S114A/A可能是中国人群AMI发病的遗传性危险因素,也是影响AMI患者预后的重要炎症性因素.     

急性白血病患儿TYMS编码区单核苷酸多态性分析

目的探讨TYMS编码区单核苷酸多态性(SNP)在急性白血病(AL)患儿和对照儿童中的等位基因频率和基因型分布特征及其与中国汉族儿童AL发生风险的关系。方法用RT-PCR-变性梯度凝胶电泳(DGGE)结合DNA直接测序技术筛查108例AL儿童和121例对照儿童的TYMS基因编码区开放阅读框的全部SNP及基因突变,分析等位基因频率及各基因型在两组人群中的分布,并进行病例、对照优势比分析以研究各SNP位点与AL发生之间的关系。结果在中国汉族儿童TYMS开放阅读框中仅筛查到2个SNP,分别为A381G和T349C。TYMS A381G各基因型在AL组的频率分布为:AA型76.8%(83/108);AG型20.4%(22/108);GG型2.8%(3/108);在对照组中各基因型频率为:AA型79.4%(96/121);AG型16.5%(20/121);GG型4.1%(5/121)。A381G(Glu127Glu)在AL患儿及对照儿童中的等位基因频率分别为13.0%和12.4%。在中国汉族儿童发现T349C(Phe117Leu)的存在,其等位基因频率为1.2%。结论 TYMS A381G与AL发生风险可能无相关性;中国汉族儿童TYMS基因存在T349C多态位点。     

高分辨率熔解曲线法检测中国北方汉族人群KIF6基因的单核苷酸多态性

目的探讨用新型基因分析法-高分辨率熔解曲线法(high resolution melting,HRM)分析中国北方汉族人群驱动蛋白分子6(KIF6)基因Trp719Arg(rs20455)的单核苷酸多态性。方法样本来自2010至2011年心内科门诊及住院的234例非致死性心肌梗死患者(病例组)和228例非冠心病人群(对照组)。取受检者静脉血样1ml,留存于-80℃超低温冰箱。采用HRM法对rs20455位点进行基因多态性分型检测。结果对照组中rs20455位点TT、TC、CC基因型频率分别为29.5%、47.4%、23.1%;T、C等位基因频率分别为47.0%和53.0%;病例组的基因型频率是TT14.0%、TC59.7%、CC26.3%,T、C等位基因频率分别为56.0%和44.0%;病例组与对照组基因型和等位基因频率在2组间分布差异有统计学意义(P均<0.05)。结论成功利用HRM对中国北方非致死性心肌梗死患者和非冠心病人群的KIF6Trp719Arg位点进行了基因分型,并发现其在心肌梗死患者和非冠心病人群中分布差异有统计学意义,提示rs20455可能是中国北方汉族人群中非致死性心肌梗死筛查的生物学标记物之一。     

ALOX12基因多态性与糖尿病和糖尿病肾病的相关性研究

目的研究ALOX12基因位点rs1126667(R261Q)单核苷酸多态性(SNP)与2型糖尿病(T2DM)及糖尿病肾病(DN)的相关性。方法在北方汉族人群中采用病例-对照方法选择223例T2DM患者(其中DN 134例、T2DM无肾病89例)和120名健康体检者(正常对照组)。应用单碱基延伸反应和基质辅助激光解吸电离飞行时间质谱技术对该基因SNP进行研究。结果 ALOX12基因rs1126667位点符合Hardy-Weinberg平衡定律。正常对照组G/G、G/A、A/A 3种基因型的频率为26%、47%和27%;T2DM组的频率分别为30%、48%和22%,相对危险度(OR)分别为1、0.8、0.76;DN组的频率分别为31%、45%和24%,OR值分别为1、0.88、0.94;T2DM无肾病组的频率分别为28%、54%和18%,OR值分别为1、1.06、0.61,各组间差异均无统计学意义(P0.05)。正常对照组、T2DM组、DN组和T2DM无肾病组A等位基因频率分别为50%、46%、47%、45%,各组间差异无统计学意义(P0.05)。结论在北方汉族人群中未发现ALOX12基因多态性与T2DM、DN有关。     

北京地区汉族人群MTHFR C677T基因多态性分析

目的探索北京地区汉族MTHFR基因多态性分布特征,荟萃(meta)分析北京地区与北方其他地区MTHFR基因多态性分布差异。方法用PCR-金磁微粒层析法检测MTHFR C677T基因,回顾性分析北京协和医院2014年9月至2018年5月3 945例体检健康者MTHFR基因多态性分布特征。查阅中外文献数据库,并对北京地区与北方其他地区汉族的MTHFR基因多态性分布比较。结果北京地区体检健康人群男性MTHFR C677T基因CC、CT和TT基因型频率分别为23.3%,50.5%和26.2%,C、T等位基因频率分别为48.6%和51.4%。女性人群MTHFR C677T基因CC、CT和TT基因型频率分别为22.7%,49.4%和27.9%,C、T等位基因频率分别为47.4%和52.6%,男、女性基因型频率与等位基因频率差异无统计学意义(P0.05)。北京地区体检人群MTHFR C677T基因CC、CT和TT基因型频率与等位基因频率均与黑龙江、吉林、河北、山东和河南等省差异有统计学意义(P0.01)。结论北京地区体检人群MTHFR C677T基因多态性在男、女性人群中的分布无差异;北京地区MTHFR基因分布有自身特点。     

中国北方汉族人群TRIB1基因rs2235108多态性与2型糖尿病合并冠心病的相关性

目的探讨中国北方汉族人群TRIB1基因rs2235108多态性与2型糖尿病(T2DM)合并冠心病(CHD)的关系。方法用PCR-限制性片段长度多态性(PCR-RFLP)检测了147例健康人对照组、96例T2DM组和75例T2DM合并CHD组TRIB1基因rs2235108多态性基因型和等位基因频率分布,分析基因多态性对T2DM和T2DM合并CHD的影响。结果我国北方汉族人群TRIB1基因rs2235108多态性CC基因型频率为81.8%,CT+TT为18.4%,C、T等位基因频率分别为90.5%、9.5%。3组研究对象的TRIB1基因rs2235108多态性基因型和等位基因频率分布差异无统计学意义(P>0.05)。3组内不同基因型间各项生化指标差异均无统计学意义(P>0.05)。logistic回归分析显示,年龄、HDL-C、高血压病史是T2DM合并CHD的独立危险因素。结论 TRIB1基因rs2235108多态性与T2DM合并CHD无明显关联性,不是我国北方汉族人群T2DM合并CHD发病的独立危险因素。     

Genetic variation in the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) is associated with myocardial infarction in the German population

Genetic variation in the genes ALOX5AP (arachidonate 5-lipoxygenase-activating protein) and LTA4H (leukotriene A4 hydrolase) has previously been shown to contribute to the risk of MI (myocardial infarction) and stroke in Icelandic and Scottish populations. Both genes encode proteins playing a role in the synthesis of the pro-inflammatory leukotriene B mediators, possibly providing a link between MI and inflammation. The aim of the present study was to investigate whether these associations could be confirmed in a large study of German MI patients. Two previously described four SNP (single nucleotide polymorphism) haplotypes of the ALOX5AP gene (termed haplotype A and B) and one SNP (rs2660899) of the LTA4H gene conferring the greatest risk of MI in previous studies were genotyped in 1211 unrelated MI cases from the German MI Family Study and in 1015 healthy married-in spouses serving as controls. Haplotype B in the ALOX5AP gene was associated with an increased risk of MI in the German population, confirming previously reported associations of this haplotype with CAD (coronary artery disease) in populations from Scotland and Italy. No association with the risk of MI was detected for haplotype A of the ALOX5AP gene or for SNP rs2660899 representing the LTA4H gene. In conclusion, haplotype B of the ALOX5AP gene is associated with an increased risk of MI in a large German study. The present study is the third independent report from a European population describing an increased risk of CAD for carriers of haplotype B of the ALOX5AP gene, which substantiates further a role of this gene in the pathogenesis of CAD in Europeans.     

Association of ALOX5AP with ischemic stroke in eastern Chinese

BACKGROUND:

5-lipoxygenase protein (ALOX5AP) has been recognized as a susceptibility gene for stroke and coronary artery diseases. The present study was to explore the role of this gene in the eastern Chinese patients with ischemic stroke.

METHODS:

Using a case-control design, we studied 658 patients with ischemic stroke and 704 unrelated population-based controls who were age- and sex-matched. The 658 patients were classified by the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Two single-nucleotide polymorphisms (SNPs) covering ALOX5AP were genotyped.

RESULTS:

The genotype frequencies of TG of the SNPs rs17222919 located in the promoter of the ALOX5AP gene were significantly higher in patients with ischemic stroke than in controls (OR^*=1.34, 95%CI^*=1.02-1.75), especially in patients with ischemic stroke caused by small-artery occlusion (SAO) (OR^*=1.40, 95%CI^*=1.02-1.93). Meanwhile, the genotype frequencies of TG and TG/GG were higher in female patients than in the controls. After specification, the genotype frequencies of TG and TG/GG were higher in the patients than in controls with hypertension. The genotype frequencies of AG and AG/GG of the SNPs rs9579646 located in the intron of the ALOX5AP gene were higher in the controls than in the patients. After specification, the genotype frequencies of TG were higher in the controls than patients without hypertension.

CONCLUSION:

The present study suggests that sequence variants in the ALOX5AP gene are significantly associated with ischemic stroke.KEY WORDS: 5-lipoxygenase activating protein (ALOX5AP), Leukotrienes (LTs), Trial of Org 10172 in Acute Stroke Treatment (TOAST), Single nucleotide polymorphisms (SNPs), Ischemic stroke     

Leukotriene B4 production in healthy subjects carrying variants of the arachidonate 5-lipoxygenase-activating protein gene associated with a risk of myocardial infarction

Leukotrienes are implicated in the pathogenesis of coronary artery disease. Recently two haplotypes (HapA and HapB) in the gene encoding ALOX5AP (arachidonate 5-lipoxygenase-activating protein), the main regulator of 5-lipoxygenase, have been associated with a doubling of the risk of myocardial infarction. Studies have also shown that treatment with a leukotriene inhibitor reduces biomarkers of coronary risk in patients carrying HapA, raising the possibility of developing genotype-specific therapy. In the present study, we examined whether carriage of HapA or HapB is associated with increased LTB(4) (leukotriene B(4)) production in healthy subjects. Age- and gender-matched healthy HapA carriers (n=21), HapB carriers (n=20) and non-A/non-B carriers (n=18), with no reported history of cardiovascular disease, were recruited following DNA screening of 1268 subjects from a population-based study. Blood neutrophils were isolated, and LTB(4) production was measured in response to stimulation with 1 mumol/l of the calcium ionophore A23187. There was no difference in the mean level for LTB(4) production in the three groups (non-A/non-B, 24.9+/-8.3 ng/10(6) cells; HapA, 22.2+/-11.9 ng/10(6) cells; HapB, 19.8+/-4.8 ng/10(6); P=0.14). The findings indicate that if either the HapA or the HapB haplotype of ALOX5AP indeed increases cardiovascular risk, then the mechanism is not simply due to a systematically observable effect of the haplotype on LTB(4) production in response to stimulation. The results suggest that knowledge of a patient's haplotype may not provide useful information on the probable clinical response to ALOX5AP inhibitors.     

Vagal Enhancement as Evidence of Residual Ischemia After Inferior Myocardial Infarction

Background: Acute inferior myocardial infarction (MI) often induces transient sinus bradycardia through vagal enhancement, known as Bezold-Jarisch reflex, which is explained by preferential distribution of vagal nerve in the inferior wall. We examined vagal activity in relation to the occurrence of residual ischemia in patients with old inferior MI and assessed its diagnostic usefulness.
Methods: Exercise myocardial scintigraphy was performed in 15 patients with old inferior MI, 19 angina pectoris (AP) patients with inferior ischemia but no MI, and 32 control subjects who had no evidence of cardiac disease. We analyzed the connection of residual ischemia in old MI with ST-segment response to exercise and with vagal activity as determined by coefficient of component variance of high frequency (CCV_HF).
Results: Exercise-induced percentage change in CCV_HF was higher in patients with old MI and residual ischemia (18.8 ± 13.5%) and AP (5.5 ± 9.7%) than old MI but no residual ischemia (–24.1 ± 4.9%) or control (–22.8 ± 4.5%, P = 0.006). Percentage change in CCV_HF > –5% had a good diagnostic value for the detection of residual ischemia in patients with old inferior MI with sensitivity of 83%, specificity of 89%, accuracy of 87%, and positive likelihood ratio of 7.50, which was higher than that of ST-segment depression (67%, 50%, 56%, and 1.33).
Conclusions: Vagal enhancement was associated with residual ischemia in old inferior MI as well as inferior AP. Measurement of CCV_HF is useful in improving the diagnostic reliability of exercise electrocardiography in patients with old inferior MI.     

Association of Sp1 Tandem Repeat Polymorphism of ALOX5 with Coronary Artery Disease in Indian Subjects

Lipoxygenases have been implicated in the pathogenesis of coronary artery disease (CAD) for its potent proinflammatory role. The Sp1 addition/deletion polymorphism in promoter region of the 5‐lipoxygenase gene (ALOX5) has been associated with increased risk of carotid atherosclerosis and myocardial infarction. To determine the role of this polymorphism in our population we performed a case–control‐genetic association study on 117 healthy controls and 119 angiographically verified CAD patients. Biochemical analysis was performed using standard automated assays. High‐density lipoprotein cholesterol (HDL‐C) and LDL‐C subfraction levels were estimated using precipitation methods. Genotyping of polymorphism in the ALOX5 (Sp1 variants) was done using PCR‐based heteroduplex analysis and automated sequencing. The Sp1 promoter repeat variants were found to be associated with CAD (p < 0.0001, OR = 4.47, 95% confidence interval = 2.58–7.74). Furthermore, the 5/5 genotype of the ALOX5 polymorphism in the healthy subjects was found to be associated with elevated HDL‐C (p= 0.004), HDL₃‐C (p= 0.04), apo A1 (p= 0.011) and sdLDL (p= 0.001). We conclude that this polymorphism influences LDL and HDL subfraction levels and is a risk factor for CAD in our population. Clin Trans Sci 2012; Volume 5: 408–411     

Polymorphisms of the endothelial nitric oxide synthase gene - no consistent association with myocardial infarction in the ECTIM study

BACKGROUND: Our aim in the present study was to determine whether endothelial NO synthase gene (ecNOS) polymorphisms are associated with myocardial infarction (MI). METHODS: Forty chromosomes from patients with MI were screened for polymorphisms of the ecNOS gene using polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) analysis and sequencing. Ten polymorphisms were detected: three in the 5' flanking sequence at positions -1474, -924 and -788, two in coding sequences 774C --> T (silent) and G894 --> T (Glu-298 --> Asp) and five in introns 2, 11, 12, 22 and 23. Five hundred and thirty-one patients with MI and 610 control subjects recruited in France and Northern Ireland in the ECTIM study were genotyped for these polymorphisms. RESULTS: Glu-298 homozygotes were more frequent among patients with MI than in control subjects in the French population [OR = 1.47 (1.03-1.97), P < 0.009], but no such difference was observed in Northern Ireland. No significant difference between cases and control subjects was detected for the other polymorphisms. Our search for a possible association of the combination of ecNOS polymorphisms with MI by logistic regression analysis was also negative. CONCLUSIONS: We have explored a set of polymorphisms of the ecNOS gene in a large case-control study of MI and found that the polymorphisms were not consistently associated with MI.