β-纤维蛋白原基因启动子区单体型与缺血性脑卒中的关联分析  

Haplotypes in the Promoter Region of β-fibrinogen Gene and Their Relationship with Ischemic Stroke in Han Population in Hainan

作　　者：邢宏运[1] 廖小平[2] 肖锋[1] 梁亮[1] 孙川[1] 黄仕雄[2] 陈晓丹[3] 文国强[2] 汤小兰[4] 刘国勋[5] 程爽[5] 蔡望伟[6] 

机构地区：[1]海南医学院生物化学教研室 [2]海南省人民医院神经内科,海口570311 [3]海南医学院附属医院检验科,海口570102 [4]海南医学院流行病学教研室,海口571102 [5]广东医学院附属医院血液研究室,湛江524001 [6]海口海南医学院生物化学教研室

出　　处：《国际遗传学杂志》2006年第5期328-335,共8页International Journal of Genetics

基　　金：国家自然科学基金(No.30060037);教育部科学技术研究重点项目(No.03147);海南医学院重点学科项目(海医科研部[2005-46])

摘　　要：目的研究β-纤维蛋白原(β-Fg)基因启动子区单体型与缺血性脑卒中的关系。方法用比浊法测定160例缺血性脑卒中患者和130例健康对照个体的血浆纤维蛋白原浓度,采用聚合酶链反应-限制性片段长度多态性法(PCR-RFLP)、等位基因特异聚合酶链反应及核苷酸序列测定法分析β- Fg基因启动子区的-1420G/A、-993C/T、-854G/A、-455G/A、-249C/T、-148C/T单核苷酸多态性(SNPs)和基因型,用EH+程序分析核苷酸多态性的连锁不平衡关系及单体型,用x2检验分析病例组和对照组之间的基因型频率、等位基因频率及单体型频率的差异,用MatInspeetor程序预测序列中的顺式作用元件。结果缺血性脑卒中组-455(GA+AA)、-148(CT+TT)基因型携带者急性期的血浆Fg水平比-455(GG)、-148(CC)基因型携带者高(P<0．05);脑卒中组与对照组之间的-993C/T、-455G/ A、-148C/T 3个位点的基因型频率和等位基因频率存在显著性差异(p<0．01),由-1420G、-993C、-854G、-455G、-249C、-148C构成的单体型H1在对照组中的频率高于病例组(P<0．05),由-1420A、-993T、-854G、-455A、-249T、-148T构成的单体型H14在病例组中的频率高于对照组(P <0．01);野生型序列存在6个不同于突变型的顺式作用元件,突变型序列出现9个不同于野生型的顺式作用元件。结论海南汉族人群中β-Fg-455G/A、-148C/T多态性与缺血性脑卒中急性期血浆Fg升高相关,单体型H14可能是与缺血性脑卒中相关的危险因素,单体型H1可能是降低缺血性脑卒中发生风险的保护性因素,单体型与缺血性脑卒中的相关性可能是由于顺式作用元件改变所致。Objective To analyze the haplotypes in promoter region of beta-fibrinogen gene and their relationship with ischemic stroke （IS）. Me.otis Plasma fibrinogen level of the IS patients and control individuals was measured by turbidimetric assay in 160 cases with ischemic stroke and 130 healthy individuals from Han population in Hainan. Genotypes were determined by PCR-RFLP, allelic specific-PCR and sequencing at polymorphisms -1420G/A,-993C/T,-854G/A,-455G/A,-249C/T,-148C/T in the promoter region of beta-fibrinogen gene. Pairwise linkage disequilibrium was calculated and haplotypes were estimated by the EH^＋ program. Statistical differences of allele, genotype and haplotype frequencies were obtained by Chi square test. Cis-elements were predicted by Matlnspector program. Results In the IS group, the Fg level of plasma is higher in the patients with -455 （ GA ＋ AA ） ,-148 （ CT ＋ TT） genotype than in the patients with- 455GG, -148CC genotype（P 〈 0.05）. There were highly significant differences in genotype frequencies and allelic frequencies at polymorphisms -993C/T,-455G/A,-148C/T between the IS group and the control （P〈0.01）. The frequencies of haplotype H1 with -1420G,-993C,-854G,-455G,-249C and -148C were higher in the control than in the IS group （ P 〈 0.05 ）, whereas haplotype H14 with -1420A ,-993T,-854G -455A,-249T and -148T are higher in the IS group than in the control（P 〈0.01 ）. Six cis-elements absent in the mutant sequences were found in the wild type sequence and nine cis-elements absent in the wild type sequences were found in the mutant sequence. Conclusion The elevation of Fg level is associated with -455 （ GA ＋ AA） ,-148 （ CT ＋ TT） genotype in the acute phase of IS. Haplotype H14 may be a risk factor associated with IS and haplotype H1 may be a protective factor in reducing the risk of isehemic stroke in Han population in Hainan. The association of haplotype with IS may be due to the change of cis-elements in the promoter region.

关 键 词：纤维蛋白原 单核苷酸多态性 缺血性脑卒中 连锁不平衡分析 单体型 

分 类 号：R743[医药卫生—神经病学与精神病学]