摘要
研究背景
生长分化因子-15(Growth Differentiation Factor-15, GDF-15)是转化生长因子β(TGF-p)成员。它在炎症、氧化应激、缺血再灌注损伤等病理情况下短期内出现高表达,在不同时期分别起到抑制炎症、抗凋亡、抗增殖等不同作用。既往研究认为GDF-15在心血管疾病急性期的大量分泌起到修复抗凋亡的作用,且其水平高和病变严重程度及不良预后相关。最新研究认为GDF-15的单核苷酸多态性(Single Nucleotide Polymorphism, SNP)影响GDF-15的水平和生物活性,进而可能影响疾病的发病和进展。GDF-15的基因型和冠脉疾病之间的关系尚不明确,它与GDF-15循环水平、病变严重程度和预后之间的关系对阐明GDF-15的作用机制至关重要。本课题旨在探讨GDF-15基因型单独及联合GDF-15血浆水平后和冠状动脉疾病之间的关系。
研究方法
选取2007年4月至2009年12月北京协和医院心内科、CCU病房、急诊科因心绞痛、拟诊冠心病入院的患者作为研究对象。这部分患者中有264例之前进行过血浆GDF-15的测定,根据临床症状及冠脉造影检查结果,分为稳定病变组(包括冠状动脉狭窄<50%和稳定型心绞痛)、急性冠脉综合征组(包括不稳定心绞痛、非ST段抬高型心肌梗死、ST段抬高型心肌梗死)和冠脉扩张组(包括冠脉单纯扩张、冠脉扩张合并狭窄),同时排除重要脏器损伤、急慢性感染、结缔组织疾病和肿瘤患者。记录患者入院临床生化指标和造影结果及其GDF-15血浆水平,并采集血样用直接测序法测定GDF-15基因中三个SNP位点(rs1059519,rs1059369和rs1058587)的基因型。同时对所有患者进行电话随访,记录终点事件及其发生时间,进行统计分析。
研究结果
rs1059519:CC基因型较等位基因G携带者(CG+GG)患ACS和CAE的风险增高(P=0.045)。等位基因C频率在病变稳定组、ACS组、CAE组依次升高,达显著性差异,P=0.017。基因型CC、CG和GG组的GDF-15血浆水平逐渐升高,达显著性差异,P=0.040。在CC型分组下,GDF-15水平在病变稳定组、ACS组和CAE组逐渐升高,达显著性差异,P=0.035。在CC型分组下,GDF-15<400ng/L和不良预后显著相关,P=0.009。在CG型分组下,GDF-15>1000ng/L和不良预后相关,P=0.022。
rs1059369:AA基因型较等位基因T携带者(AT+TT)患ACS和CAE的风险增高(P=0.017)。等位基因A频率在病变稳定组、ACS组、CAE组依次显著升高(P=0.008)。
rs1059519、rs1059369和rs1058587三个位点的基因型与不良预后无显著相关性,与再通治疗获益也无显著相关性。
研究结论
GDF-15的基因型和冠脉疾病的严重程度相关。rs1059519的基因型显著影响GDF-15的分泌水平,分组除去基因型的干扰作用后,GDF-15水平表现出和疾病严重程度显著的正相关。在不同的基因型下,用GDF-15水平评估预后的分界值不同。
Background
GDF-15is a member of the TGF-β cytokine superfamily. It is induced by various forms of stress, such as inflammation, oxidative stress, ischemia-reperfusion injury and so on. Many studies suggest that a large amount of GDF-15is secreted to resist apoptosis during the acute phase of cardiovascular disease, and high level of GDF-15is associated with severity of the disease and poor prognosis. Single Nucleotide Polymorphisms (SNP) of GDF-15are found to be associated with the bioactivity of this protein, and that means genotypes may play an important role in GDF-15-related phenomenons. GDF-15plasma level and genotypes may provide diagnostic and prognostic information in patients with coronary artery disease.
Methods
Blood samples were obtained after CAG from264patients with chest uncomfortable. GDF-15genotypes were determined by direct sequencing method. Clinical and biochemical information was recorded and all patients were followed up.
Result
rs1059519:Genotype CC group have a higher risk of ACS and CAE, P=0.045. The three clinic groups have different frequencies of allele C, P=0.017. The genotypes are associated with GDF-15plasma level. In genotype CC group, GDF-15<400ng/L is associated with poor prognosis and in genotype CG group, GDF-15>1000ng/L is associated with bad prognosis, P=0.022.
rs1059369:Genotype AA group have a higher risk of ACS and CAE, P=0.017. The three clinic groups have different frequencies of allele A, P=0.008. No three SNPs are associated with the poor prognosis and PCI benefit.
Conclusions
GDF-15genotypes are associated with severity of coronary artery disease significantly and GDF-15plasma level is associated with severity of coronary artery disease and poor prognosis significantly only after remove the confounding effect of genotypes.
引文
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