MMP-2、TIMP-2基因启动子区多态性与NHL临床特点及预后的关系

摘要

目的 研究基质金属蛋白酶-2(MMP-2)和金属蛋白酶组织抑制剂-2(TIMP-2)基因启动子区单核苷酸多态性(SNPs)与非霍奇金淋巴瘤(NHL)临床特点和预后的关系.方法 NHL患者575例采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法检测MMP4-1306C/T、-735C/T和TIMP-2-418G/C 3个SNPs的基因型分布,分析其与NHL发病风险及临床病理参数的关系.结果 MMp-2-1306C/T和-735C/T的C/C基因型及TIMP-2-418G/C的G/G基因型分布频率较高,分别为69.74％、63.66％和65.22％,符合Hardy-Weinberg平衡(P分别为0.110、0.385、0.677).Ann Arbor分期Ⅲ、Ⅳ期者-735C/T的C/T、TT+CT基因型和T等位基因分布频率较Ⅰ、Ⅱ期显著增高(P均＜0.05).骨髓浸润NHL患者-1306C/T的T/T基因型分布频率低于C/C基因型(P＜0.05).肿瘤最大直径＞5 cm者较≤5 cm者-1306C/T的C/T、T/T、CT+TT基因型、T等位基因及-1306C/-735T单体型分布频率显著降低(P均＜0.05);-735 C/T的T/T基因型在肿瘤最大直径＞5 cm者中的分布频率较≤5 cm者显著升高(P＜0.05).有B症状者-1306T/-735C和-1306C/-735C单体型分布频率显著低于无B症状者(P均＜0.05).MMP-2-735C/T的T/T基因型者较C/C和C/T基因型者3年总生存率显著下降(P均＜0.05).结论 MMP-2和TIMP-2基因启动子区多态性可能与NHL的易感性有关.%Objective To investigate the clinical features and prognostic relationship between the single nucleotide polymorphisms (SNPs) in matrix metalloproteinases-2 (MMP-2) and tissue inhibitors of metalloproteinase-2 (TIMP-2) promoter region and non-Hodgkin's lymphoma (NHL).Methods A retrospective study of non-Hodgkin's lymphoma (NHL) in 575 patients was conducted.Three polymorphisms [MMP-2 (-1306C/T and-735C/T) and TIMP-2 gene (-418G/C)] were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.The possible correlations between the three polymorphisms and clinical pathological parameters in patients with NHL were examined.Results The distribution frequencies of the CC genotypes in MMP-2-1306 C/T and-735C/T and GG genotype in TIMP-2-418 G/C were higher (69.74％,63.66％ and 65.22％,respectively),and within the range of Hardy-Weinberg equilibrium (P =0.110,0.385 and 0.677,respectively).The incidence of the CT,TT + CT genotypes and T allele of-735C/T was significantly higher in stage Ⅲ and Ⅳ patients compared to stage Ⅰ and Ⅱ patients (all P ＜ 0.05).The TT genotype of the-1306C/T gene was significantly less frequent compared to CC genotype in bone marrow infiltration cases(P ＜0.05).The CT,TT,CT + TT genotypes and T allele in patients exhibiting the-1306C/T polymorphism were significantly less frequent in patients with a large tumor size compared to a smaller tumor(all P＜0.05).The incidence of the TT genotype of the-735C/T polymorphism was significantly higher in patients with a large tumor compared to those with a smaller tumor (P ＜0.05).The frequency of the-1306C/-735T haplotype in patients with a smaller tumor size was significantly higher compared to patients with a large tumor(P ＜ 0.05).The-1306T/-735C and-1306C/-735C haplotypes were significantly less frequent in patients with B-symptoms compared to those without (all P ＜ 0.05).Interestingly,patients with the TT genotype of-735C/T exhibited a lower rate of survival (Log-rank test,all P ＜0.05).Conclusion These findings suggest that certain MMP-2 and TIMP-2 gene polymorphisms are associated with the susceptibility of NHL.