ALOX5AP和PDE4D基因多态性与缺血性卒中

缺血性卒中是遗传因素和环境因素共同作用导致的一种多基因遗传性疾病.对冰岛人群的研究首次揭示了5-脂氧合酶激活蛋白(5-1ipoxygenase activating protein,ALOX5 AP)和磷酸二酯酶4D(phosphodiesterase 4D,PDE4D)基因多态性与缺血性卒中的相关性.随后,很多学者围绕这2种基因进行了大量研究,但目前的研究结果仍有分歧.文章就ALOX5AP和PDE4D基因多态性与缺血性卒中的研究现状和进展进行了综述.     

5-脂氧合酶激活蛋白（ALOX5AP）基因单倍体型与心肌梗死易感性相关：人类基因组流行病学研究的荟萃分析

目的既往研究提示ALOX5AP基因变异与心肌梗死（Myocardial infarction,MI）相关,但这些研究大多样本较小,结论亦不一致。本文拟系统评价ALOX5AP基因变异与MI易感性的关系。对象与方法系统检索PubMed（1967．1—2009．5）、Embase（1967．1-2009．5）数据库及维普（1989．2009）、CNKI（1979—2009）中文期刊数据库,并通过阅读相关综述及文章的参考文献进一步获取信息。对目前已发表的评估ALOX5AP基因变异与MI关系的候选基因关联研究进行荟萃分析。应用固定效应模型（Fixed—effect models）计算比值比（Oddsratio,OR）及其95％可信限（CI）,用以描述ALOX5AP基因变异与MI的关系。结果共有5项探讨ALOX5AP基因HapA单倍体型（SG13S25G—SG13S114T．SG13S89G—SG13S32A）与MI关系的研究（合计MI病例2778人,对照2484人）及4项评估ALOX5AP基因HapB单倍体型（SG13S377A—SG13S114A—SG13S41A—SG13S35G）与MI关系的研究（合计MI病例1999人,对照1860人）纳入荟萃分析。5项关于HapA单倍体型的研究间无明显异质性（P=0．111,I^2=46．8％）。与非携带者相比,ALOX5AP基因HapA单倍体型携带者使MI的易感性增加24％（OR：1．24,95％可信限1．06—1．45,P=0．006）。4项关于HapB的研究亦无明显异质性（P=0．148,I^2=43．9％）;与非携带者相比,ALOX5AP基因HapB单倍体型携带者使MI的易感性增加31％（OR：1．31,95％可信限1．01—1．70,P=0．04）。结论本研究提示ALOX5AP基因HapA、HapB单倍体型与MI的易感性增加有关。     

血清白三烯B4水平与AMI发病风险和ALOX5AP基因SG13S114T/A多态性的相关性

目的:探讨中国苏南地区汉族人群血清白三烯(LT)B4水平与急性心肌梗死(AMI)发病风险和花生四烯酸5-脂氧合酶激活蛋白(ALOX5AP)基因SG13S114T/A多态性的相关性。方法:采用酶联免疫吸附试验和聚合酶链反应-限制性片段长度多态性方法对262例AMI患者(AMI组)和132例非冠心病者(对照组)分别检测血清LTB4水平(M/IQR)和ALOX5AP基因SG13S114T/A多态性。结果:AMI组和对照组均存在ALOX5AP基因SG13S114T/A多态性。血清LTB4水平在AMI组(477.97/370.52ng·L-1)明显高于对照组(200.57/236.65ng·L-1)(P0.01),与吸烟呈正相关(P0.01,R2=0.039),与性别、年龄、高血压、糖尿病和血脂异常均无关。AMI组ALOX5AP基因SG13S114位点AA、AT和TT任何基因型之间的血清LTB4水平均无显著差异(517.98/392.00ng·L-1∶492.31/427.55ng·L-1∶495.29/398.54ng·L-1),在同性别AMI亚组中亦无明显差异。结论:中国苏南地区汉族人群血清LTB4水平明显升高,并与AMI发病风险相关,但与ALOX5AP基因SG13S114多态性无相关性。     

新疆维吾尔族及汉族脑梗死病人ALOX5AP基因rs4293222位点多态性比较分析

目的探讨新疆维吾尔族及汉族脑梗死病人5-脂氧合酶激活蛋白(ALOX5AP)基因rs4293222位点多态性的差异。方法采用病例-对照研究方法,利用聚合酶链反应和DNA基因测序法对100例病人ALOX5AP基因rs4293222位点多态性的各基因型及等位基因频率多态性进行测定,比较新疆地区维吾尔族和汉族脑梗死病人不同基因型的差异,并统计结果。结果维吾尔族与汉族ALOX5AP基因rs4293222位点比较,差异无统计学意义(P0.05)。结论汉族和维吾尔族脑梗死ALOX5AP基因rs4293222位点基因型和基因频率无差异。     

血清白三烯B4水平与不稳定型心绞痛发病风险和ALOX5AP基因SG13S114T/A多态性的关联

目的:探讨中国苏南地区汉族人群不稳定型心绞痛(UAP)患者血清白三烯(LT)B4水平与UAP发病风险和花生四烯酸5-脂氧合酶激活蛋白(ALOX5AP)基因SG13S114T/A多态性的相关性。方法:以141例UAP患者(UAP组)和132例非冠心病患者(对照组)为研究对象,应用聚合酶链反应-限制性片段长度多态性方法检测ALOX5AP基因SG13S114T/A多态性,应用酶联免疫吸附试验检测血清中的LTB4水平[以中位数/四分位数间距(M/IQR)表示]。结果:UAP组血清LTB4水平显著高于对照组(352.52/255.48ng/L:200.28/237.10ng/L,P<0.01),经多因素(性别、年龄、高血压、吸烟、糖尿病和血脂)Logistic回归分析显示,血清LTB4水平与UAP的发病风险相关。在UAP组中,ALOX5AP基因SG13S114T/A位点AA、AT和TT三种基因型之间的血清LTB4水平均差异无统计学意义(347.36/201.92ng/L:361.89/262.23ng/L:365.18/268.43ng/L,均P>0.05),且同年龄段亚组(<60岁和≥60岁)的该位点3种基因型之间的血清LTB4水平亦均差异无统计学意义(均P>0.05)。结论:在中国苏南地区汉族人群中,UAP患者血清LTB4水平显著升高,且与UAP的发病风险显著相关,但不受ALOX5AP基因SG13S114T/A多态性的影响。     

血清白三烯B4水平、ALOX5AP基因SG13S89G/A多态性与急性心肌梗死的关联性研究

目的:探讨中国常州地区汉族人群血清白三烯(LT)B4水平、花生四烯酸5-脂氧合酶激活蛋白(ALOX5AP)基因SG13S89G/A多态性和急性心肌梗死(AMI)三者的相互关联性。方法:以262例AMI患者(AM I组)和132例非冠心病患者(对照组)作为研究对象,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SG13S89G/A多态性,同时采用酶联免疫吸附试验检测血清LTB4水平(以中位数/四分位数间距表示)。结果:对照组与AMI组ALOX4AP基因SG13S89G/A位点的(AA+GA)基因型(7.58%︰4.96%)、GG基因型(92.42%︰95.04%)以及A等位基因(4.17%︰2.67%)频率均差异无统计学意义;多变量Logistic回归分析显示,该位点多态性与AMI发病风险无显著相关性;AMI组血清LTB4水平显著高于对照组(477.97/370.52pg/ml︰200.57/236.65pg/ml,P<0.01);多变量Logistic回归分析显示,血清LTB4水平与AMI发病风险有显著相关性(P<0.01);AMI组和对照组的组内(AA+GA)基因型和GG基因型之间的血清LTB4水平比较差异无统计学意义。结论:中国常州地区汉族人群AMI患者血清LTB4水平显著升高,ALOX5AP基因SG13S89G/A多态性与AMI易感性无关,且不影响血清LTB4水平。     

ALOX5AP基因多态2354T/A和MTHFR基因多态677C/T的协同作用显著增加脑梗塞的易患性

目的研究MTHFR多态性和编码5-脂氧合酶激活蛋白的基因ALOX5AP多态性，尤其是基因之间的相互作用，是否与脑卒中的易患性相关。方法采用PCR．RFLP方法，对来自7个临床中心的1823名对照和1832名脑卒中患者检测了基因ALOX5AP和MTHFR的3个多态性，基因分型结果经测序进一步确证。多元logistic回归方法校正了传统危险因素后分析基因多态性与脑卒中的独立相关性。检测7个与脑卒中不相关的微卫星多态标记在病例一对照人群的频率分布以评估人群层化程度。结果MTHFR677TT基因型与男性脑梗塞的发病风险呈弱相关（OR，1．45；95％CI：1．04-2．02；P=0．020），ALOX5AP2354AA基因型也增加男性脑梗塞1．55倍的发病风险（95％CI：1．03．2．35；PP=0．038）。当个体同时携带MTHFR677TT和ALOX5AP2354AA基因型时，男性脑梗塞的相对患病风险率显著增加至3．58倍（（95％CI：1．72-7．43；P=0．001）。微卫星多态性标记的各主要等位基因片段的频率在病例和对照组无显著性差异。结论MTHFR677TT基因型和ALOX5AP2354AA基因型的协同作用与增加的男性脑梗塞患病风险呈显著相关。对于多因素复杂性疾病，综合分析弱效基因的相互作用有助于了解个体易患脑卒中的遗传背景。     

浙江南部地区人群5-脂氧合酶激活蛋白和磷酸二酯酶4D基因突变与缺血性脑卒中的研究

目的为探索浙江南部地区人群5-脂氧合酶激活蛋白(ALOX5AP)基因中SG13S89、SG13S114和磷酸二酯酶4D(PDE4D)基因中单核苷酸多态性83与缺血性脑卒中的关系。方法选择脑梗死患者394例为脑梗死组,另选无脑梗死382例为对照组。采用PCR和基质辅助激光解析/电离飞行时间质谱法,分析ALOX5AP基因中的SG13S89(rs4769874)、SG13S114(rs10507391)和PDE4D基因中单核苷酸多态性83(rs966221)的多态性。结果与对照组比较,脑梗死组SG13S89基因AG型、A等位基因频率明显升高(4.1%vs 1.3%,P<0.05;2.0%vs0.7%,P<0.05);。多因素logistic回归分析显示,调整高血压、糖尿病和年龄后,SG13S89的AG基因型相对于GG基因型有较高的脑卒中风险(OR=4.24,95%CI:1.17～15.32,P=0.027)。SG13S89等位基因分布与大动脉粥样硬化型和小动脉闭塞型脑梗死差异无统计学意义(P>0.05)。SG13S89的AG基因型与女性人群发生脑卒中相关(P=0.022),但A等位基因在女性脑卒中人群中差异无统计学意义(P>0.05)。结论 rs4769874AG基因型和A等位基因频率可增高缺血性脑卒中风险,可能是该基因与血管炎性反应和通透性增加导致脑梗死的机制相关。但未发现PDE4D基因单核苷酸多态性83突变与脑卒中相关。     

Notch3基因多态、MTHFR基因多态和ALOX5AP基因多态的多位点联合交互作用显著增加血栓性脑卒中的风险

目的研究Notch3基因、MTHFR基因和ALOX5AP基因多态之间的多位点交互作用是否与脑卒中的患病风险相关。方法采用病例对照设计，对来自全国7个临床中心的对照和脑卒中患者检测了Notch3、MTHFR、VKORC1、APOA1和ALOX5AP基因的8个多态性，基因分型结果经测序进一步确证。用Generalized Muhifactor—Dimensionality Reduction（GMDR）方法检测基因与基因之间的交互作用。结果当个体同时携带Notch3 381TT、MTHFR 677TT和ALOX5AP 2354AA基因型时，携带者血栓性脑卒中的相对患病风险率增加至3．72倍（95％CI：1．235～11．209；P〈0．05）。结论Notch 3381TT、MTHFR 677TT和ALOX5AP 2354AA基因型的多位点联合交互作用显著增加血栓性脑卒中患病风险。对基因与基因之间的交互作用的分析，有助于更深入的研究复杂疾病的基因型和表型间的关系。     

花生四烯酸5-脂氧合酶激活蛋白基因多态性与急性冠状动脉综合征的易感性

目的探讨花生四烯酸5脂氧合酶激活蛋白(ALOX5AP)基因SG1 3S114T/A多态性与急性冠状动脉综合征(ACS)的易感性。方法选择住院的胸痛患者714例,将确诊为ACS的患者377例作为ACS组,非ACS患者337例作为对照组,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SG13S114T/A多态性,并进行logistic回归分析。结果 ACS组患者AA、AT和TT基因型频率分别为1 3.79%、50.93%和35.28%,对照组患者分别为12.76%、38.58%和48.66%,2组AT和TT基因型频率差异有统计学意义(P=0.041,0.020);ACS组男性AT基因型频率高于对照组(P=0.040),女性TT基因型频率低于对照组(P=0.013)。SG13S114T/A位点AT和TT基因型以及T等位基因是所有ACS(P=0.004、0.001和0.013)和男性ACS(P=0.014、0.005和0.020)发病的危险因素。结论 ALOX5AP基因SG1 3S114T/A多态性AT和TT基因型以及T等位基因可能与老年人,特别是老年男性ACS的易感性相关。     

The association between the gene encoding 5-lipoxygenase activating protein and abdominal aortic aneurysms

BackgroundGenetic variation in the gene ALOX5AP, encoding arachidonate 5-lipoxygenase-activating protein, have been suggested to increase risk for myocardial infarction and stroke. Leukotrienes (LTs) that derive from the 5-lipoxygenase (5-LO) cascade have been implicated in the pathogenesis of abdominal aortic aneurysm (AAA).Methods and resultsThe association of the ALOX5AP haplotypes with AAA was assessed in a large population-based cohort of 613 men aged ≥65 years with screen-detected AAAs and 707 randomly selected age-matched controls without AAA. Taqman assays were used to assess seven previously described single nucleotide polymorphisms (SNPs) of ALOX5AP. Haplotypes A and B were defined by the four SNPs (SG13S25, SG13S114, SG13S89, SG13S32) and (SG13S377, SG13S114, SG13S41, SG13S35), respectively. After adjustment for cardiovascular risk factors, there were no significant differences in the distribution of ALOX5AP haplotypes between cases and controls.ConclusionA genetic predisposition to up-regulation of LT mediators is unlikely to play a dominant role in the pathogenesis of AAA.     

Association between ALOX5AP gene polymorphisms and coronary artery disease in the Han population of North China

Objectives Recent evidence have implicated specific gene polymorphisms of arachidonate 5-lipoxygenase-activating protein(ALOX5AP),and 2 at-risk haplotypes (HapA,HapB ) in myocardial infarction(MI) and stroke, whereas other studies have been conflicting and to date,no data concerning coronary artery disease(CAD) are available in the Han population of North China.The aim of the present study was to investigate the possible associations between the variants of ALOX5AP gene and susceptibility to CAD in the Han population of North China.Methods We sequenced the promoter,all of the exons,splite site region and 3’untranslated region of ALOX5AP gene,and 7 single nucleotide polymorphisms(SNPs) were found.Three(-1340T/G,+ 8733T/C,+20616G/C) of these polymorphisms were evaluated in 656 patients with angiographically proven CAD and 678 controls with normal coronary angiograms using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) assay.Allelic,genotypic and haplo-typic association testing were performed using Shesis and Phase version 2.1 software package.Multiple logistic regression was used to control for the presence of vascular risk factors.Results While none of the single nucleotide polymorphism (SNP) was found to be associated with CAD risk individually,there was an association with the 3 SNP haplo-types. We identified a protective haplotype -1340T,+8733C and +20616G(Bonferroni-corrected P=0.000002984,OR = 0.623,95%CI=0.519-0.748) and a risk haplotype -1340G, +8733C and +20616G(Bonferroni-corrected P =0.000018, OR=1.728,95%CI=1.375-2.171).The frequencies of all alleles were in Hardy |= Weinberg equilibrium.Conclusions Our data suggest that unique haplotype combinations in the ALOX5AP gene may play a role in the etiology of CAD.     

ALOX5AP expression, but not gene haplotypes, is associated with obesity and insulin resistance

OBJECTIVE: Inflammation in adipose tissue may link obesity to insulin resistance and atherosclerosis. Arachidonate 5-lipoxygenase activating protein (ALOX5AP) gene is involved in the pathogenesis of atherosclerotic cardiovascular disease (CVD). We investigated ALOX5AP expression in adipose tissue, and association of gene polymorphisms with obesity and insulin resistance. DESIGN: For gene expression analysis in adipose tissue, we studied 12 lean and 36 obese women, eight lean and 13 obese men, and nine women before and 2-4 years after gastric banding surgery. For genetic analysis, we studied 231 nonobese and 350 obese men. RESULTS: The ALOX5AP protein, 5-lipoxygenase activating protein (FLAP), as well as 5-lipoxygenase (5LO) itself, were detected in adipocytes. The mRNA expression of ALOX5AP in subcutaneous adipose tissue was increased in obesity and normalized following weight reduction. High adipose tissue mRNA expression of ALOX5AP is associated with insulin resistance as measured by homeostasis model assessment (HOMA(IR)). ALOX5AP haplotypes that associate with CVD are not associated with obesity or insulin resistance. CONCLUSION: ALOX5AP is present in adipose tissue, where its expression is associated with body weight and HOMA(IR), and may provide a link between adipose tissue, inflammation and insulin resistance. Investigated ALOX5AP haplotypes are not major primary risk factors for obesity and insulin resistance.     

Validation of the association between the gene encoding 5-lipoxygenase-activating protein and myocardial infarction in a Japanese population.

BACKGROUND: Recently, the 5-lipoxygenase activating protein gene (ALOX5AP) was reported to confer a risk of myocardial infarction (MI) and stroke, independent of conventional risk factors. The purpose of the present study was to validate those findings in a Japanese population. METHODS AND RESULTS: The study population consisted of 1,875 subjects (males 871, females 1,004) recruited from the Suita study (control group) and 353 subjects (males 306, females 47) with MI. The promoter, all of the exons, and 3'UTR regions of ALOX5AP were sequenced in 96 subjects, and 8 polymorphisms were found. There were significant differences in the frequencies of the haplotypes constructed from the 2 SNPs (A162C and T8733A) between the control and MI groups. Multiple logistic analysis indicated that the homozygous genotype of the (CA) haplotype was significantly associated with a reduced risk for MI. CONCLUSION: The hypothesis that ALOX5AP contributes to susceptibility for MI was validated in a Japanese population.     

5脂氧合酶激活蛋白基因单核苷酸多态性与冠心病的关联研究

目的探讨5-脂氧合酶激活蛋白基因2354T/A和16699G/A多态性与冠心病的关系。方法采用聚合酶链反应—限制片长多态性技术,对282例经冠状动脉造影证实的冠心病患者和79例对照者进行检测,分析5-脂氧合酶激活蛋白基因2354T/A和16699G/A多态性的基因型和等位基因频率分布情况,检验多态位点与冠心病的关联。结果 5-脂氧合酶激活蛋白基因2354T/A和16699A/G多态性在病例组和对照组均以TT、GG基因型为主。A等位基因为少见型。连锁不平衡分析显示2354T/A,16699G/A间不存在连锁不平衡(D’=0.798,r2=0.037)。单因素分析显示以上2个多态未显示与冠心病的相关性,应用Logistic回归模型将混杂因素矫正后进行分析单个多态位点与疾病的关系时,以上2个多态同样未显示与冠心病的相关性。将以上多态全部纳入构建单体型,有两种单体型频率较高分别为:AG28.6%、TG68.9%,单体型分析显示,两组间比较差异无统计学意义(P>0.05)。结论 5-脂氧合酶激活蛋白基因2354T/A和16699G/A多态性与中国天津汉族人群冠心病易感性无明显关联。