转化生长因子β1基因启动子区基因多态性与贲门腺癌发病风险的关联研究

Correlation of polymorphisms in the promoter region of transforming growth factor β1 with the risk of developing gastric cardia adenocarcinoma

目的:探讨转化生长因子β1(transforming growth factor-β1,TGF-β1)基因启动子区C-509T、G-800A和C-988A单核苷酸多态性(single nucleotide polymorphism,SNP)与中国北方人群贲门腺癌(gastric cardia adenocarcinoma,GCA)遗传易感性的关系。方法:分别采用PCR-限制性片段长度多态性(restriction fragment length polymorphism,RFLP)技术和PCR-扩增阻滞突变系统(amplification refractory mutation system,ARMS)的方法检测214例GCA患者和298名健康对照的TGF-β1 C-509T、G-800A和C-988A多态性分布情况,同时采用ELISA方法检测血清TGF-β1水平。对110例GCA患者术后的切除肿瘤组织采用免疫组织化学方法检测TGF-β1蛋白表达。结果:TGF-β1基因C-509T多态性位点的基因型和等位基因型频率在GCA组和健康对照组间的分布差异有统计学意义(P<0.05);T等位基因携带者患GCA的风险是C等位基因的1.46倍[经性别、年龄和上消化管肿瘤家族史校正后的优势比(odd ratio,OR)=1.46,95%可信区间(confidence interval,CI)为1.05～2.06];与CC基因型相比,携带CT和TT基因型可显著增加GCA的发病风险(校正后的OR分别为1.84和2.02,95%CI分别为1.30～2.37和1.37～2.59)。TGF-β1基因G-800A和C-988A多态性位点的基因型及等位基因型频率在GCA患者组和健康对照组之间的总体分布差异均无统计学意义(P>0.05)。GCA患者血清TGF-β1水平显著高于健康对照(P<0.01),C-509T位点携带T等位基因的GCA患者血清TGF-β1水平高于非携带者(P<0.05)。GCA组织中TGF-β1蛋白的阳性表达率显著高于癌旁组织(65.5%vs15.5%,P<0.01),C-509T位点携带T等位基因的GCA患者TGF-β1蛋白的阳性表达率高于非携带者(P<0.05)。结论:TGF-β1基因启动子区C-509T位点T等位基因可能是中国北方人群对GCA的遗传易感基因,携带T等位基因的个体可能通过促进TGF-β1的高度表达进而增加了GCA的发病风险。

Objective：To investigate the possible association of C-509T,G-800A,and C-988A single nucleotide polymorphisms（SNP） in the promoter region of transforming growth factor-β1（TGF-β1） gene with the susceptibility to gastric cardia adenocarcinoma（GCA） in a population of Northern China.Methods：Polymerase chain reaction restriction fragment length polymorphism（PCR-RFLP） and polymerase chain reaction amplification refractory mutation system（PCR-ARMS） analysis were used to detect the distribution of SNPs of C-509T,G-800A and C-988A in 214 GCA patients and 298 healthy controls,respectively.The level of TGF-β1 was measured using ELISA and the protein expression of TGF-β1 in tumor tissues and corresponding normal tissues was detected by immunohistochemistry method.Results：The overall genotype and allelotype distributions of C-509T polymorphism of TGF-β1 gene in GCA patients were significantly different from those in healthy controls（P0.05）.The subjects with T allelotype had significantly increased risk of developing GCA compared with those with C allelotype carriers [after adjustment for gender,age,and family history of upper digestive tract tumor,the adjusted odds ratio（OR） =1.46,95% confidence interval（CI） =1.05-2.06].Compared with CC genotype,the subjects with CT and TT genotypes had significantly increased risk of developing GCA（adjusted OR=1.84 and 2.02,respectively;95%CI=1.30-2.37 and 1.37-2.59,respectively）.The genotype and allelotype distributions of G-800A and C-988A polymorphism of TGF-β1 were not significantly different between GCA patients and healthy controls（P0.05）.The serum level of TGF-β1 was significantly higher in GCA patients than that in healthy controls（P0.01） and it was significantly higher in C-509T T allelotype carriers than non C-509T carriers（P0.05）.The protein expression of TGF-β1 in GCA tumor tissues was significantly higher than that in corresponding normal tissues（65.5% vs 15.5%,P0.01） and it was higher in C-509T T allelotype carriers than non C-509T carriers（P0.05）.Conclusion：T allelotype of C-509T in the promoter region of TGF-β1 may be one of the genetic predisposition genes for developing GCA in Northern China and T allelotype carriers may have increased risk of developing GCA by stimulating the over-expression of TGF-β1.