One major area of etiological research to which the Cooperative Family Registry for Colorectal Cancer Studies (Colon CFR) is committed is candidate gene association studies. The present application addresses genotypes as well as biomarkers involved in the oxidative stress pathway. We have the following specific aims. 1. To conduct a family-based case-control association study of oxidative stress-related genes, including myeloperoxidase (MPO), endothelial cell nitric oxide synthase (ecNOS), manganese superoxide dismutase (MnSOD), selenium-dependent glutathione peroxidase (GPX1), catalase (CAT), glutathione S- transferase A1 (GSTA1), glutathione S-transferase M1 (GSTM1), glutathione S-transferase T1 (GSTT1), glutathione S-transferase P1 (GSTP1), NAD(P)H:quinone oxidoreductase (NQ01), catechol-O-methyl transferase (COMT), paraoxonase 1 (PON1), heme oxygenase (HO1), and peroxisome proliferator activated receptor gamma (PPARg), in colorectal cancer development. 1.1. To assess the potential modifying effects of the candidate genes on protective factors for colorectal cancer, including marine n-3 fatty acids, non-steroidal anti-inflammatory drugs (NSAIDs), physical exercise, dietary isothiocyanates (ITC), vitamin D and calcium, and folate. 1.2. To assess the potential modifying effects of the candidate genes on the positive association between alcohol intake and colorectal cancer risk. 2. To determine if certain protective (marine n-3 fatty acids, NSAIDs, physical exercise, ITC, vitamin D and calcium, and folate) and risk-enhancing (alcohol intake) factors for colorectal cancer are associated with plasma lipid peroxidation products [malondialdehyde, (MDA) and lipid peroxides] among controls. 2.1. To determine if oxidative stress- related genes are associated with lipid peroxidation products (MDA and lipid peroxides) among control subjects. 2.2. To determine if the protective/risk factor-lipid peroxidation associations are modified by oxidative stress-related genes. 3. To conduct a family-based case-control association study to assess the role of plasma lipid peroxidation products in colorectal cancer development using an exploratory analyses with a latent variable approach. 4. To conduct a case-case association study to determine if morphological markers of apoptosis in tumor and surrounding free tissue differ among cases with varying exposure levels of a given putative environmental/genetic risk factor. ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?
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