Transforming growth factor beta one and colorectal neoplasia: A case-control examination of adenoma and carcinoma in Hawaii.

摘要

Background. In normal epithelium, including intestinal epithelium, TGFbeta1 acts as a growth inhibitor. During the carcinogenic process, transformed cells may become resistant to TGFbeta signaling and TGFbeta1 then acts as a tumor promoter. Preliminary evidence suggests several SNPs in the TGFbeta1 gene, including C-509T, L10P, and P25A, have been associated with altered levels of TGFbeta1. Other SNPs, including G-800A and T263I, are suspected to influence transcription or activation. Evidence of relationships between circulating TGFbeta1 and risk factors of human chronic diseases stems mostly from laboratory studies. Methods . To characterize associations of demographics, lifestyle, plasma lipids, insulin-like growth factor-I and binding proteins I and III, inflammatory markers, and genetic variation in TGFbeta1 with circulating TGFbeta1, we conducted a cross-sectional analysis of 269 adenoma cases and 538 controls from an HMO-based study of colorectal adenomas in Hawaii. To investigate the association with genetic variation in TGFbeta1 and colorectal neoplasia, we used tagSNPs and haplotype blocks and examined their association with 271 cases of colorectal adenoma and 544 controls, and 535 cases of colorectal adenocarcinoma and 656 controls. All participants were of Japanese, Caucasian or Native Hawaiian ancestry. Results. There was a statistically significant inverse correlation between age (-0.12, p 0.001) and serum TGFbeta1 and direct correlations with smoking (0.08, p=0.04) and alcohol drinking (0.08, p=0.02). Increasing numbers of the variant G allele for tagSNP rs6957, were associated with lower serum TGFbeta1 in all races combined (means and 95% CI for AA=30.7, 29.6-31.7; AG=32.4, 31.0-33.8; GG=28.6, 25.1-32.0; p= 0.03) after adjusting for age and other factors. Carriers of the variant allele for tagSNP rs 11466345 had a statistically significantly lower risk of adenocarcinoma (AG vs. AA, OR=0.9, 95% CI: 0.7,1.2; GG vs. AA, OR= 0.4, 95% CI:0.2-0.7, p-trend =0.01). Haplotypes carrying this variant were also statistically significantly associated with a reduced risk of adenocarcinoma (OR=0.3, 95% CI: 0.1-0.8). Although not statistically significant, associations were similar in the adenoma study. Conclusions. Circulating TGFbeta1 was lower in older individuals but higher with increased cigarette smoking and alcohol drinking histories. These results suggest the 3' region of TGFbeta1 is associated with genetic susceptibility to colorectal neoplasia.