Oxidative Stress, DNA Repair & Colorectal Adenoma Risk

描述(申请人提供)：建议的研究目的是研究结直肠腺瘤与氧化应激决定因素的关系，包括饮食习惯、血清铁蛋白(铁摄入量的标志)、氧化损伤的生物标志物、血清抗氧化剂水平，以及抗氧化剂、花生四烯酸代谢(炎症相关)和DNA修复酶的遗传变异。拟议的工作范围(称为“新研究”)仅限于使用生物样本和问卷数据进行的实验室和统计分析，这两项研究以前在北卡罗来纳州和明尼苏达州进行了两项基于结肠镜检查的散发性结直肠腺瘤病例对照研究(父母研究)，在方法上非常相似。为新研究建议的分析都不是家长研究设计和范围的一部分。父母研究中的病例包括经病理证实的偶发腺瘤性息肉患者，而对照组是接受结肠镜检查并被发现没有腺瘤性息肉的无腺瘤性息肉病史的患者。最终样本量包括778例病例和920名对照。所有参与者都完成了邮寄的问卷，其中包括息肉或结肠癌的家族史、饮食信息(通过使用Willett食物频率问卷)、体力活动、生殖变量、体脂分布及其原因(S)和导致结肠镜检查的事件顺序。这项新研究的实验室分析将包括测量氧化DNA损伤(8-OHdG)和脂质过氧化(Isoprostanes)的生物标记物、脂溶性胡萝卜素和生育酚(抗氧化剂)和血清铁蛋白(潜在促氧化性铁摄入量的标记物)的水平，以及五种抗氧化剂基因(GSTT1、GSTM1、MnSOD、EC-SOD和GPX1)和五种花生四烯酸代谢基因(COX-2、LOX-5、LOX-12、LOX15和PPAR-y)的基因分型。我们还将评估参与DNA碱基切除修复的主要基因的SNPs，包括OGG1、APE1、XRCC1、ERCC5等。结果数据将使用多变量无条件Logistic回归模型进行分析。将特别注意识别潜在的基因-基因、基因-生活方式和基因-表型交互作用。

DESCRIPTION (provided by applicant): The objective of the proposed study is to examine the association between colorectal adenoma and determinants of oxidative stress including dietary habits, serum ferritin (marker of iron intake), biomarkers of oxidative damage, serum antioxidant levels, as well as genetic variation in antioxidant, arachidonic acid- metabolizing (inflammation-related) and DNA repair enzymes. The proposed scope of work (referred to as the 'New Study') is limited to laboratory and statistical analyses using biological samples and questionnaire data from a two previously conducted, and methodologically very similar, colonoscopy-based case-control studies of sporadic colorectal adenoma (Parent studies): one conducted in North Carolina and another conducted in Minnesota. None of the analyses proposed for the New Study were part of the Parent Studies design and scope. Cases included in the Parent Studies were pathology-confirmed, incident adenomatous polyp patients, and controls were patients with no previous history of adenomatous polyps who underwent colonoscopy and were found to be free of adenomatous polyps. The final sample size included 778 cases and 920 controls. All participants completed mailed questionnaires, which included information on family history of polyps or colon cancer, dietary information (through use of a Willett Food Frequency Questionnaire), physical activity, reproductive variables, body fat distribution, and their reason(s) for and the sequence of events leading to colonoscopy. Blood was drawn, processed by various protocols, and stored as Buffy coats, nuclear pellets, serum, and plasma at -86¿C. The laboratory analysis for the New Study will include measuring biomarkers of oxidative DNA damage (8-OHdG) and lipid peroxidation (isoprostanes), levels of lipid-soluble carotenoids and tocopherols (antioxidants) and serum ferritin (marker of potentially pro- oxidant iron intake), and genotyping for polymorphisms of five antioxidant genes (GSTT1, GSTM1, MnSOD, EC-SOD, and GPX1) and five arachidonic acid-metabolizing genes (COX-2, LOX-5, LOX-12, LOX15 and PPAR-y). We will also evaluate the SNPs of the main genes involved in DNA base excision repair including OGG1, APE1, XRCC1, ERCC5 and several others. The resulting data will be analyzed using multivariate unconditional logistic regression models. Particular attention will be paid to identification of potential gene- gene, gene-lifestyle, and gene-phenotype interactions.