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Neoplasia-1 Gene with Serum Levels and Risk of Colorectal β Factor Association of Genetic Variation in the Transforming Growth

In the normal intestinal epithelium transforming growth factor B-1 (TGFB-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 TGFB-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 TGFB-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 TGFB-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); Pdifference = 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. [Cancer Res 2008;68(4):1236–44]