ALOX5AP基因和IL-1A基因多态性与缺血性卒中的相关性
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摘要
ALOX5AP基因和IL-1A基因多态性与缺血性卒中的相关性
研究背景
脑血管病是严重危害人类健康的常见病、多发病,是人类三大死亡原因之一;缺血性卒中(IS)的发病率占脑血管疾病发病率的80%。虽然其确切遗传机制尚不清楚,但近些年人们通过多态性关联分析等方法己经报告了一些与IS有关的新易感性基因,如ApoE、PDE4D、ALOX5AP、IL-1A等基因。但是针对这些候选基因在不同地区、针对不同种族的关联性研究结果均未得到有效的重复和肯定。我国北方地区为IS的高发区,有必要进行一项针对我国北方地区汉族人群IS易感基因的病例对照研究。
动脉粥样硬化的形成和发展是IS的重要病理生理基础,而炎症反应在动脉粥样硬化的形成过程中具有重要的意义。因此本研究选取ALOX5AP基因和IL-1A基因这两个炎症相关基因,采用候选基因病例对照的研究方法,分析了由DECODE研究组命名的单倍型HapA的AOX5AP基因四个位点(SG13S25A/G、SG13S32A/C、SG13S89A/G、SG13S114A/T)及IL-1A基因-889位点的基因型、等位基因型在IS组、IS亚组及对照组中频率分布差异,从而探讨ALOX5AP基因、IL-1A基因多态性和中国北方汉族人群IS的相关性,为更详尽的了解IS发病潜在的遗传机制提供分子流行病学依据,并为早期诊断IS提供更多的分子生物学指标。
研究方法
采用病例-对照研究方法,IS组选取中国北方IS患者472例,男283例、女189例,年龄在40-80岁间,均为汉族,彼此无亲缘关系;选取性别、年龄与IS组相匹配的健康个体312例作为对照组,男183例、女129例;在此基础上将IS组按病因不同分为大血管组(血栓性脑梗死组)和小血管组(腔隙性脑梗死组)。应用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)的方法检测AOX5AP基因SG13S32位点、SG13S89位点和IL-1A-889位点的多态性,应用基质辅助激光解吸附电离飞行时间质谱法(MALDI-TOF)检测SG13S114位点、SG13S25位点多态性;基因分型结果经双脱氧末端终止测序法进一步确认。用拟合优度x~2检验验证每个位点SNP基因型在抽样群体中的分布是否符合Hardy-Weinberg平衡。对于单位点的SNP数据,采用SPSS13.0统计软件x~2Fisher's精确概率法检验其基因型、等位基因型在对照组与IS组及各亚组中的频率分布差异、风险度分析,最后结合临床资料,对相关数据进行条件Logistic回归方法排除传统混杂因素的干扰,以P＜0.05为检验水准。用Shesis在线软件计算ALOX5AP基因单倍型的频率。用UNPHASED软件分析ALOX5AP基因与IL-1A基因对IS的联合作用。
研究结果
1、所有研究对象的每个SNP基因型在抽样群体中的分布均符合Hardy-Weinberg平衡(P＞0.05),表示所选取的样本具有人群代表性适合做遗传学分析。
2、ALOX5AP基因多态性在对照组与IS组及IS亚组中频率分布:SG13S32位点C等位基因频率IS组明显高于对照组(OR=1.271;95%CI:1.027-1.572;P=0.028);SG13S114位点AA基因型频率大血管组明显高于对照组(OR=1.987;95%CI:1.138-3.471;P=0.014),应用条件Logistic回归校正后仍有统计学差异(OR=1.479;95%CI:1.024-2.135:P=0.037)。
3、ALOX5AP基因单倍型在对照组与IS组及IS亚组中频率分布:HapA单倍型频率分布在对照组、IS组及IS亚组中没有差异;GCGA单倍型的频率IS组明显高于对照组(OR＝1.683;95%CI:1.138-2.487;P=0.008),大血管组也高于对照组(OR=1.629;95%CI:1.047-2.532;P=0.029),小血管组与对照组差别更加明显(OR=1.806;95%CI:1.156-2.822;P=0.009);GAGA单倍型的频率IS组低于对照组(OR=0.763;95%CI:0.583-0.988;P=0.048),大血管组的频率也低于对照组(OR=0.719;95%CI:0.522-0.99;P=0.042)。
4、不同性别的ALOX5AP基因单倍型的频率分布差异:所有单倍型在男、女性IS组与对照组中的频率分布未见到显著性差异。
5、IL-1A基因多态性在对照组与IS组及IS亚组中频率分布:L-1A-889 TT基因型频率大血管组明显高于对照组(OR=2.473;95%CI:1.129-5.42;P=0.02),应用Logistic校正后仍有统计学意义(OR=1.581;95%CI:1.003-2.493;P=0.047);其等位基因T的频率大血管组也高于对照组(OR=1.540;95%CI:1.075-2.204;P=0.018)。IL-1A-889基因多态性在男、女性别中分布无差异。
6、ALOX5AP基因与IL-1A基因的联合作用:同时携带ALOX5AP基因GCGA单倍型和IL-1A-889位点T等位基因的频率IS组高于对照组(OR＝1.608;95%CI:1.067-2.423:P=0.022)。
结论
1、ALOX5AP基因SG13S114位点AA基因型可能是中国北方汉族人群血栓性脑梗死的独立的风险因素,其风险性主要来源于A等位基因。
2、SG13S32位点C等位基因可以增加患血栓性脑梗死的遗传易感性。
3、ALOX5AP基因HapA单倍型与IS没有相关性。
4、ALOX5AP基因GCGA单倍型可能是IS的风险单倍型,GAGA可能是IS的保护性单倍型。
5、ALOX5AP基因多态性与IS的相关性与性别无关。
6、IL-1A基因-889位点TT基因型可能是血栓性脑梗死的独立的风险因素,其遗传易感性主要来源于等位基因T。
7、IL-1A-889基因多态性与IS的相关性与性别无关。
8、ALOX5AP基因GCGA单倍型与IL-1A-889位点T等位基因的协同作用可以显著增加中国北方汉族人群患IS的遗传易感性。
Objective
Cerebrovascular disease(CVD)is one of the three major causes of death,and is harmful to human health.Ischemic stroke(IS)of incidence of cerebrovascular disease accounted for 80%.IS is a heterogeneous multifactorial disorder.Epidemiological data provide substantial evidence for a genetic component to the disorder,but the extent of predisposition is unknown.Genetic variance determines IS genetic predisposition. Although the exact mechanisms are not clarified,in recent years through polymorphisms linkage analysis some new susceptible genes have been reported such as apolipoproteinE(ApoE),phosphodiesterase 4D(PDE4D),Interleukin-1A(IL-1A), and arachidonate 5-lipoxygenase-activating protein(ALOX5AP)gene.However the association results of these candidate genes in different regions and for different ethnic population have not been effectively reapeated and confirmed.In view of northern Chinese population with higher incidence of IS,it is necessary to carry out an association study of candidated susceptible genes aimed at northern China region Han population IS.
Atherosclerosis is an important pathophysiological basis of IS,and inflammatory reaction process is of great significance in atherosclerosis formation,so our study selected inflammation-related ALOX5AP and IL-1A gene.By introducing candidate genes case-control association analysis,we mesured ALOX5AP gene haplotype HapA four SNPs(SG13S25A/G、SG13S32A/C、SG13S89A/G、SG13S114A/T)and IL-1A-889 C/T SNP genotype and allele frequencies between IS group,IS subgroups and control group,and evaluated the association between these two genes SNPs and IS.So we can provide IS molecular epidemiology data for comprehensively understanding IS potential genetic mechanisms and more early IS molecular biology diagnosis indicators.
Materials and methods
A case-control design was introduced.The subjects of IS group were consecutively recruited from northern China region patients with a total of 472 cases male 283,female 189,aged 40-80 years old,Han nationality,no consanguinity with each other.The controls matched by age,sex,and ethnic orign were recruited from the same patients geographic region,with a total of 312 cases,male 183,female 129. Accordting to the different causes the patients were divided into two subgroups:the large vessels group(thrombotic cerebral infarction group) and the small vessels group(lacunar infarction group).ALOX5AP gene SG13S32,SG13S89,and IL-1A-889 SNPs were genotyped by polymerase chain reaction and restriction fragment length polymorphism(PCR-RFLP) analysis.ALOX5AP SG13S114 and SG13S25 SNPs were genotyped by means of Matrix-assisted laser desorption ionization time-of-flight mass spectrometry(MALDI-TOF) primer extension reaction.Genotyping results were confirmed by dideoxy termination squencing method.SPSS 13.0 statistical software was used for data processing.Continuous variables were expressed as mean±SE and were assessed by One-Way ANOVA.Genotype and allele frequencies were calculated for control group and each of the patient groups.Univariate comparisons of allele and genotype distributions were done using x~2 test.The x~2 goodness of fit test was used to test for deviation of genotype distribution from Hardy-Weinberg equilibrium. Conditional Logistic Regression adjusted for IS traditional risk factors including age, blood pressure,blood sugar,blood lipids and smoking.The influence of AlOX5AP and IL-1A gene polymorphisms on IS was indicated by odds ratio(OR) and 95% confidenc(CI) with P＜0.05 as significant criteria.Haplotype-based analysis was infered by using Shesis online-software.The synergistic action of ALOX5AP gene and IL-1A gene for IS was analysed by UNPHASED 3.0.7 version software.
Results
1.The genotype frequencies of all SNPs conformed to the expectations of Hardy-Weinberg equilibrium(P>0.05).It was suggested that the selected samples could represent the population and were suitable for genetic analysis.
2.ALOX5AP gene SNPs frequencies distributions among the patients and the controls:SG13S32 C allele frequencies of the IS group were higher than the control group(OR=1.271;95%CI:1.027-1.572;P=0.028);SG13 S 114 AA genotyp frequencies of the large vessels group were higher than the control group(OR=1.987;95%CI: 1.138-3.471;P=0.014),and after conditional logistic regression the differece was still significant(OR=1.479;95%CI:1.024-2.135;P=0.037).
3.ALOX5AP gene haplotype frequencies among the patients and the controls: ALOX5AP gene HapA haplotype frequencies were normal among the patients and the controls;GCGA haplotype frequencies of the IS group were higher than the control group(OR=1.683;95%CI:1.138-2.487;P=0.008),the frequencies of the large vessels were higher than the control group(OR=1.629;95%CI:1.047-2.532;P=0.029),and the frequencies of the small vessels group were remarkably higher than the control group(OR=1.806;95%CI:1.156-2.822;P=0.009);GAGA haplotype frequencies of the IS group were lower than the control group(OR=0.763;95%CI:0.583-0.988; P=0.048),and the frequencies of the large vessels group were lower than the control group(OR=0.719;95%CI:0.522-0.99;P=0.042)
4.ALOX5AP gene haplotype gender-specific frequencies distributions: Significant differences of all the haplotypes were not observed in the male and female IS group and control group.
5.L-1A-889 SNPs frequencies distributions among the patients and the controls: IL-1A-889 TT frequencies of the IS group were higher than the control group (OR=2.473;95%CI:1.129-5.42;P=0.02),and after conditional logistic regression the difference was still significant(OR=1.581;95%CI:1.003-2.493;P=0.047); IL-1A-889 T allele frequencies of the large vessels group were higher than the control group(OR=1.540;95%CI:1.075-2.204;P=0.018).IL-1A-889 gene polymorphisms distributions were not different among male and female.
6.ALOX5AP gene and IL-1A gene synergistic reaction:The individuals who carried the haplotype GCGA and IL-1A-889 C allele suffered IS with the 1.608 folds risk(OR=1.608;95%CI:1.067-2.423;P=0.022).
Conclusions
1.ALOX5AP gene SG13S114 AA genotype might be the independent risk factors of northern China region han population thrombotic cerebral infarction,and its risk mainly came from T allele.
2.SG13S32 C allele can increase genetic susceptibilty of thrombotic cerebral infaction.
3.The association ofALOX5AP gene HapA haplotype with IS was not identified.
4.ALOX5AP gene GCGA haplotype might be at-risk haplotype of IS,and GAGA haplotype might be protective haplotype of IS.
5.The association of ALOX5AP gene with IS was not related with male and female sex.
6.IL-1A-889 TT genotype could be independent risk factor of thrombotic cerebral infarction,and its genetic susceptibility mainly came from T allele.
7.The association of IL-1A-889 with IS was not related with male and female sex.
8.ALOX5AP and IL-1A gene polymorphisms can synergistically confer higher risk for IS of northern China region population.
研究背景
脑血管病是严重危害人类健康的常见病、多发病,是人类三大死亡原因之一;缺血性卒中(IS)的发病率占脑血管疾病发病率的80%。虽然其确切遗传机制尚不清楚,但近些年人们通过多态性关联分析等方法己经报告了一些与IS有关的新易感性基因,如ApoE、PDE4D、ALOX5AP、IL-1A等基因。但是针对这些候选基因在不同地区、针对不同种族的关联性研究结果均未得到有效的重复和肯定。我国北方地区为IS的高发区,有必要进行一项针对我国北方地区汉族人群IS易感基因的病例对照研究。
动脉粥样硬化的形成和发展是IS的重要病理生理基础,而炎症反应在动脉粥样硬化的形成过程中具有重要的意义。因此本研究选取ALOX5AP基因和IL-1A基因这两个炎症相关基因,采用候选基因病例对照的研究方法,分析了由DECODE研究组命名的单倍型HapA的AOX5AP基因四个位点(SG13S25A/G、SG13S32A/C、SG13S89A/G、SG13S114A/T)及IL-1A基因-889位点的基因型、等位基因型在IS组、IS亚组及对照组中频率分布差异,从而探讨ALOX5AP基因、IL-1A基因多态性和中国北方汉族人群IS的相关性,为更详尽的了解IS发病潜在的遗传机制提供分子流行病学依据,并为早期诊断IS提供更多的分子生物学指标。
研究方法
采用病例-对照研究方法,IS组选取中国北方IS患者472例,男283例、女189例,年龄在40-80岁间,均为汉族,彼此无亲缘关系;选取性别、年龄与IS组相匹配的健康个体312例作为对照组,男183例、女129例;在此基础上将IS组按病因不同分为大血管组(血栓性脑梗死组)和小血管组(腔隙性脑梗死组)。应用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)的方法检测AOX5AP基因SG13S32位点、SG13S89位点和IL-1A-889位点的多态性,应用基质辅助激光解吸附电离飞行时间质谱法(MALDI-TOF)检测SG13S114位点、SG13S25位点多态性;基因分型结果经双脱氧末端终止测序法进一步确认。用拟合优度x~2检验验证每个位点SNP基因型在抽样群体中的分布是否符合Hardy-Weinberg平衡。对于单位点的SNP数据,采用SPSS13.0统计软件x~2Fisher's精确概率法检验其基因型、等位基因型在对照组与IS组及各亚组中的频率分布差异、风险度分析,最后结合临床资料,对相关数据进行条件Logistic回归方法排除传统混杂因素的干扰,以P＜0.05为检验水准。用Shesis在线软件计算ALOX5AP基因单倍型的频率。用UNPHASED软件分析ALOX5AP基因与IL-1A基因对IS的联合作用。
研究结果
1、所有研究对象的每个SNP基因型在抽样群体中的分布均符合Hardy-Weinberg平衡(P＞0.05),表示所选取的样本具有人群代表性适合做遗传学分析。
2、ALOX5AP基因多态性在对照组与IS组及IS亚组中频率分布:SG13S32位点C等位基因频率IS组明显高于对照组(OR=1.271;95%CI:1.027-1.572;P=0.028);SG13S114位点AA基因型频率大血管组明显高于对照组(OR=1.987;95%CI:1.138-3.471;P=0.014),应用条件Logistic回归校正后仍有统计学差异(OR=1.479;95%CI:1.024-2.135:P=0.037)。
3、ALOX5AP基因单倍型在对照组与IS组及IS亚组中频率分布:HapA单倍型频率分布在对照组、IS组及IS亚组中没有差异;GCGA单倍型的频率IS组明显高于对照组(OR＝1.683;95%CI:1.138-2.487;P=0.008),大血管组也高于对照组(OR=1.629;95%CI:1.047-2.532;P=0.029),小血管组与对照组差别更加明显(OR=1.806;95%CI:1.156-2.822;P=0.009);GAGA单倍型的频率IS组低于对照组(OR=0.763;95%CI:0.583-0.988;P=0.048),大血管组的频率也低于对照组(OR=0.719;95%CI:0.522-0.99;P=0.042)。
4、不同性别的ALOX5AP基因单倍型的频率分布差异:所有单倍型在男、女性IS组与对照组中的频率分布未见到显著性差异。
5、IL-1A基因多态性在对照组与IS组及IS亚组中频率分布:L-1A-889 TT基因型频率大血管组明显高于对照组(OR=2.473;95%CI:1.129-5.42;P=0.02),应用Logistic校正后仍有统计学意义(OR=1.581;95%CI:1.003-2.493;P=0.047);其等位基因T的频率大血管组也高于对照组(OR=1.540;95%CI:1.075-2.204;P=0.018)。IL-1A-889基因多态性在男、女性别中分布无差异。
6、ALOX5AP基因与IL-1A基因的联合作用:同时携带ALOX5AP基因GCGA单倍型和IL-1A-889位点T等位基因的频率IS组高于对照组(OR＝1.608;95%CI:1.067-2.423:P=0.022)。
结论
1、ALOX5AP基因SG13S114位点AA基因型可能是中国北方汉族人群血栓性脑梗死的独立的风险因素,其风险性主要来源于A等位基因。
2、SG13S32位点C等位基因可以增加患血栓性脑梗死的遗传易感性。
3、ALOX5AP基因HapA单倍型与IS没有相关性。
4、ALOX5AP基因GCGA单倍型可能是IS的风险单倍型,GAGA可能是IS的保护性单倍型。
5、ALOX5AP基因多态性与IS的相关性与性别无关。
6、IL-1A基因-889位点TT基因型可能是血栓性脑梗死的独立的风险因素,其遗传易感性主要来源于等位基因T。
7、IL-1A-889基因多态性与IS的相关性与性别无关。
8、ALOX5AP基因GCGA单倍型与IL-1A-889位点T等位基因的协同作用可以显著增加中国北方汉族人群患IS的遗传易感性。
Objective
Cerebrovascular disease(CVD)is one of the three major causes of death,and is harmful to human health.Ischemic stroke(IS)of incidence of cerebrovascular disease accounted for 80%.IS is a heterogeneous multifactorial disorder.Epidemiological data provide substantial evidence for a genetic component to the disorder,but the extent of predisposition is unknown.Genetic variance determines IS genetic predisposition. Although the exact mechanisms are not clarified,in recent years through polymorphisms linkage analysis some new susceptible genes have been reported such as apolipoproteinE(ApoE),phosphodiesterase 4D(PDE4D),Interleukin-1A(IL-1A), and arachidonate 5-lipoxygenase-activating protein(ALOX5AP)gene.However the association results of these candidate genes in different regions and for different ethnic population have not been effectively reapeated and confirmed.In view of northern Chinese population with higher incidence of IS,it is necessary to carry out an association study of candidated susceptible genes aimed at northern China region Han population IS.
Atherosclerosis is an important pathophysiological basis of IS,and inflammatory reaction process is of great significance in atherosclerosis formation,so our study selected inflammation-related ALOX5AP and IL-1A gene.By introducing candidate genes case-control association analysis,we mesured ALOX5AP gene haplotype HapA four SNPs(SG13S25A/G、SG13S32A/C、SG13S89A/G、SG13S114A/T)and IL-1A-889 C/T SNP genotype and allele frequencies between IS group,IS subgroups and control group,and evaluated the association between these two genes SNPs and IS.So we can provide IS molecular epidemiology data for comprehensively understanding IS potential genetic mechanisms and more early IS molecular biology diagnosis indicators.
Materials and methods
A case-control design was introduced.The subjects of IS group were consecutively recruited from northern China region patients with a total of 472 cases male 283,female 189,aged 40-80 years old,Han nationality,no consanguinity with each other.The controls matched by age,sex,and ethnic orign were recruited from the same patients geographic region,with a total of 312 cases,male 183,female 129. Accordting to the different causes the patients were divided into two subgroups:the large vessels group(thrombotic cerebral infarction group) and the small vessels group(lacunar infarction group).ALOX5AP gene SG13S32,SG13S89,and IL-1A-889 SNPs were genotyped by polymerase chain reaction and restriction fragment length polymorphism(PCR-RFLP) analysis.ALOX5AP SG13S114 and SG13S25 SNPs were genotyped by means of Matrix-assisted laser desorption ionization time-of-flight mass spectrometry(MALDI-TOF) primer extension reaction.Genotyping results were confirmed by dideoxy termination squencing method.SPSS 13.0 statistical software was used for data processing.Continuous variables were expressed as mean±SE and were assessed by One-Way ANOVA.Genotype and allele frequencies were calculated for control group and each of the patient groups.Univariate comparisons of allele and genotype distributions were done using x~2 test.The x~2 goodness of fit test was used to test for deviation of genotype distribution from Hardy-Weinberg equilibrium. Conditional Logistic Regression adjusted for IS traditional risk factors including age, blood pressure,blood sugar,blood lipids and smoking.The influence of AlOX5AP and IL-1A gene polymorphisms on IS was indicated by odds ratio(OR) and 95% confidenc(CI) with P＜0.05 as significant criteria.Haplotype-based analysis was infered by using Shesis online-software.The synergistic action of ALOX5AP gene and IL-1A gene for IS was analysed by UNPHASED 3.0.7 version software.
Results
1.The genotype frequencies of all SNPs conformed to the expectations of Hardy-Weinberg equilibrium(P>0.05).It was suggested that the selected samples could represent the population and were suitable for genetic analysis.
2.ALOX5AP gene SNPs frequencies distributions among the patients and the controls:SG13S32 C allele frequencies of the IS group were higher than the control group(OR=1.271;95%CI:1.027-1.572;P=0.028);SG13 S 114 AA genotyp frequencies of the large vessels group were higher than the control group(OR=1.987;95%CI: 1.138-3.471;P=0.014),and after conditional logistic regression the differece was still significant(OR=1.479;95%CI:1.024-2.135;P=0.037).
3.ALOX5AP gene haplotype frequencies among the patients and the controls: ALOX5AP gene HapA haplotype frequencies were normal among the patients and the controls;GCGA haplotype frequencies of the IS group were higher than the control group(OR=1.683;95%CI:1.138-2.487;P=0.008),the frequencies of the large vessels were higher than the control group(OR=1.629;95%CI:1.047-2.532;P=0.029),and the frequencies of the small vessels group were remarkably higher than the control group(OR=1.806;95%CI:1.156-2.822;P=0.009);GAGA haplotype frequencies of the IS group were lower than the control group(OR=0.763;95%CI:0.583-0.988; P=0.048),and the frequencies of the large vessels group were lower than the control group(OR=0.719;95%CI:0.522-0.99;P=0.042)
4.ALOX5AP gene haplotype gender-specific frequencies distributions: Significant differences of all the haplotypes were not observed in the male and female IS group and control group.
5.L-1A-889 SNPs frequencies distributions among the patients and the controls: IL-1A-889 TT frequencies of the IS group were higher than the control group (OR=2.473;95%CI:1.129-5.42;P=0.02),and after conditional logistic regression the difference was still significant(OR=1.581;95%CI:1.003-2.493;P=0.047); IL-1A-889 T allele frequencies of the large vessels group were higher than the control group(OR=1.540;95%CI:1.075-2.204;P=0.018).IL-1A-889 gene polymorphisms distributions were not different among male and female.
6.ALOX5AP gene and IL-1A gene synergistic reaction:The individuals who carried the haplotype GCGA and IL-1A-889 C allele suffered IS with the 1.608 folds risk(OR=1.608;95%CI:1.067-2.423;P=0.022).
Conclusions
1.ALOX5AP gene SG13S114 AA genotype might be the independent risk factors of northern China region han population thrombotic cerebral infarction,and its risk mainly came from T allele.
2.SG13S32 C allele can increase genetic susceptibilty of thrombotic cerebral infaction.
3.The association ofALOX5AP gene HapA haplotype with IS was not identified.
4.ALOX5AP gene GCGA haplotype might be at-risk haplotype of IS,and GAGA haplotype might be protective haplotype of IS.
5.The association of ALOX5AP gene with IS was not related with male and female sex.
6.IL-1A-889 TT genotype could be independent risk factor of thrombotic cerebral infarction,and its genetic susceptibility mainly came from T allele.
7.The association of IL-1A-889 with IS was not related with male and female sex.
8.ALOX5AP and IL-1A gene polymorphisms can synergistically confer higher risk for IS of northern China region population.
引文
1 Dichgans M.Genetics ofischaemic stroke.Lancet Neurol,2007,6:149-161.
2 Rosand J,Altshuler D,et al.Human Genome Sequence Variation and the Search for Genes Influencing Stroke.Stroke,2003,34:2512-2517.
3 Rosand J,Altshuler D,et al.Human Genome Sequence Variation and the Search for Genes Influencing Stroke.Stroke,2003,34:2512-2517.
4 Dichgans M,Markus HS.Genetic Association Studies in Stroke Methodological Issues and Proposed StandardCriteria.Stroke,2005,36:2027-2031.
5 Nilsson-Ardnor S,Janunger T,Wiklund Per-Gunnar,et al.Genome-Wide Linkage Scan of Common Stroke in Families From Northern Sweden.Stroke,2007,38:34-40.
6 Gretarsdottir S,Sveinbj(o|¨)rnsdottir S,Jonsson HH,et al.Localization of a Susceptibility Gene for Common Forms of Stroke to 5q12.Am J Hum Genet,2002,70:593-603.
7 Helgadottir A,Manolescu A,Thorleifsson G,et al.The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke.Nat Genet,2004,36:233-238.
8 曹立梅,毕桂南.5-脂氧合酶与脑缺血再灌注.国外医学脑血管病疾病分册,2004,12:850-852.
9 周斌,陈新生.5-脂氧合酶在中枢神经系统的作用.生理科学进展,2003,34:77-79.
10 李杰萍,梁统.5-脂氧合酶及其基因表达调控的研究进展.国外医学临床生物化学与检验学分册,2003,24:225-232.
11 Ohtsuki T,Matsumoto M,Hayashi Y,et al.Reperfusion induces 5-lipoxygenase translocation and leukotriene C4 Production in ischemic brain.Am J Physiol,1995,268:1249-1257.
12 Datta K,Biswal SS,Xu J,et al.A relationship between 5-lipoxygenase-activating protein and bcl-xL expression in murine pro-B lymphocytic FL5.12 cells.J Biol Chem,1998,273:28163-28169.
13 FalkE,ShalPK,FusterV.Coronary plaquedisruption.Circulation,1995,92:657-671.
14 Dwyer JH,Allayee H,Dwyer KM,et al.Arachidonate 5-lipoxygenase promoter genotype,dietary arachidonic acid,and atherosclerosis.N Eng J Med,2004,350:29-37.
15 杨俊卿,周岐新.5-脂氧合酶途径-研究神经元退行性疾病的新耙点.生命科学研究,2003,7:12-16.
16 Evans JF,Ferguson AD,Mosley RT,et al.What's all the FLAP about?:5-1ipoxygenase-activating protein inhibitors for inflammatory diseases.Cell,2008,29:72-78.
17 Blondal T,Waage BG,Smarason SV,et al.A novel MALDI-TOF based methodology for genotyping single nucleotide polymorphisms.Nucleic Acids Res,2003,31:e155.
18 杨何义,蔡耘,王杰,等.生物质谱作为 SNP 分型检测方法的研究.质谱学报,2003,24:449-455.
19 唐剑频,侯一平.基质辅助激光解析/离子化飞行时间质谱分析多态性遗传标记.中华医学遗传学杂志.,2005,22:185-188.
20 Rebbeck TR,Spitz M,Wu X.Assessing the function of genetic variants in candidate gene association studies.Nat RevGenet,2004,5:589-597.
21 Balding DJ.A tutorial on statistical methods for population association studies.Nat Rev Genet,2006,7:781-791.
22 Setakis E,Stirnadel H,Balding DJ.Logistic regression protects against population structure in genetic association studies.Genome Res,2006,16.:290-296.
23 Shi YY,He L.SHEsis,a powerful software platform for analyses of linkage disequilibrium,haplotype construction,and genetic association at polymorphism loci.Cell Res,2005,15:97-8.
24 Li J,Pan YC,Li YX,et al.Analysis and Application of SNP and Haplotype in the Human Genome.ActaGeneticsSinica,2005,32:879-889.
25 Dudbridge F.Pedigree disequilibrium tests for multilocus haplotypes.Genet Epidemiol,2003,52:115-121.
26 Bitstein D,Risch N.Discovering genotypes underlying human phenotypes:past successes for mendelian disease,future approaches for complexdisease.Nat Genet,2003,33:228-237.
27 金丽江.2005年卒中和脑血管疾病的遗传学研究进展.中国卒中杂志,2006,1:78-79.
28 曾昭书,丁梅,朱运良,等.PCR-RFLP 法分析北方汉族人群 HLA-B 基因多态生.法医学杂志,2006,22:193-195.
29 Topol EJ,Smith J,Plow EF,et al.Genetic susceptibility to myocardial infarction and coronary artery disease.Hum Mol Genet,2006,15:117-123.
30 Cheng J,Liu J,Li X,et al.Effect of polymorphisms of endothelial nitric oxide synthase on ischemic stroke:a case-control study in a Chinese population.Clin Chim Acta,2008,392:46-51.
31 Cheng J,Liu X,Li J,et al.Insulin-like growth factor-1 receptor polymorphism and ischemic stroke:a case-control study in Chinese population.ActaNeurol Scand,2008,118:333-338.
32 Shi C,Kang X,Wang Y,et al.The coagulation factor V Leiden,MTHFRC677T variant and Enos 4ab polymorphism in young Chinese population with ischemic stroke.Clin Chim Acta,2008,396:7-9.
33 Mallolas J,Hurtado O,Castellanos M,et al.A polymorphism in the EAAT2 promoter is associated with higher glutamate concentrations and higher frequency of progressing stroke.J ExpMed,2007,203:711-717.
34 顾丰.单核苷酸多态性及其数据库.中华医学遗传学杂志,2001,18:479-481.
35 Bensen JT,Langefeld CD,Hawkins GA,et al.Necleotide variation,haplotype structure,and association with end-stage renal disease of human interleukin-1 gene cluster,Genomics,2003,82:194-217.
36 汪维鹏,倪坤仪,周国华.单核苷酸多态性检测方法的研究进展.遗传,2006,28:117-126.
37 Stephens M,Smith N J,Donnelly P.A new statistical method for haplotype reconstruction from population data.Am J Hum Genet.2001,68:978-989.
38 顾明亮,褚嘉佑.基于标签单核苷酸多态性单倍型和单倍域的构建及其在关联研究中的应用.中华医学遗传学杂志,2007,24:660-665.
39 Yandava CN,Kennedy BP,Pillari A,et al.Cytogenetic and radiation hybrid mapping of human arachidonate 5-1ipoxygenase-activating protein(ALOX5AP)to chromosome 13q12.Genomics,1999,56:131-133.
40 梁庆成,高强.ALOX5AP与卒中.国际脑血管病杂志,2006,14:388-389.
41 Helgadottir A,Gretarsdottir S,St Clair D,et al.Association between the gene Encoding 5-Lipoxygenase-Activating protein and Stroke Replicated in a Scottish Population.AM J Hum Genet,2005,76:505-509.
42 L(?)hmussaar E,Gschwendtner A,Mueller JC,et al.ALOX5AP Gene and the PDE4D Gene in a Central European Population of Stroke Patients.Stroke,2005,36:731-736.
43 Kaushal R,Pal P,Alwell K,et al.Association of ALOX5AP with ischemic stroke:a population-based case-control study.Hum Genet,2007,121:601-608.
44 Shah SH,Hauser ER,Crosslin D,et al.ALOX5AP variants are associated with in-stent restenosis after percutaneous coronary intervention.Atherosclerosis,2008,doi:10.1016/j.
45 Kostulas K,Gretarsdottir S,Kostulas V,et al.PDE4D and ALOX5AP genetic variants and risk for Ischemic Cerebrovascular Disease in Sweden.J Neurol Sci,2007,263:113-117.
46 Zee RY,Cheng S,Hegener HH,et al.Genetic variants of arachidonate 5-1ipoxygenase-activating protein,and risk of incident myocardial infarction and ischemic stroke:anestedcase-control approach.Strole,2006,37:2007-2011.
47 Koch W,Hoppmann P,Mueller JC,et al.No association of polymorphisms in the gene encoding 5-lipoxygenase-activating protein and myocardial infarction in a large central European population.GenetMed,2007,9:123-129.
48 Rothwell NJ,Luheshi GN.Interleukin 1 in the brain:biology,pathology and therapeutic target.TrendsNeurosci,2000,13:618-625.
49 周刚,刘利民,等.白细胞介素-1 基因多态性与疾病.细胞与分子免疫学杂志,2007,23:190-192.
50 AlyH,KhashabaMT,E1-AyoutyM,etal.IL-lbeta,IL-6 and TNF-alpha and outcomes of neonatal hypoxic ischemic encephalopathy.Brain,2006,28:178-182.
51 Wei X,Chen X,Fontanilla C.C/T conversion alters interleukin-1A promoter function in a human astrocyte cell line.Life Sci,2007,80:1152-1156.
52 徐朴,李艳.白细胞介素-1 基因多态性的研究进展.国外医学临床生物化学与检验学分册,2003,24:347-348.
53 卞杰勇,张世明,周岱.白细胞介素-1 与缺血性脑损伤.国外医学脑血管疾病分册,2001,9:300-302.
54 Murphy GM Jr,Claassen JD,DeVoss J J,et al.Rate of cognitive decline in AD is accelerated by theinterleukin-1-alpha-889~*l allele.Neurology,2001,56:1595-1597.
55 Um JY,Moon KS,Lee KM,et al.Interleukin-1 gene cluster polymorphisms in cerebral infarction.Cytokine,2003,5,23:41-46.
56 Worrall BB,Brott TG,Brown RD Jr,et al.ILl RN VNTR Polymorphism in Ischemic Stroke Analysis in 3 Populations.Stroke,2006,38:1189-1196.
57 Pinteaux E,Rothwell NJ,Boutin H.Neuroprotective actions of endogenous interleukin-1receptor antagonist(IL-1ra)are mediated by glia.Glia,2006,53:551-556.
58 Li MG,Katsura K,Nomiyama H,et al.Regulation of the interleukin-1-induced signaling pathways by a novel member of the protein phosphatase 2C family(PP2Cepsilon).J Biol Chem,2003,278:12013-12021.
59 Furuichi K,Wada T,Iwata Y,et al.Interleukin-1-dependent sequential chemokine expression and inflammatory cell infiltration in ischemia-reperfusion injury.Crit Care Med,2006,34:2447-2455.
60 Zhang F,Hu EC,Gerzenshtein J.The Expression of Proinflammatory Cytokines in the Rat Muscle Flap With Ischemia-Reperfusion Injury.Ann Plast Surg,2005,54:313-317.
61 Iacoviello L,Di Castelnuovo A,Gattone M,et al.Polymorphisms of the interleukin-lbeta gene affect the risk of myocardial infarction and ischemic stroke at young age and the response of mononuclear cells to stimulation in vitro.Arterioscler Thromb Vasc Biol,2005,25:222-227.
62 D(?)niz-Naranjo MC,Mu(?)oz-Fernandez C,Alemany-Rodr(?)guez MJ,et al.Cytokin IL-1 beta but not IL-1 alpha promoter polymorphism is associated with Alzheimer disease in a population from the Cornary Islands,Spain.Eur J Neurol,2008,15:1080-1084.
63 Rogers J.An IL-1 alpha susceptibility polymorphism in Alzheimer's disease:New fuel for the inflammation hypothesis.Neurology,2000,55:464-465.
64 Zanardini R,Bocchio-Chiavetto L,Scassellati C,et al.Association between IL-1 beta-511 C/T and IL-1RA(86bp)n repeats polymorphisms and schizophrenia.J Psychiatr Res,2003,37:457-62.
65 Wanderer AA.Ischemic-reperfusion syndromes:biochemical and immunologic rationale for IL-1 targeted therapy.Clin Immunol,2008,128:127-132.
66 Gromadzka G,Sarzynska-Dlugosz I,Czlonkowska A.IL1RN intron 2 polymorphism caused by variable number tandem repeats is associated with 1-year outcome in patients with ischaemic stroke.J Neurol Neurosurg Psychiatry,2000,78:183-186.
67 Lai J,Zhou D,Xia S,et al.Association of interleukin-1 gene cluster polymorphisms with ischemic stroke in a Chinese population.Neurology India,2006,54:366-369.
68 Dominici R,Cattaneo M,Malferrari G,et al.Cloning and functional analysis of the allelic polymorphism in the transcription regulatory region of interleukin-1 alpha.Immunogenetics,2002,54:82-86.
69 Devaraj S,Jialal I.Alpha-tocopherol decreases tumor necrosis factor-alpha mRNA and protein from activated human monocytes by inhibition of 5-lipoxygenase.Free Radic Bio Med,2005,38:1212-1220.
1 Martin D.Genetics of ischaemic stroke.Lancet Neurol,2007,6:149-61.
2 Risch NJ.Searching for Genetic Determinants in the New Millennium.Nature,2000,405:847-856.
3 Rosand J,Altshuler D,et al.Human Genome Sequence Variation and the Search for Genes Influencing Stroke.Stroke,2003,34:2512-2517.
4 Martin D,Hugh S,et al.Genetic Association Studies in Stroke Methodological Issues and Proposed StandardCriteria.Stroke,2005,36:2027-2031.
5 金丽江.2005年卒中和脑血管疾病的遗传学研究进展.中国卒中杂志,2006,1:78-79.
6 顾丰.单核苷酸多态性及其数据库.中华医学遗传学杂志,2001,18:479-481.
7 L(?)hmussaar E,Gschwendtner A,Mueller JC,et al.ALOX5AP Gene and the PDE4D Gene in a Central European Population of Stroke Patients.Stroke,2005,36:731-736.
8 Helgadottir A,Manolescu A,Thorleifsson G,et al.The gene encoding 5-1ipoxygenase activating protein confers risk of myocardial infarction and stroke.Nat Genet,2004,36:233-238.
9 曹立梅,毕桂南.5-脂氧合酶与脑缺血再灌注.国外医学脑血管病疾病分册,2004,12:850-852.
10周斌,陈新生.5-脂氧合酶在中枢神经系统的作用.生理科学进展,2003,34(11):77-79.
11 Topol E J,Smith J,Plow EF,et al.Genetic susceptibility to myocardial infarction and coronary artery disease.Hum Mol Genet,2006,15:117-123.
12 Choi JH,Park HS,Oh HB,et al.Leukotriene-related gene polymorphisms in ASA-intolerant asthma:an association with a haplotype of 5-lipoxygenase.Hum Genet,2004,114:337-344.
13李杰萍,梁统.5-脂氧合酶及其基因表达调控的研究进展.国外医学临床生物化学与检验学分册,2003,24:225-232.
14 Ohtsuki T,Matsumoto M,Hayashi Y,et al.Reperfusion induces 5-1ipoxygenase translocation and leukotriene C4 Production in ischemic brain.Am J Physiol,1995,268:1249-1257.
15 Datta K,Biswal SS,Xu J,et al.A relationship between 5-lipoxygenase-activating protein and bcl-xL expression in murine pro-B lymphocytic FL5.12 cells.J Biol Chem,1998,273:28163-28169.
16 Falk E,Shah PK,Fuster V.Coronary plaque disruption.Circulation,1995,92:657-671.
17 Dwyer JH,Allayee H,Dwyer KM,et al.Arachidonate 5-lipoxygenase promoter genotype,dietary arachidonic acid,and atherosclerosis.N Engl J Med,2004,350:29-37.
18 Helgadottir A,Gretarsdottir S,St Clair D,et al.Association between the gene Encoding 5-Lipoxygenase-Activating protein and Stroke Replicated in a Scottish Population.Am J Hum Genet,2005,76:505-509.
19 Zhang WL,Yang XM,Shi J,et al.Polymmorphism of SG 13S 114T/A in the ALOX5AP Gene and the Risk for Stroke in a Large Chinese Cohort.Yi Chuan Xue Bao,2006,33:678-684.
20 张伟丽,石佳,杨晓敏,等.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.中国分子心脏病学杂志,2005,5:395-400.
21 Kaushal R,Pal P,Alwell K,et al.Association of ALOX5AP with ischemic stroke:a population-based case-control study.Hum Genet,2007,121:601-608.
1 Rothwell NJ,Luheshi GN.Interleukin 1 in the brain:biology,pathology and therapeutic target.TrendsNeurosci,2000,13:618-625.
2 Sonna LA,Fujiita J,et al.Molecular biology of thermoregulation:effects of heat and cold stress on mammalian gene expression.Physiol,2002,92:1725-1745.
3 周刚,刘利民,等.白细胞介素-1 基因多态性与疾病.细胞与分子免疫学杂志,2007,23:190-192.
4 卞杰勇,张世明,周岱.白细胞介素-1 与缺血性脑损伤.国外医学脑血管疾病分册,2001,9:300-302.
5 Pinteaux E,Rothwell NJ,Boutin H.Neuroprotective actions of endogenous interleukin-1receptor antagonist(IL-lra)are mediated by glia.Glia,2006,53:551-556.
6 Warren AY,Harvey L,Shaw RW,et al.Interleukin-1 beta secretion from cord blood mononuclear cells in vitro involves P2X 7 receptor activation.Reprod Sci,2008,15:189-194.
7 Aly H,KhashabaMT,El-AyoutyM,et al.IL-1beta,IL-6 and TNF-alpha and outcomes of neonatal hypoxic ischemic encephalopathy.Brain,2006,28:178-182.
8 Zhang F,Hu EC,Gerzenshtein J,et al.The expression of proinflammatory cytokines in the rat muscle flap with ischemia-reperfusion injury.Ann Plast Surg,2005,54.:313-317.
9 Li MG,Katsura K,Nomiyama H,et al.Regulation of the interleukin-1-induced signaling pathways by a novel member of the protein phosphatase 2C family(PP2Cepsilon).J Biol Chem,2003,278:12013-12021.
10 Rogers J.An IL-1 alpha susceptibility polymorphism in Alzheimer's disease:New fuel for the inflammation hypothesis.Neurology,2000,55:464-465.
11 Furuichi K,Wada T,Iwata Y,et al.Interleukin-1-dependent sequential chemokine expression and inflammatory cell infiltration in ischemia-reperfusion injury.Crit Care Med,2006,34:2447-2455.
12 Gromadzka G,Sarzynska-Dlugosz I,CzlonkowskaA.IL1RN intron 2 polymorphism caused by variable number tandem repeats is associated with 1-year outcome in patients with ischaemic stroke.J Neurol Neurosurg Psychiatry,2000,78:183-186.
13 Guijarro C,Egido J.Transcription factor-kappa B(NF-kappa B)and renal disease.Kindey Int,2001,59:415-424.
14 BensenJT,LangefeldCD,Hawkins GA,etal.Necleotidevariation,haplotypestructure, and association with end-stage renal disease of human interleukin-1 gene cluster,Genomics,2003,82:194-217.
15 Murphy GM Jr,Claassen JD,DeVoss JJ,et al.Rate of cognitive decline in AD is accelerated by the interleukin-1-alpha-889*1 allele.Neurology,2001,56:1595-1597.
16 Um JY,Moon KS,Lee KM,et al.Interleukin-1 gene cluster polymorphisms in cerebral infarction.Cytokine,2003,5,23:41-46.
17 D(?)niz-Naranjo MC,Mu(?)oz-Fernandez C,Alemany-Rodr(?)guez MJ,et al.Cytokin IL-1 beta but not IL-1 alpha promoter polymorphism is associated with Alzheimer disease in a population from the Cornary Islands,Spain.Eur J Neurol,2008,15:1080-1084.
18 Lai J,Zhou D,Xia S,et al.Association of interleukin-1 gene cluster polymorphisms with ischemic stroke in a Chinese population.Neurology India,2006,54:366-369.
19 Worrall BB,Brott TG,Brown RD Jr,et al.IL1RN VNTR Polymorphism in Ischemic Stroke Analysis in 3 Populations.Stroke,2006,38:1189-1196.
20 Francis SE,Camp NJ,Burton AJ,et al.Interleukin 1 receptor antagonist gene polymorphism and restenosis after coronary angioplasty.Heart,2001,86:336-340.
21 Zanardini R,Bocchio-Chiavetto L,Scassellati C,et al.Association between IL-1beta-511C/T and IL-IRA(86bp)n repeats polymorphisms and schizophrenia.J Psychiatr Res,2003,37:457-462.
2 Rosand J,Altshuler D,et al.Human Genome Sequence Variation and the Search for Genes Influencing Stroke.Stroke,2003,34:2512-2517.
3 Rosand J,Altshuler D,et al.Human Genome Sequence Variation and the Search for Genes Influencing Stroke.Stroke,2003,34:2512-2517.
4 Dichgans M,Markus HS.Genetic Association Studies in Stroke Methodological Issues and Proposed StandardCriteria.Stroke,2005,36:2027-2031.
5 Nilsson-Ardnor S,Janunger T,Wiklund Per-Gunnar,et al.Genome-Wide Linkage Scan of Common Stroke in Families From Northern Sweden.Stroke,2007,38:34-40.
6 Gretarsdottir S,Sveinbj(o|¨)rnsdottir S,Jonsson HH,et al.Localization of a Susceptibility Gene for Common Forms of Stroke to 5q12.Am J Hum Genet,2002,70:593-603.
7 Helgadottir A,Manolescu A,Thorleifsson G,et al.The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke.Nat Genet,2004,36:233-238.
8 曹立梅,毕桂南.5-脂氧合酶与脑缺血再灌注.国外医学脑血管病疾病分册,2004,12:850-852.
9 周斌,陈新生.5-脂氧合酶在中枢神经系统的作用.生理科学进展,2003,34:77-79.
10 李杰萍,梁统.5-脂氧合酶及其基因表达调控的研究进展.国外医学临床生物化学与检验学分册,2003,24:225-232.
11 Ohtsuki T,Matsumoto M,Hayashi Y,et al.Reperfusion induces 5-lipoxygenase translocation and leukotriene C4 Production in ischemic brain.Am J Physiol,1995,268:1249-1257.
12 Datta K,Biswal SS,Xu J,et al.A relationship between 5-lipoxygenase-activating protein and bcl-xL expression in murine pro-B lymphocytic FL5.12 cells.J Biol Chem,1998,273:28163-28169.
13 FalkE,ShalPK,FusterV.Coronary plaquedisruption.Circulation,1995,92:657-671.
14 Dwyer JH,Allayee H,Dwyer KM,et al.Arachidonate 5-lipoxygenase promoter genotype,dietary arachidonic acid,and atherosclerosis.N Eng J Med,2004,350:29-37.
15 杨俊卿,周岐新.5-脂氧合酶途径-研究神经元退行性疾病的新耙点.生命科学研究,2003,7:12-16.
16 Evans JF,Ferguson AD,Mosley RT,et al.What's all the FLAP about?:5-1ipoxygenase-activating protein inhibitors for inflammatory diseases.Cell,2008,29:72-78.
17 Blondal T,Waage BG,Smarason SV,et al.A novel MALDI-TOF based methodology for genotyping single nucleotide polymorphisms.Nucleic Acids Res,2003,31:e155.
18 杨何义,蔡耘,王杰,等.生物质谱作为 SNP 分型检测方法的研究.质谱学报,2003,24:449-455.
19 唐剑频,侯一平.基质辅助激光解析/离子化飞行时间质谱分析多态性遗传标记.中华医学遗传学杂志.,2005,22:185-188.
20 Rebbeck TR,Spitz M,Wu X.Assessing the function of genetic variants in candidate gene association studies.Nat RevGenet,2004,5:589-597.
21 Balding DJ.A tutorial on statistical methods for population association studies.Nat Rev Genet,2006,7:781-791.
22 Setakis E,Stirnadel H,Balding DJ.Logistic regression protects against population structure in genetic association studies.Genome Res,2006,16.:290-296.
23 Shi YY,He L.SHEsis,a powerful software platform for analyses of linkage disequilibrium,haplotype construction,and genetic association at polymorphism loci.Cell Res,2005,15:97-8.
24 Li J,Pan YC,Li YX,et al.Analysis and Application of SNP and Haplotype in the Human Genome.ActaGeneticsSinica,2005,32:879-889.
25 Dudbridge F.Pedigree disequilibrium tests for multilocus haplotypes.Genet Epidemiol,2003,52:115-121.
26 Bitstein D,Risch N.Discovering genotypes underlying human phenotypes:past successes for mendelian disease,future approaches for complexdisease.Nat Genet,2003,33:228-237.
27 金丽江.2005年卒中和脑血管疾病的遗传学研究进展.中国卒中杂志,2006,1:78-79.
28 曾昭书,丁梅,朱运良,等.PCR-RFLP 法分析北方汉族人群 HLA-B 基因多态生.法医学杂志,2006,22:193-195.
29 Topol EJ,Smith J,Plow EF,et al.Genetic susceptibility to myocardial infarction and coronary artery disease.Hum Mol Genet,2006,15:117-123.
30 Cheng J,Liu J,Li X,et al.Effect of polymorphisms of endothelial nitric oxide synthase on ischemic stroke:a case-control study in a Chinese population.Clin Chim Acta,2008,392:46-51.
31 Cheng J,Liu X,Li J,et al.Insulin-like growth factor-1 receptor polymorphism and ischemic stroke:a case-control study in Chinese population.ActaNeurol Scand,2008,118:333-338.
32 Shi C,Kang X,Wang Y,et al.The coagulation factor V Leiden,MTHFRC677T variant and Enos 4ab polymorphism in young Chinese population with ischemic stroke.Clin Chim Acta,2008,396:7-9.
33 Mallolas J,Hurtado O,Castellanos M,et al.A polymorphism in the EAAT2 promoter is associated with higher glutamate concentrations and higher frequency of progressing stroke.J ExpMed,2007,203:711-717.
34 顾丰.单核苷酸多态性及其数据库.中华医学遗传学杂志,2001,18:479-481.
35 Bensen JT,Langefeld CD,Hawkins GA,et al.Necleotide variation,haplotype structure,and association with end-stage renal disease of human interleukin-1 gene cluster,Genomics,2003,82:194-217.
36 汪维鹏,倪坤仪,周国华.单核苷酸多态性检测方法的研究进展.遗传,2006,28:117-126.
37 Stephens M,Smith N J,Donnelly P.A new statistical method for haplotype reconstruction from population data.Am J Hum Genet.2001,68:978-989.
38 顾明亮,褚嘉佑.基于标签单核苷酸多态性单倍型和单倍域的构建及其在关联研究中的应用.中华医学遗传学杂志,2007,24:660-665.
39 Yandava CN,Kennedy BP,Pillari A,et al.Cytogenetic and radiation hybrid mapping of human arachidonate 5-1ipoxygenase-activating protein(ALOX5AP)to chromosome 13q12.Genomics,1999,56:131-133.
40 梁庆成,高强.ALOX5AP与卒中.国际脑血管病杂志,2006,14:388-389.
41 Helgadottir A,Gretarsdottir S,St Clair D,et al.Association between the gene Encoding 5-Lipoxygenase-Activating protein and Stroke Replicated in a Scottish Population.AM J Hum Genet,2005,76:505-509.
42 L(?)hmussaar E,Gschwendtner A,Mueller JC,et al.ALOX5AP Gene and the PDE4D Gene in a Central European Population of Stroke Patients.Stroke,2005,36:731-736.
43 Kaushal R,Pal P,Alwell K,et al.Association of ALOX5AP with ischemic stroke:a population-based case-control study.Hum Genet,2007,121:601-608.
44 Shah SH,Hauser ER,Crosslin D,et al.ALOX5AP variants are associated with in-stent restenosis after percutaneous coronary intervention.Atherosclerosis,2008,doi:10.1016/j.
45 Kostulas K,Gretarsdottir S,Kostulas V,et al.PDE4D and ALOX5AP genetic variants and risk for Ischemic Cerebrovascular Disease in Sweden.J Neurol Sci,2007,263:113-117.
46 Zee RY,Cheng S,Hegener HH,et al.Genetic variants of arachidonate 5-1ipoxygenase-activating protein,and risk of incident myocardial infarction and ischemic stroke:anestedcase-control approach.Strole,2006,37:2007-2011.
47 Koch W,Hoppmann P,Mueller JC,et al.No association of polymorphisms in the gene encoding 5-lipoxygenase-activating protein and myocardial infarction in a large central European population.GenetMed,2007,9:123-129.
48 Rothwell NJ,Luheshi GN.Interleukin 1 in the brain:biology,pathology and therapeutic target.TrendsNeurosci,2000,13:618-625.
49 周刚,刘利民,等.白细胞介素-1 基因多态性与疾病.细胞与分子免疫学杂志,2007,23:190-192.
50 AlyH,KhashabaMT,E1-AyoutyM,etal.IL-lbeta,IL-6 and TNF-alpha and outcomes of neonatal hypoxic ischemic encephalopathy.Brain,2006,28:178-182.
51 Wei X,Chen X,Fontanilla C.C/T conversion alters interleukin-1A promoter function in a human astrocyte cell line.Life Sci,2007,80:1152-1156.
52 徐朴,李艳.白细胞介素-1 基因多态性的研究进展.国外医学临床生物化学与检验学分册,2003,24:347-348.
53 卞杰勇,张世明,周岱.白细胞介素-1 与缺血性脑损伤.国外医学脑血管疾病分册,2001,9:300-302.
54 Murphy GM Jr,Claassen JD,DeVoss J J,et al.Rate of cognitive decline in AD is accelerated by theinterleukin-1-alpha-889~*l allele.Neurology,2001,56:1595-1597.
55 Um JY,Moon KS,Lee KM,et al.Interleukin-1 gene cluster polymorphisms in cerebral infarction.Cytokine,2003,5,23:41-46.
56 Worrall BB,Brott TG,Brown RD Jr,et al.ILl RN VNTR Polymorphism in Ischemic Stroke Analysis in 3 Populations.Stroke,2006,38:1189-1196.
57 Pinteaux E,Rothwell NJ,Boutin H.Neuroprotective actions of endogenous interleukin-1receptor antagonist(IL-1ra)are mediated by glia.Glia,2006,53:551-556.
58 Li MG,Katsura K,Nomiyama H,et al.Regulation of the interleukin-1-induced signaling pathways by a novel member of the protein phosphatase 2C family(PP2Cepsilon).J Biol Chem,2003,278:12013-12021.
59 Furuichi K,Wada T,Iwata Y,et al.Interleukin-1-dependent sequential chemokine expression and inflammatory cell infiltration in ischemia-reperfusion injury.Crit Care Med,2006,34:2447-2455.
60 Zhang F,Hu EC,Gerzenshtein J.The Expression of Proinflammatory Cytokines in the Rat Muscle Flap With Ischemia-Reperfusion Injury.Ann Plast Surg,2005,54:313-317.
61 Iacoviello L,Di Castelnuovo A,Gattone M,et al.Polymorphisms of the interleukin-lbeta gene affect the risk of myocardial infarction and ischemic stroke at young age and the response of mononuclear cells to stimulation in vitro.Arterioscler Thromb Vasc Biol,2005,25:222-227.
62 D(?)niz-Naranjo MC,Mu(?)oz-Fernandez C,Alemany-Rodr(?)guez MJ,et al.Cytokin IL-1 beta but not IL-1 alpha promoter polymorphism is associated with Alzheimer disease in a population from the Cornary Islands,Spain.Eur J Neurol,2008,15:1080-1084.
63 Rogers J.An IL-1 alpha susceptibility polymorphism in Alzheimer's disease:New fuel for the inflammation hypothesis.Neurology,2000,55:464-465.
64 Zanardini R,Bocchio-Chiavetto L,Scassellati C,et al.Association between IL-1 beta-511 C/T and IL-1RA(86bp)n repeats polymorphisms and schizophrenia.J Psychiatr Res,2003,37:457-62.
65 Wanderer AA.Ischemic-reperfusion syndromes:biochemical and immunologic rationale for IL-1 targeted therapy.Clin Immunol,2008,128:127-132.
66 Gromadzka G,Sarzynska-Dlugosz I,Czlonkowska A.IL1RN intron 2 polymorphism caused by variable number tandem repeats is associated with 1-year outcome in patients with ischaemic stroke.J Neurol Neurosurg Psychiatry,2000,78:183-186.
67 Lai J,Zhou D,Xia S,et al.Association of interleukin-1 gene cluster polymorphisms with ischemic stroke in a Chinese population.Neurology India,2006,54:366-369.
68 Dominici R,Cattaneo M,Malferrari G,et al.Cloning and functional analysis of the allelic polymorphism in the transcription regulatory region of interleukin-1 alpha.Immunogenetics,2002,54:82-86.
69 Devaraj S,Jialal I.Alpha-tocopherol decreases tumor necrosis factor-alpha mRNA and protein from activated human monocytes by inhibition of 5-lipoxygenase.Free Radic Bio Med,2005,38:1212-1220.
1 Martin D.Genetics of ischaemic stroke.Lancet Neurol,2007,6:149-61.
2 Risch NJ.Searching for Genetic Determinants in the New Millennium.Nature,2000,405:847-856.
3 Rosand J,Altshuler D,et al.Human Genome Sequence Variation and the Search for Genes Influencing Stroke.Stroke,2003,34:2512-2517.
4 Martin D,Hugh S,et al.Genetic Association Studies in Stroke Methodological Issues and Proposed StandardCriteria.Stroke,2005,36:2027-2031.
5 金丽江.2005年卒中和脑血管疾病的遗传学研究进展.中国卒中杂志,2006,1:78-79.
6 顾丰.单核苷酸多态性及其数据库.中华医学遗传学杂志,2001,18:479-481.
7 L(?)hmussaar E,Gschwendtner A,Mueller JC,et al.ALOX5AP Gene and the PDE4D Gene in a Central European Population of Stroke Patients.Stroke,2005,36:731-736.
8 Helgadottir A,Manolescu A,Thorleifsson G,et al.The gene encoding 5-1ipoxygenase activating protein confers risk of myocardial infarction and stroke.Nat Genet,2004,36:233-238.
9 曹立梅,毕桂南.5-脂氧合酶与脑缺血再灌注.国外医学脑血管病疾病分册,2004,12:850-852.
10周斌,陈新生.5-脂氧合酶在中枢神经系统的作用.生理科学进展,2003,34(11):77-79.
11 Topol E J,Smith J,Plow EF,et al.Genetic susceptibility to myocardial infarction and coronary artery disease.Hum Mol Genet,2006,15:117-123.
12 Choi JH,Park HS,Oh HB,et al.Leukotriene-related gene polymorphisms in ASA-intolerant asthma:an association with a haplotype of 5-lipoxygenase.Hum Genet,2004,114:337-344.
13李杰萍,梁统.5-脂氧合酶及其基因表达调控的研究进展.国外医学临床生物化学与检验学分册,2003,24:225-232.
14 Ohtsuki T,Matsumoto M,Hayashi Y,et al.Reperfusion induces 5-1ipoxygenase translocation and leukotriene C4 Production in ischemic brain.Am J Physiol,1995,268:1249-1257.
15 Datta K,Biswal SS,Xu J,et al.A relationship between 5-lipoxygenase-activating protein and bcl-xL expression in murine pro-B lymphocytic FL5.12 cells.J Biol Chem,1998,273:28163-28169.
16 Falk E,Shah PK,Fuster V.Coronary plaque disruption.Circulation,1995,92:657-671.
17 Dwyer JH,Allayee H,Dwyer KM,et al.Arachidonate 5-lipoxygenase promoter genotype,dietary arachidonic acid,and atherosclerosis.N Engl J Med,2004,350:29-37.
18 Helgadottir A,Gretarsdottir S,St Clair D,et al.Association between the gene Encoding 5-Lipoxygenase-Activating protein and Stroke Replicated in a Scottish Population.Am J Hum Genet,2005,76:505-509.
19 Zhang WL,Yang XM,Shi J,et al.Polymmorphism of SG 13S 114T/A in the ALOX5AP Gene and the Risk for Stroke in a Large Chinese Cohort.Yi Chuan Xue Bao,2006,33:678-684.
20 张伟丽,石佳,杨晓敏,等.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.中国分子心脏病学杂志,2005,5:395-400.
21 Kaushal R,Pal P,Alwell K,et al.Association of ALOX5AP with ischemic stroke:a population-based case-control study.Hum Genet,2007,121:601-608.
1 Rothwell NJ,Luheshi GN.Interleukin 1 in the brain:biology,pathology and therapeutic target.TrendsNeurosci,2000,13:618-625.
2 Sonna LA,Fujiita J,et al.Molecular biology of thermoregulation:effects of heat and cold stress on mammalian gene expression.Physiol,2002,92:1725-1745.
3 周刚,刘利民,等.白细胞介素-1 基因多态性与疾病.细胞与分子免疫学杂志,2007,23:190-192.
4 卞杰勇,张世明,周岱.白细胞介素-1 与缺血性脑损伤.国外医学脑血管疾病分册,2001,9:300-302.
5 Pinteaux E,Rothwell NJ,Boutin H.Neuroprotective actions of endogenous interleukin-1receptor antagonist(IL-lra)are mediated by glia.Glia,2006,53:551-556.
6 Warren AY,Harvey L,Shaw RW,et al.Interleukin-1 beta secretion from cord blood mononuclear cells in vitro involves P2X 7 receptor activation.Reprod Sci,2008,15:189-194.
7 Aly H,KhashabaMT,El-AyoutyM,et al.IL-1beta,IL-6 and TNF-alpha and outcomes of neonatal hypoxic ischemic encephalopathy.Brain,2006,28:178-182.
8 Zhang F,Hu EC,Gerzenshtein J,et al.The expression of proinflammatory cytokines in the rat muscle flap with ischemia-reperfusion injury.Ann Plast Surg,2005,54.:313-317.
9 Li MG,Katsura K,Nomiyama H,et al.Regulation of the interleukin-1-induced signaling pathways by a novel member of the protein phosphatase 2C family(PP2Cepsilon).J Biol Chem,2003,278:12013-12021.
10 Rogers J.An IL-1 alpha susceptibility polymorphism in Alzheimer's disease:New fuel for the inflammation hypothesis.Neurology,2000,55:464-465.
11 Furuichi K,Wada T,Iwata Y,et al.Interleukin-1-dependent sequential chemokine expression and inflammatory cell infiltration in ischemia-reperfusion injury.Crit Care Med,2006,34:2447-2455.
12 Gromadzka G,Sarzynska-Dlugosz I,CzlonkowskaA.IL1RN intron 2 polymorphism caused by variable number tandem repeats is associated with 1-year outcome in patients with ischaemic stroke.J Neurol Neurosurg Psychiatry,2000,78:183-186.
13 Guijarro C,Egido J.Transcription factor-kappa B(NF-kappa B)and renal disease.Kindey Int,2001,59:415-424.
14 BensenJT,LangefeldCD,Hawkins GA,etal.Necleotidevariation,haplotypestructure, and association with end-stage renal disease of human interleukin-1 gene cluster,Genomics,2003,82:194-217.
15 Murphy GM Jr,Claassen JD,DeVoss JJ,et al.Rate of cognitive decline in AD is accelerated by the interleukin-1-alpha-889*1 allele.Neurology,2001,56:1595-1597.
16 Um JY,Moon KS,Lee KM,et al.Interleukin-1 gene cluster polymorphisms in cerebral infarction.Cytokine,2003,5,23:41-46.
17 D(?)niz-Naranjo MC,Mu(?)oz-Fernandez C,Alemany-Rodr(?)guez MJ,et al.Cytokin IL-1 beta but not IL-1 alpha promoter polymorphism is associated with Alzheimer disease in a population from the Cornary Islands,Spain.Eur J Neurol,2008,15:1080-1084.
18 Lai J,Zhou D,Xia S,et al.Association of interleukin-1 gene cluster polymorphisms with ischemic stroke in a Chinese population.Neurology India,2006,54:366-369.
19 Worrall BB,Brott TG,Brown RD Jr,et al.IL1RN VNTR Polymorphism in Ischemic Stroke Analysis in 3 Populations.Stroke,2006,38:1189-1196.
20 Francis SE,Camp NJ,Burton AJ,et al.Interleukin 1 receptor antagonist gene polymorphism and restenosis after coronary angioplasty.Heart,2001,86:336-340.
21 Zanardini R,Bocchio-Chiavetto L,Scassellati C,et al.Association between IL-1beta-511C/T and IL-IRA(86bp)n repeats polymorphisms and schizophrenia.J Psychiatr Res,2003,37:457-462.