MMP3基因启动子区多态性与动脉粥样硬化斑块细胞外基质稳定性的相关性

摘要

目的 探讨MMP3基因启动子区5A/6A多态性与动脉粥样硬化斑块细胞外基质稳定性之间的相关性.方法 连续入选成功行经皮冠状动脉介入治疗后住院复查造影的患者776例,收集其临床资料、MMP3基因型以及第二次入院时的MMP3血清含量.用包含MMP3基因启动子区目的片段的重组质粒转染HepG2载体细胞,观察基因多态性对于MMP3基因表达活性的影响.结果 对比第一次入院资料,急性心肌梗死(acute myocardial infarction,AMI)患者携带MMP3突变型基因型(5A/5A+5A/6A)的比例明显高于对照组(37.6％ vs.24.9％,P＜0.01).携带5A等位基因者有64.1％发生AMI,而携带6A等位基因者仅有50.1％发生AMI,差异有统计学意义(P ＜0.01).再狭窄组MMP3野生型基因型(6A/6A)的比例明显高于非再狭窄组(79.5％ vs.66.5％,P＜0.01).携带5A等位基因者9.5％发生再狭窄,而携带6A等位基因者16.2％发生再狭窄,差异有统计学意义(P＜0.01).再狭窄组的MMP3血清含量低于非再狭窄组,携带突变型基因型者高于携带野生型基因者,差异有统计学意义(P＜0.01).pGL2-Basic/6A在体外的表达活性明显低于pGL2-Basic/5A.结论 MMP3启动子区域5A/6A多态性差异将导致基因转录活性不同,从而影响细胞外基质的降解或推积,造成动脉粥样硬化斑块稳定性的差异,进而在同一组人群中引起急性心肌梗死或支架术后再狭窄两种不同的病理过程.%Objective To assess the association of 5A/6A polymorphism in the promoter region of MMP3 gene with the stability of extracellular matrix of atherosclerotic plaque.Methods Clinical data of 776 consecutive patients undergoing percutaneous coronary intervention (PCI) was reviewed.MMP3 gene polymorphisms and serum level of MMP3 for the second admission were collected.The target gene fragment containing MMP3 promoter region was transfected into HepG2 vector cells.The influence of the polymorphism on the expression of the MMP3 gene was determined in vitro.Results Compared with the first admission data,the proportion of mutant MMP3 genotypes (5A/5A+5A/6A) was significantly higher in patients with acute myocardial infarction (AMI) compared with the control group (37.6％ vs.24.9％,P ＜0.01).64.1％ of the patients carrying the 5A allele had AMI,whereas only 50.11％ of those carrying the 6A allele had AMI (P＜0.01).The proportion of wild-type MMP3 genotype (6A/6A) was significantly higher in the stenotic group compared with the non-restenosis group (79.5％ vs.66.5％,P＜0.01).Restenosis has occurred in 9.5 ％ of patients harboring the 5A allele compared with 16.2 ％ in those carrying the 6A allele (P＜0.01).In addition,serum level of MMP3 in the restenosis group was significantly lower than that of the non-restenosis group (P＜0.01).In vitro studies confirmed that the expression of pGL2-Basic/6A was significantly lower than that of pGL2-Basic/5A.Conclusion The 5A/6A polymorphism in the promoter region of the MMP3 gene may influence its transcriptional activity and impact on the degradation or push-up of extracellular matrix,resulting in a difference in the stability of atherosclerosis plaques,which in turn may induce different pathological processes in AMI or restenosis after stenting.