中国北方汉族人群FGB基因与冠心病的关联研究
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摘要
背景:心肌梗死(Myocardial infarction,MI)是世界范围内最主要的死亡原因之一,约90%的心肌梗死是由动脉粥样斑块破裂并继发血栓形成导致冠状动脉急性阻塞所引起的。动脉血栓形成是MI病理过程中最主要的致病环节之一。纤维蛋白原是一种急性期蛋白,它山肝脏合成。当机体处于感染状态时,血浆中的纤维蛋白原水平会显著增高。纤维蛋白原作为血栓形成过程中凝血作用激活的最后一个靶点,通过聚集血小板和促进纤维斑块的形成,在血栓形成和延展过程中起到十分关键的作用,在欧美及日本等国家所进行的流行病学研究也已证实血浆纤维蛋白原水平与纤维蛋白原基因变异均和MI相关。由于纤维蛋白原β链(Fibrinogenβ-chain)的合成是纤维蛋白原合成的限速步骤,因此,纤维蛋白原β链(Fibrinogenβ-chain,FGB)基因变异被科学家们大量关注。既往的研究中已发现FGB基因-455G/A、-148C/T等多态与MI相关,但这种关联也可能是这些位点与功能性多态连锁不平衡所造成的。因此,我们考虑采用候选基因途径基因组扫描策略,系统筛查中国北方汉族人群FGB基因编码区和侧翼序列,识别所有多态位点,并进一步在病例-对照研究中探讨潜在的功能多态位点与MI的关系。
材料和方法:选取1997年10月至2000年9月期间阜外心血管病医院病房收治的北京地区汉族急性MI后存活的患者509例;选择年龄、性别与病例匹配的北京社区人群507例作为对照组。对每一个参加者均详细填写调查表,包括疾病个人史、家族史、吸烟与饮酒史和药物使用情况,并测量血压、身高、体重、腰围及臀围等,计算体重指数和腰臀比值,测定脂质等生化指标。为研究FGB基因序列中是否存在未知的功能性多态位点,我们先在病例人群中随机选取48例样本,利用基因组DNA直接测序筛查出基因编码区及部分调节区的全部序列变异:然后根据既往研究热点及测序所获得结果,分别在启动子区、编码区及3'侧翼序列各选择1个频率大于5%的多态位点,在全部个体中应用聚合酶链反应-限制性片断长度多态性分析(PCR-RFLP)方法进行基因型鉴定。方差分析及χ~2检验用于单变量分析,多元非条件Logistic回归分析用于检验多态位点与疾病的独立关联及与环境因素的交互作用。用2LD程序计算连锁不平衡系数,EH程序估计单体型频率,Haplo.score程序检验单体型与疾病的独立关联,Haplo.glm程序检验单体型和环境因素的交互作用。
结果:1.我们在FGB基因5.7 kb的测序范围内共发现18个多态位点,均为单核苷酸多态(SNP)。其中有6个SNP为首次报道,它们是位于内含子4中的5092G/A、内含子6中的6493T/C和6401G/A、编码区的3501G/A(CyslllTyr)、6264A/T(Asn309Tyr)和位于3'侧翼序列的8588G/A,但后三个多态在我们的研究人群中少见等位基因频率较低。2.研究最多的启动子区多态-455G/A和R448K等在国人中的频率和高加索人群相似(均≈20%)。3.基因内部常见的多态间存在紧密连锁不平衡。4.单变量分析提示在显性、隐性及加性三种模式下,-455G/A、R448K和8558C/G三个多态均与MI关联。但调整了其它传统的心血管病危险因素后,只有R448K在显性模型下(RK+KK∶RR,OR=0.71,P=0.026)及8558C/G在隐性模型下(GG∶GC+CC,OR=0.28,P=0.046)仍然与MI保持显著关联。5。连锁不平衡和单体型分析显示,-455G/A、R448K和8558C/G三个多态间存在几乎完全的连锁不平衡,并主要组成两种相对立的单体型-455G-448R-8558G和-455A-448K-8558C,前者与MI的危险性增加相关联,而后者与MI的危险性降低相关联。单体型和吸烟间似乎存在交互作用,而和年龄及性别间不存在交互作用。
结论:在中国北方汉族人群中,在调整了传统危险因素后,FGB基因R448K多态与MI独立关联,提示该基因可能与国人MI的发生相关。
Background:Myocardial infarction(MI),one of the leading causes of death worldwide,is a complex disorder influenced by multiple genetic and environmental factors.Approximately 90%of MI results from an acute thrombus that obstructs an atherosclerotic coronary artery.As the last target of coagulation,fibrinogen plays a pivotal role in the hemostatic balance by representing the substrate for fibrin clot formation,and the support for platelet aggregation.Fibrinogen is an acute phase protein,synthesized in the liver,the plasma levels of which acutely rise during inflammatory conditions.In some large prospective studies in Europe and the United States,elevated plasma fibrinogen levels has been shown to be strongly associated with the genetic variants in fibrinogen genes and an independent predictor of MI.In recent years,several polymorphisms in the genes for fibrinogen have been associated with increased plasma fibrinogen.The FGB gene(fibrinogenβ-chain gene) has been more extensively studied because theβ-chain synthesis is the limiting step in the production of mature fibrinogen.The association between MI and some polymorphisms in FGB gene,such as-455G/A and-148C/T,had been found in some studies,but others had not.The inconsistent results might be due to linkage relationships with other unidentified functional genetic variants in the FGB gene.The aim of the present study was to scan the whole FGB gene,and to identify all putative functional polymorphisms and further investigate whether these polymorphisms are associated with MI in Nothem Chinese Hart population.
Methods:A case-control design was applied in this study.In brief,509 unrelated CHD patients who surrived an acute MI were enrolled from hospitalized patients of Fu Wai Hospital between October 1997 and September 2000.507 age-and sex-matched subjects were randomly recruited from individuals participating in a community-based survey of cardiovascular risk factors in Beijing.A detail of questionnaires about the risk factors of cardiovascular disease was available and physical examination was carried out in all subjects.We randomly selected 48 patients to detect all polymorphisms of the FGB gene by directly sequencing.We selected three polymorphisms in the FGB gene for genotyping by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) in all subjects. Univariate analysis was applied to measure the association of each polymorphism with MI.Multivariate analysis was performed to investigate the independent or interactive effect of polymorphisms/haplotypes on MI.Statistical analysis was conducted using the SPSS 13.0 version for Windows,2LD program and EH program, in conjunction with the haplo.score and haplo.glm programs.
Results:(1) In a total length of 5.7 kb explored,we identified 18 SNPs,of which 6 were first reported,they were 5092G/A(intron 4),6401G/A and 6493T/C(intron 6), CyslllTyr(exon 3),Asn309Tyr(exon 6) and 8588G/A(3' flanking region) respectively.However,the latter three polymorphisms appeared only once in the 48 samples,their frequencies were less than 5%.(2) Allele frequencies of the most studied polymorphisms such as-455G/A and R448K are similar between our population and Caucasian populations.(3) Complete or nearly complete LD between polymorphisms was frequently observed.(4) Univariate analyses indicated that the 3 FGB polymorphisms were associated with MI in all of three genetic models(i.e. dominant,recessive and additive models).After adjusting other risk factors,however, only individuals carrying the 448K allele had an approx.30%reduction in risk of developing MI(OR 0.71,95%CI 0.52-0.96),and homozyosity for 8558G was associated with a 70%decreased risk of MI(GG:GC+CC,OR=0.28,P=0.046). Haplotype analyses showed that the A-K-G haplotype(-455A,448K,8558G) was associated with a protective effect against MI,whereas the most common haplotype (G-R-C) was related to an increased risk of MI,even after adjusting for environmental risk factors.
Conclusions:Our study demonstrated the first evidence of a significant association between the FGB R448K polymorphism and MI in a Chinese Han population,which possession of the 448K allele may be protective against developing MI.However,the results should be interpreted with caution,given the small sample size.A larger cohort will ultimately be required to confirm whether or not this association is real.
材料和方法:选取1997年10月至2000年9月期间阜外心血管病医院病房收治的北京地区汉族急性MI后存活的患者509例;选择年龄、性别与病例匹配的北京社区人群507例作为对照组。对每一个参加者均详细填写调查表,包括疾病个人史、家族史、吸烟与饮酒史和药物使用情况,并测量血压、身高、体重、腰围及臀围等,计算体重指数和腰臀比值,测定脂质等生化指标。为研究FGB基因序列中是否存在未知的功能性多态位点,我们先在病例人群中随机选取48例样本,利用基因组DNA直接测序筛查出基因编码区及部分调节区的全部序列变异:然后根据既往研究热点及测序所获得结果,分别在启动子区、编码区及3'侧翼序列各选择1个频率大于5%的多态位点,在全部个体中应用聚合酶链反应-限制性片断长度多态性分析(PCR-RFLP)方法进行基因型鉴定。方差分析及χ~2检验用于单变量分析,多元非条件Logistic回归分析用于检验多态位点与疾病的独立关联及与环境因素的交互作用。用2LD程序计算连锁不平衡系数,EH程序估计单体型频率,Haplo.score程序检验单体型与疾病的独立关联,Haplo.glm程序检验单体型和环境因素的交互作用。
结果:1.我们在FGB基因5.7 kb的测序范围内共发现18个多态位点,均为单核苷酸多态(SNP)。其中有6个SNP为首次报道,它们是位于内含子4中的5092G/A、内含子6中的6493T/C和6401G/A、编码区的3501G/A(CyslllTyr)、6264A/T(Asn309Tyr)和位于3'侧翼序列的8588G/A,但后三个多态在我们的研究人群中少见等位基因频率较低。2.研究最多的启动子区多态-455G/A和R448K等在国人中的频率和高加索人群相似(均≈20%)。3.基因内部常见的多态间存在紧密连锁不平衡。4.单变量分析提示在显性、隐性及加性三种模式下,-455G/A、R448K和8558C/G三个多态均与MI关联。但调整了其它传统的心血管病危险因素后,只有R448K在显性模型下(RK+KK∶RR,OR=0.71,P=0.026)及8558C/G在隐性模型下(GG∶GC+CC,OR=0.28,P=0.046)仍然与MI保持显著关联。5。连锁不平衡和单体型分析显示,-455G/A、R448K和8558C/G三个多态间存在几乎完全的连锁不平衡,并主要组成两种相对立的单体型-455G-448R-8558G和-455A-448K-8558C,前者与MI的危险性增加相关联,而后者与MI的危险性降低相关联。单体型和吸烟间似乎存在交互作用,而和年龄及性别间不存在交互作用。
结论:在中国北方汉族人群中,在调整了传统危险因素后,FGB基因R448K多态与MI独立关联,提示该基因可能与国人MI的发生相关。
Background:Myocardial infarction(MI),one of the leading causes of death worldwide,is a complex disorder influenced by multiple genetic and environmental factors.Approximately 90%of MI results from an acute thrombus that obstructs an atherosclerotic coronary artery.As the last target of coagulation,fibrinogen plays a pivotal role in the hemostatic balance by representing the substrate for fibrin clot formation,and the support for platelet aggregation.Fibrinogen is an acute phase protein,synthesized in the liver,the plasma levels of which acutely rise during inflammatory conditions.In some large prospective studies in Europe and the United States,elevated plasma fibrinogen levels has been shown to be strongly associated with the genetic variants in fibrinogen genes and an independent predictor of MI.In recent years,several polymorphisms in the genes for fibrinogen have been associated with increased plasma fibrinogen.The FGB gene(fibrinogenβ-chain gene) has been more extensively studied because theβ-chain synthesis is the limiting step in the production of mature fibrinogen.The association between MI and some polymorphisms in FGB gene,such as-455G/A and-148C/T,had been found in some studies,but others had not.The inconsistent results might be due to linkage relationships with other unidentified functional genetic variants in the FGB gene.The aim of the present study was to scan the whole FGB gene,and to identify all putative functional polymorphisms and further investigate whether these polymorphisms are associated with MI in Nothem Chinese Hart population.
Methods:A case-control design was applied in this study.In brief,509 unrelated CHD patients who surrived an acute MI were enrolled from hospitalized patients of Fu Wai Hospital between October 1997 and September 2000.507 age-and sex-matched subjects were randomly recruited from individuals participating in a community-based survey of cardiovascular risk factors in Beijing.A detail of questionnaires about the risk factors of cardiovascular disease was available and physical examination was carried out in all subjects.We randomly selected 48 patients to detect all polymorphisms of the FGB gene by directly sequencing.We selected three polymorphisms in the FGB gene for genotyping by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) in all subjects. Univariate analysis was applied to measure the association of each polymorphism with MI.Multivariate analysis was performed to investigate the independent or interactive effect of polymorphisms/haplotypes on MI.Statistical analysis was conducted using the SPSS 13.0 version for Windows,2LD program and EH program, in conjunction with the haplo.score and haplo.glm programs.
Results:(1) In a total length of 5.7 kb explored,we identified 18 SNPs,of which 6 were first reported,they were 5092G/A(intron 4),6401G/A and 6493T/C(intron 6), CyslllTyr(exon 3),Asn309Tyr(exon 6) and 8588G/A(3' flanking region) respectively.However,the latter three polymorphisms appeared only once in the 48 samples,their frequencies were less than 5%.(2) Allele frequencies of the most studied polymorphisms such as-455G/A and R448K are similar between our population and Caucasian populations.(3) Complete or nearly complete LD between polymorphisms was frequently observed.(4) Univariate analyses indicated that the 3 FGB polymorphisms were associated with MI in all of three genetic models(i.e. dominant,recessive and additive models).After adjusting other risk factors,however, only individuals carrying the 448K allele had an approx.30%reduction in risk of developing MI(OR 0.71,95%CI 0.52-0.96),and homozyosity for 8558G was associated with a 70%decreased risk of MI(GG:GC+CC,OR=0.28,P=0.046). Haplotype analyses showed that the A-K-G haplotype(-455A,448K,8558G) was associated with a protective effect against MI,whereas the most common haplotype (G-R-C) was related to an increased risk of MI,even after adjusting for environmental risk factors.
Conclusions:Our study demonstrated the first evidence of a significant association between the FGB R448K polymorphism and MI in a Chinese Han population,which possession of the 448K allele may be protective against developing MI.However,the results should be interpreted with caution,given the small sample size.A larger cohort will ultimately be required to confirm whether or not this association is real.
引文
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