福建省汉族女性乳腺癌患者MMP9基因的多态性研究

Association of Polymorphisms of MMP9 Gene with Breast Cancer in Han Women Population of Fujian Province

目的探讨福建地区汉族女性基质金属蛋白酶9基因(MMP9)的单体型标签单核苷酸多态性位点(htSNP)与乳腺癌遗传易感性的关系。方法采取以自然人群为基础的病例对照研究设计,选取福建地区经组织学确诊的汉族女性乳腺癌患者251例和年龄频数匹配的女性健康对照者255例。采用基质辅助激光解吸电离飞行时间质谱或聚合酶链反应-限制性内切酶片段长度多态性方法对MMP9的5个htSNP(rs17576、rs2250889、rs3787268、rs17577和rs3918254)进行基因分型。非条件Logistic回归模型被用以估计各SNP基因型与乳腺癌发病风险、临床病理特点的关系,单体型分析则采用R软件的Haplo.Stats程序包进行。结果 MMP9基因rs17577的A等位基因型携带者增加了乳腺癌的发病风险(OR=1.581,95%CI 1.082～2.310),GA+AA基因型的携带者发生乳腺癌的风险是GG基因型携带者的1.6倍(OR=1.668,95%CI 1.098～2.533);其余4个位点的基因型与等位基因型频率分布在乳腺癌组和正常对照组之间无显著性差异(P>0.05)。含有rs17577危险等位基因型A的单体型GCGCA携带者发生乳腺癌的风险是单体型GCACG携带者的1.5倍(OR=1.543,95%CI1.018～2.337)。而且rs3918254位点CT+TT基因型携带者发生高级别乳腺癌的风险是CC基因型患者的2.6倍(OR=2.632,95%CI 1.331～5.204)。结论 MMP9基因rs17577多态性位点与乳腺癌的遗传易感性显著相关;而rs3918254的CT+TT基因型有可能成为乳腺癌不良预后的分子指标。

Objective To investigate the association of MMP9 gene Haplotype tagging single nu- cleotide polymorphisms （htSNPs） with breast cancer in Han women population of Fujian province. Meth- ods A population based case-control association study was carried out in 251 breast cancer patients and 255 age-matched healthy women controls of Han nationality from Fujian province. Five htSNPs in MMP9 gene was determined by Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry （MALDI-TOF MS） or polymerase chain reaction-amplified genes with restriction endonucleases （PCR-RFLP）. Unconditional logistic regression was used to calculate odds ratios （OR） and 95% confidence in- tervals （95% CI） as estimates of relative risk for the single locus alleles and genotypes. To assess the as- sociation between inferred haplotypes and risk of breast cancer, Haplo. stats were used. Results The A allele and GA＋AA genotypes at rs17577 were associated with increased risk of breast cancer significantly （OR=I. 581, 95% CI 1. 082~2. 310 and OR=1. 668, 95% CI 1. 098~2. 533 respectively）. While the other four htSNPs showed no significant association with breast cancer. Haplotype association analysis showed that the GCGCA haplotype, comprised of the risk allele at rs17577, was associated with an in- creased risk of breast cancer （OR 1. 543, 950//00 CI 1. 018~2. 337, P=0. 045）, as compared to the most common haplotype GCACG. Moreover, for MMP9 rs3918254, the T-carriers （CT＋TT genotype） were more likely to bear tumors of greater aggressiveness （histological grade Ⅱ＋Ⅲ ） than C/C-carriers （grade Ⅰ ） （OR=2. 632, 95% CI 1. 331~5. 204）. Conclusions rs17577 is signicantly associated with risk of breast cancer. And CT＋TT genotypes of rs3918254 might be an indicator of histopathological grade in breast cancer.