P-选择素基因多态性与脓毒症遗传易感性及严重程度关联性研究

Associated Research about P-selectin Gene Polymorphism and Pyemic Gentic Susceptibility and Secerity

作者: 专业:急诊医学 导师:刘保池 年度:2010 学位:硕士  院校: 郑州大学

Keywords

P-Selectin, sepsis, mononucleotide polymorphism, dominant heredity

        背景和目的:脓毒症是感染和/或创伤引起的全身炎症反应综合征(systemic inflammatory reaction syndrome, SIRS),是诱发脓毒症休克和多器官功能障碍综合征(MODS)的重要原因。临床流行病学资料统计显示,严重创伤、休克、外科大手术后等患者并发脓毒症是临床危重患者的重要死亡原因。虽然感染菌株毒力、数量等外部因素是引起脓毒症的根源,而机体的性别、年龄和遗传易感基因等内部因素对脓毒症的发生、发展和转归也起到了极为重要的作用。探讨基因背景与脓毒症的关系可以更加科学地认识脓毒症的发病机制,且为脓毒症的早期诊断、预后判定及治疗带来新的机遇。鉴于P-选择素在介导炎症过程中白细胞的起始黏附和血栓的形成中起重要作用,故将P-选择素基因定为本实验的候选基因。方法:对P-选择素基因多态性位点的位置、重要性、连锁不平衡状态和次要等位频率等进行综合分析后,确定P-选择素基因上的候选多态性位点。在河南人群中选取无亲缘关系的255例脓毒症患者和260例对照个体,利用GenomeLab SNPstream分型平台对候选多态性位点进行分型,应用非条件logistic回归模型进行关联性分析,在两种遗传模式中对脓毒症遗传易感性和严重程度进行统计分析,计算比值比和95%可信区间,同时在遗传易感性分析中校正性别、年龄、烟酒史和慢性病史对统计结果的影响,在严重程度分析中还校正了APACHEⅡ的影响。结果:在多态性位点与脓毒症遗传易感性的分析中,rs3917647_C/T位点的两个等位在病例和对照组中的频率分布有显著性差异(P=0.013),T等位频率在对照组中明显增高,是脓毒症保护性因素,显性遗传模式中,C/T-T/T联合基因型相对于参考基因型C/C可降低导致脓毒症的发生率,发病风险是C/C基因型的0.62倍,[P=0.016,OR(95%CI):0.62(0.42-0.92)]。rs3753306_A/G位点的两个等位在病例和对照组中的频率分布有显著性差异(P=0.003),G等位频率在对照组中明显增高,是脓毒症保护性因素,显性遗传模式中,A/G-G/G联合基因型相对于参考基因型A/A可降低导致脓毒症的发生率,发病风险是A/A基因型的0.53倍,[P=0.0086,OR(95%CI):0.53(0.33-0.86)]。rs2244529_C/T位点的两个等位在病例和对照组中的频率分布有显著性差异(P=0.007),C等位频率在对照组中明显增高,是脓毒症保护性因素,显性遗传模式中,T/C-C/C联合基因型相对于参考基因型T/T可降低导致脓毒症的发生率,发病风险是T/T基因型的0.61倍,[P=0.01,OR(95%CI):0.61 (0.42-0.89)]。在单体型分析中发现单体型T-A-C-A-T-C具有保护作用可防止脓毒症的发生,其P值=0.027和OR (95% CI)值为0.22(0.06-0.84)。在多态性位点和脓毒症严重程度的分析中6个SNP均与严重程度无明显关联。结论:P-选择素中rs3917647、rs2244529、rs3753306等3个多态性位点与脓毒症遗传易感性关联,rs3917647位点的T等位可降低脓毒症的发病风险,C/T和T/T基因型可减少导致脓毒症的发生,rs2244529位点的G等位可降低脓毒症的发病风险,A/G和G/G基因型可减少导致脓毒症的发生,rs3753306位点的C等位可降低脓毒症的发病风险,T/C和C/C基因型可减少导致脓毒症的发生。在单体型分析中P-选择素单体型T-A-C-A-T-C为脓毒症的保护性因素,可降低脓毒症的发病风险。
    Background and Objective:Sepsis is SIRS that is caused by infection and/or trauma, is an important reason that induce sepsis shock and MODS. Evid by clinical epidemiological data statistics, the important reason that induce patient who suffers from severe trauma, shock or surgery to death is complicating sepsis. Although bacteria strain virulence and amount is the key to induce sepsis, intrinsic factor include sex, age, heredity predisposing genes and so on is very important to pyemic development and consequence. It could be to comprehend pathogenesis about sepsis more scientifically, to bring new chance element for early diagnosis, judgment prognosis and cure to sepsis by investigation the relationship between gene and sepsis. SELP was selected as my experiment object, because it’s a important role about WBC initiation adhesion in inflammation and thrombus formation.Methods:Candidate SNP in SELP were confirmed in considering all four factors, including location in gene, association with other diseases, linkage disequilibrium status and minor allele frequency. The experiment object consisted of 255 patients with sepsis and 260 volunteers as control who all from Henan community. GenomeLab SNPstream genotyping platform were employed to genotype. Unconditional logistic regression analysis was performed to analyze the association of polymorphisms with risk and severity of sepsis in five genetic models. P values, odds ratios (ORs), and 95% confidence intervals (CIs) were calculated. We adjusted four confounding factors, including age, sex, smoking-drinking history and chronic diseases history status for analysis of susceptibility to sepsis. In analyzing the severity of sepsis, another confounding factor-APACHEⅡscoring was also considered.Results:In the tests of association between SNPs and risk of sepsis, there is significant difference between frequencies of allele C and T of rs3917647 (P=0.013). Frequencies of allele T is higher in control group than case. T allele can diminish the probability of risk of sepsis. In the dominant model, C/T-T/T combination genotype is associated with diminished susceptibility to sepsis (P=0.016) with OR (95%CI) being 0.62(0.42-0.92). Frequencies of allele G of rs3753306 is higher in control group than case (P=0.003). In the dominant model, A/G-G/G combination genotype is associated with diminished susceptibility to sepsis (P=0.0086) with OR (95%CI) being 0.53 (0.33-0.86). Frequencies of allele C of rs2244529 is higher in control group than case (P=0.007). In the dominant model, T/C-C/C combination genotype is associated with diminished susceptibility to sepsis (P=0.01) with OR (95%CI) being 0.61 (0.42-0.89). T-A-C-A-T-C haplotype of SELP is associated with diminished susceptibility to sepsis (P=0.027) with OR (95%CI) being 0.22(0.06-0.84). Single SNP analyzing show all 6 SNPs of SELP isn’t associated with severity of sepsis in two genetic models.Conclusion:3 SNPs of SELP are associated with susceptibility to sepsis in dominant model, including rs3917647、rs2244529、rs3753306. T allele of rs3917647 can diminish the probability of risk of sepsis. In the dominant model, C/T-T/T combination genotype is associated with diminished susceptibility to sepsis. G allele of rs2244529 can diminish the probability of risk of sepsis. In the dominant model, A/G-G/G combination genotype is associated with diminished susceptibility to sepsis. C allele of rs3753306 can diminish the probability of risk of sepsis. In the dominant model, T/C-C/C combination genotype is associated with diminished susceptibility to sepsis.T-A-C-A-T-C haplotype of SELP is associated with diminished susceptibility to sepsis.
        

P-选择素基因多态性与脓毒症遗传易感性及严重程度关联性研究

摘要4-6
Abstract6-7
英文缩略词注释9-10
论文正文10-48
    前言10-14
    1 材料与方法14-24
        1.1 确定入选人群14-16
        1.2 主要试剂、耗材和仪器16-19
        1.3 实验方法19-24
    2.结果24-38
        2.1 哈温平衡检验27-28
        2.2 遗传易感性分析28-32
        2.3 脓毒症严重程度关联性分析32-38
    3.讨论38-42
    4.结论42-44
    参考文献44-48
综述48-60
    参考文献56-60
致谢60-62
个人简历62
在学期间发表的学术论文62
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