Association of genetic variation in the transforming growth factor beta-1 gene with serum levels and risk of colorectal neoplasia.
Association of genetic variation in the transforming growth factor beta-1 gene with serum levels and risk of colorectal neoplasia.
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DOI：
10.1158/0008-5472.can-07-2144
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发表时间：
2008-02
期刊：
影响因子：
11.2
通讯作者：
B. Saltzman;J. Yamamoto;R. Decker;L. Yokochi;A. Theriault;T. Vogt;L. Le Marchand
中科院分区：
文献类型：
--
作者：
B. Saltzman;J. Yamamoto;R. Decker;L. Yokochi;A. Theriault;T. Vogt;L. Le Marchand
在正常肠上皮细胞中，转化生长因子β-1(TGFbeta-1)作为生长抑制因子，但在恶性细胞中，它可能作为肿瘤促进剂。然而，关于TGFB1基因的遗传变异及其与循环水平和结直肠癌风险的关系的信息有限。为了研究TGFB1基因座上循环TGFbeta-1基因的遗传变异[标记单核苷酸多态(TagSNP)和单倍型与频率&>0.05]与大肠肿瘤风险的关系，我们在夏威夷的日裔美国人、高加索人和夏威夷原住民中进行了两项病例对照研究(包括271例结直肠腺瘤病例和544例对照，以及结直肠腺癌病例和656例对照)。采用双抗体夹心ELISA法测定研究对象血清中的转化生长因子β1水平。调整年龄等因素后，TagSNP rs6957变异A等位基因与较高的血清TGFbeta-1[AA或AG的平均值(单位ng/毫升)和95%可信区间(95%CI)，32.6(30.6~34.7)；GG，29.0(25.1~32.9)；P(差值)=0.05]相关。TagSNP rs11466345变异G等位基因纯合携带者患腺癌的风险显著降低[AG与AA：优势比(OR)，0.9(95%CI，0.7~1.2)；GG与AA：OR，0.4(95%CI，0.2~0.7)；P(趋势)=0.01]。携带这两种变异的单倍型与腺癌风险的降低也有统计学意义(OR，0.3；95%CI，0.1-0.8)。虽然没有统计学意义，但腺瘤的相应OR的方向和大小是相似的。这些结果提示TGFB1基因3‘端含有SNP rs11466345的单倍型与大肠肿瘤的遗传易感性有关。
In the normal intestinal epithelium transforming growth factor beta-1 (TGFbeta-1) acts as a growth inhibitor, but in malignant cells it may act as a tumor promoter. However, only limited information is available on genetic variation in the TGFB1 gene and its relationship to circulating levels and risk of colorectal cancer. To characterize associations of genetic variation [tagging single-nucleotide polymorphisms (tagSNP) and haplotypes with frequency >0.05] at the TGFB1 locus with circulating TGFbeta-1 and risk of colorectal neoplasia, we conducted two case-control studies (including 271 colorectal adenoma cases and 544 controls, and 535 colorectal adenocarcinoma cases and 656 controls) among Japanese Americans, Caucasians, and Native Hawaiians in Hawaii. Serum TGFbeta-1 was measured by sandwich ELISA among the subjects of the first study. The variant A allele for tagSNP rs6957 was associated with higher serum TGFbeta-1 [means (in ng/mL) and 95% confidence interval (95% CI) for AA or AG, 32.6 (30.6-34.7); GG, 29.0 (25.1-32.9); P(difference) = 0.05] after adjusting for age and other factors. Homozygous carriers of the variant G allele for tagSNP rs11466345 had a statistically significantly lower risk of adenocarcinoma [AG versus AA: odds ratio (OR), 0.9 (95% CI, 0.7-1.2); GG versus AA: OR, 0.4 (95% CI, 0.2-0.7); P(trend) = 0.01]. The haplotype carrying both variants was also statistically significantly associated with a reduced risk of adenocarcinoma (OR, 0.3; 95% CI, 0.1-0.8). Although not statistically significant, the direction and magnitude of the corresponding ORs were similar for adenoma. These results suggest that a haplotype containing SNP rs11466345 at the 3' end of TGFB1 is associated with genetic susceptibility to colorectal neoplasia.