Molecular Epidemiology of Colorectal Adenomas

描述（由申请人提供）：我们的总体目标是对大肠腺瘤（公认的大肠癌（CRC）的前体）病因学中所选的感兴趣的代谢途径内的基因和基因-基因和基因环境相互作用的主要影响进行更有针对性的研究。在这项应用的母研究中，我们有1,610名受试者（778例病例和832例对照）的DNA和风险因素数据。我们有以下具体目标：1）研究选择的基因和环境因素相关的叶酸相关途径。具体而言，我们建议研究MTHFR，MTRR，ADH 3，这可能会影响叶酸代谢，和XRCC 1，XRCC 3，OGG 1，和MGMT，这可能会参与DNA修复与叶酸代谢相关的损伤。 此外，我们已经掌握了RBC叶酸、同型半胱氨酸和DNA甲基化的数据，这些数据将在适当的情况下纳入这些数据的统计分析。2)研究可能参与胆汁酸代谢或转运的基因。具体而言，我们建议研究SLC 10A 2，基因编码的回肠钠依赖性胆汁酸转运蛋白（ISBT），沿着与VDR和EPHX 1基因。我们还将进行分析，以调查这些基因的主要影响是否似乎被选定的环境因素所改变，这些环境因素被假设为通过对胆汁酸的影响来影响结直肠腺瘤或癌症的风险。3)在体外系统地表征流行病学感兴趣的选定基因中的所有非同义SNP，例如EPHX 1，（别名mEH）和MTHFR，通过克隆酶的定点诱变、过表达和适当的测定，并在体外系统地表征5'和3' UTR中的所有SNP在一些实施方案中，所述方法包括将流行病学感兴趣的选定基因的非翻译区（非翻译区）插入适当的报告构建体中，例如表达修饰的萤火虫荧光素酶。我们选择待表征等位基因的基本原理在研究设计和方法章节中进行了描述; 4）由于托马斯和Cortessis博士进一步开发了一种更好地分析复杂代谢途径的统计方法，我们将此方法应用于本研究生成的数据。

DESCRIPTION (provided by applicant): Our overall objective is to conduct more directed studies of main effects of genes and gene-gene and gene environment interactions within selected metabolic pathways of interest in the etiology of colorectal adenomas, accepted precursors of colorectal cancer (CRC). In the parent study for this application, we have DNA and risk factor data on 1,610 subjects (778 cases and 832 controls). We have the following specific aims: 1) Study selected genes and environmental factors relevant to a folate-related pathway. Specifically, we propose to study MTHFR, MTRR, ADH3, which may affect folate metabolism, and XRCC1, XRCC3, OGG1, and MGMT, which may be involved in DNA repair of damage associated with folate metabolism. In addition, we have data already in hand on RBC folates, homocysteine, and DNA methylation that will be incorporated into statistical analyses of these data where appropriate. 2) Study genes that may be involved in the metabolism or transport of bile acids. Specifically, we propose to study SLC10A2, the gene encoding the ilieal sodium-dependent bile acid transporter (ISBT), along with the VDR and EPHX1 genes. We will also conduct analyses to investigate if the main effects of these genes appear to be modified by selected environmental factors that have been hypothesized to affect risk of colorectal adenomas or cancer via an effect on bile acids. 3) To characterize systematically in vitro all non-synonymous SNPs in selected genes of epidemiologic interest, such as EPHXl (alias mEH) and MTHFR, by site-directed mutagenesis of the cloned enzyme, overexpression and appropriate assays, and to characterize systematically in vitro all SNPs in the 5' and 3' UTRs (untranslated region) of selected genes of epidemiologic interest in appropriate reporter constructs, e.g. expressing modified firefly luciferase. Our rationale for selecting alleles to be characterized is described in the Study Design and Methods section; 4) As a statistical method to better analyze complex metabolic pathways is further developed by Drs. Thomas and Cortessis, we will apply this method to data generated by this study.