基质金属蛋白酶-3基因多态性与脑卒中亚型的相关性

Association of matrix metalloproteinase-3 gene polymorphisms with subtypes of ischemic stroke

目的探讨中国北方汉族人群基质金属蛋白酶-3 （matrix metalloproteinase-3, MMP-3 ）基因多态性与缺血性脑卒中（ischemic stroke，IS）亚型的相关性。方法应用病例对照研究，选取289例急性缺血性脑卒中患者（发病≤3d）和175名同期健康体检者。卒中组按急性卒中治疗低分子肝素试验病因分型法分为大动脉粥样硬化性 （large artery atherosclerotic, LAA）脑卒中185例，小动脉闭塞性（ small artery occlusion, SAO）脑卒中104例。选取MMP-3基因rs3025058（-11715A／6A），rs522616（-709A／G）及rs679620（133A／G）3个常见单核苷酸多态性（single nucleotide polymorphisms, SNPs）位点，应用聚合酶链反应限制性片段长度多态性或直接测序法对MMP-3基因3个SNP位点进行基因分型。结果3个位点存在不完全连锁不平衡，且基因多态性均与LAA型脑卒中相关（P％0．05）。在显性模型中，rs3025058位点5A5A＋5A6A基因型携带者患LAA型脑卒中的风险是6A6A基因型携带者的1．72倍（P=0．017，OR=1．72，95％CI：1．10-2．69）；rs522616位点GG＋AG基因型携带者患LAA型脑卒中的风险是AA基因型携带者的0．52倍（P=0．005，OR：0．52，95％CI：0．33-0．82）；rs679620位点AA＋GA基因型携带者患LAA型脑卒中的风险是AA基因型携带者的1．55倍（P=0．042，OR-1．55，95％CI：1．01-2．37）。但是，3个SNPs基因型和等位基因频率在对照组与SAO型脑卒中之间差异无统计学意义（P〉0．05）。另外，LAA组5A-A-A及6A-A-A单倍型高于对照组，差异有统计学意义（P〈0．05），而6A_pG单倍型显著低于对照组（P〈0．01）。结论MMP-3血清水平在LAA型脑卒中急性期增高明显，SAO型脑卒中次之；中国北方汉族人群MMP-3基因rs3025058，rs522616及rs679620多态性可能与LAA型脑卒中易感性相关。

Objective To assess the association between matrix metalloproteinase-3 （MMP-3） gene polymorphisms and subtypes of ischemic stroke （IS） in northern Han Chinese population. Method A total of 289 patients with acute IS （within 3 days after the onset, including 185 with large artery atherosclerosis （LAA） and 104 for small artery occlusion （SAO）） and 175 matched healthy controls were recruited for this case-control study. Polymerase chain reaction-restriction fragment length polymorphism （PCR-RFLP） or sequence-based typing （SBT） was carried out to analyze 3 SNPs of the MMP-3 gene. Results An incomplete linkage disequilibrium （LD） block was constructed with the 3 SNPs, and the distribution of genotypes of the 3 SNPs differed between the LAA group and controls in a dominant model： Carriers of 5A allele （SA5A＋SA6A） of the rs3025058 locus were 1.72 times more susceptible to LAA stroke comparedwith carriers of 6A6A alleles （P=0. 017, OR= 1.72, 95%CI= 1. 10-2.69）, carriers of G alleles （GG＋ AG） of the rs522616 locus were 0.52 times more susceptible to LAA stroke compared with carriers of AA alleles （P=0. 005, OR=0. 52, 95%CI=0.33-0.82）, whilst carriers of A allele of the rs679620 locus were 1.55 times more susceptible to LAA stroke compared with carriers of GG alleles （P=0. 042, OR= 1.55, 95%CI=1.01-2.37）. However, no significant difference has been found between particular genotypes of such SNPs between SAO patients and controls （P〉0.05）. Furthermore, 5A-A-A and 6A-A-A haplotypes were significantly more common in LAA group than the controls （P〈0.05）, whilst 6A-G-G haplotype has been the opposite （P 〈 0. 01）. Conclusion Our study has demonstrated that serum MMP-3 level is significantly increased at acute stage of LAA as well as SAO type strokes. There may be an association of rs3025058, rs522616 and rs679620 of MMP-3 gene with susceptibility to LAA stoke in northern Han Chinese population.