基质金属蛋白酶3、7基因多态性与脑星形胶质细胞瘤发病风险的关系

Correlations of Polymorphisms in Matrix Metalloproteinase-3 and -7 Promoters to Susceptibility to Brain Astrocytoma

背景与目的:基质金属蛋白酶(matrix metalloproteinases,MMPs)是肿瘤发生、侵袭和转移过程中的关键酶之一。MMPs基因启动子区的单核苷酸多态性(single nucleotide polymorphism,SNPs)可通过影响基因的转录和蛋白的表达而影响肿瘤的发生、发展。本研究旨在探索MMP-3、MMP-7启动子区基因多态性与脑星形胶质细胞瘤发病风险的关系。方法:以聚合酶链反应-限制性片段长度多态性分析方法,检测236例成人星形胶质细胞瘤及365例健康对照的MMP-3-11715A/6A及MMP-7-181A/G多态性的基因型。结果:(1)MMP-3等位基因型及基因型总体分布在肿瘤患者组和健康对照组之间差异无统计学意义(P>0.05)。根据性别、发病年龄、病理分级进行的分层分析显示,与6A/6A基因型相比,MMP-35A/5A和5A/6A基因型个体患肿瘤的发病风险与其它基因型个体差异无统计学意义;(2)MMP-7基因型在肿瘤患者组及健康对照组中的分布差异有统计学意义(P=0.001)。与A/A基因型相比,A/G及G/G基因型可显著增加星形胶质细胞瘤的发病风险,经性别、年龄较正的OR值分别为1.69及2.77(95%CI=1.01～2.84及1.27～6.02)。分层分析显示,G/G基因型可使45岁以下人群及男性个体发生星形胶质细胞瘤的风险增加3倍左右,G/G基因型携带者发生Ⅱ～Ⅳ级星形胶质细胞瘤的风险增加3倍左右,且A/G基因型可增加Ⅱ级星形胶质细胞瘤的发病风险约2倍。结论:MMP-7-181A/G多态性可能影响星形胶质细胞瘤的发病风险,而MMP-3-11715A/6A多态性与此肿瘤的易感性可能无关。

BACKGROUND ＆ OBJECTIVE： Matrix metalloproteinases （MMPs） are key enzymes involved in tumor development, invasion and metastasis. The single nucleotide polymorphisms （SNPs） in the promoter regions of MMP genes may influence tumor development and progression via modulating mRNA transcription and protein expression. This study was to explore the correlations of the promoter SNPs in MMP-3 and MMP-7 genes to susceptibility to brain astrocytoma. METHODS. The genotype of MMP-3 -1171 5A/6A and MMP-7 -181A/G polymorphisms in 236 patients with brain astrocytoma and 366 healthy controls was detected by polymerase chain reaction-restrictive fragment length polymorphism （PCR-RFLP）. RESULTS： The allelotype and overall genotype distribution of MMP-3 SNP among the astrocytoma patients and healthy controls were similar （P〉0.05）. Stratified by sex, age, and histological grade, the susceptibility to brain astrocytoma among the subjects with 5A/5A and 5A/6A genotypes and the subjects with 6A/6A genotype were similar （P〉0.05）, The overall genotype distribution of MMP-7 SNP among the astrocytoma patients and healthy controls were significantly different （P = 0.001）. Compared with the A/A genotype, both the G/G and the A/G genotypes significantly increased the susceptibility to astrocytoma [sex- and age-adjusted odds ratio （OR） = 2.77 and 1.69, 95% confidence interval （CI）=1.27-6.02 and 1.01-2.84, respectively]. Stratification analysis showed that the G/G genotype significantly increased the susceptibility to astrocytoma in men （adjusted OR = 3.24, 95% CI = 1.12- 9.41） and in the individuals younger than 45 years （adjusted OR = 3.16, 95% CI = 1.09-9.16）. When stratified by histological grade, the A/G genotype increased the susceptibility to grade Ⅱ astrocytoma by about 2 folds （adjusted OR = 2.06, 95% CI = 1.05 - 4.05）, while the G/G genotype increased the susceptibility to grade Ⅱ -Ⅳ astrocytoma by about 3 folds. CONCLUSION： MMP-7 -181A/G polymorphism may influence the susceptibility to astrocytoma, while MMP-3-1171 5A/6A polymorphism has no correlation to the susceptibility.