Risk of colorectal neoplasias probably involves the interactions of genetic and environmental factors. Among these, abnormal DNA methylation is relatively common, although little is known about its etiology. In this project, we propose to conduct investigations of several environmental and genetic factors as they relate to a commend end-point in the Program Project, adenoma recurrence. Using data and biological samples from our recently completed Wheat Bran Fiber (WBF) trial, our ongoing study of ursodeoxycholic acid (UDCA), and those from our propose trial of selenium and celecoxib, we propose to: 1) examine if folate status (assessed by dietary intake and plasma levels), high plasma homocysteine, or the methylenetetrahydrofolate reductase (MTHFR) gene is associated gene methylation, assessed by the presence of the CpG island methylator phenotype (CIMP); 2- compare the effects of selenium or celecoxib intervention on the recurrence of adenomatous polyps among individuals with low gluathione S-transferase (GST) status (assessed as GSTM null and/or GSTT1 null genotypes and those with the high activity groups; 3) assess whether the presence of the MTHFR polymorphism modifies the effect between selenium or cerecoxib intervention on the recurrence of adenomatous polyps among individuals with low gluathione S-transferase (GST) status (assessed as GSTM1 null and/or GSTT1 null genotypes) and those with the high activity groups; 3) assess whether the presence of the MTHFR polymorphism modifies the effect between selenium and/or celecoxib intervention and adenoma recurrence; and, 4) assess the modifying effect between selenium and/or celecoxib intervention and adenoma recurrence; and, 4) assess the modifying effect of the N-acetyltransferase 1 and 2 genes, and the cytochrome P40 1A2 phenotype in the association of dietary heterocyclic aromatic amines and adenoma recurrence. The proposed studies will evaluate the role of prominent genetic and epidemiologic factors as they relate to gene methylation and adenoma recurrence in a large sample of prospectively collected data. The relative importance of the proposed interactions can only be appreciated through their investigation in a large comprehensive setting using a well-characterized population, as proposed in this project. While we estimate that we will have over 4,000 study participants available, we have designed these studies in a cost-effective manner, with adequate power to test the proposed hypotheses.
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