Oxidative Stress, DNA Repair & Colorectal Adenoma Risk

描述（由申请方提供）：拟定研究的目的是检查结直肠腺瘤与氧化应激决定因素之间的相关性，包括饮食习惯、血清铁蛋白（铁摄入量的标志物）、氧化损伤生物标志物、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。拟定的工作范围（称为“新研究”）仅限于实验室和统计分析，使用来自先前进行的两项方法学非常相似的散发性结直肠腺瘤基于结肠镜检查的病例对照研究（母研究）的生物样本和问卷数据：一项在北卡罗来纳州进行，另一项在明尼苏达州进行。新研究拟定的分析均不属于母研究设计和范围的一部分。母研究中纳入的病例为经病理学证实的偶发腺瘤性息肉患者，对照组为既往无腺瘤性息肉病史、接受结肠镜检查并发现无腺瘤性息肉的患者。最终样本量包括778例病例和920例对照。所有参与者都完成了邮寄问卷，其中包括息肉或结肠癌家族史，饮食信息（通过使用Willett食物频率问卷），体力活动，生殖变量，体脂分布以及导致结肠镜检查的原因和事件顺序。抽取血液，通过各种方案处理，并在-86 ℃下储存为血沉棕黄层、核沉淀、血清和血浆。新研究的实验室分析将包括测量氧化DNA损伤（8-OHdG）和脂质过氧化的生物标志物（异前列烷）、脂溶性类胡萝卜素和生育酚水平（抗氧化剂）和血清铁蛋白（潜在的促氧化铁摄入的标志物）和五个抗氧化基因多态性的基因分型（GSTT 1、GSTM 1、MnSOD、EC-SOD和GPX 1）和五个花生四烯酸代谢基因（考克斯-2、LOX-5、LOX-12、LOX 15和PPAR-y）。我们还将评估参与DNA碱基切除修复的主要基因的SNP，包括OGG 1，APE 1，XRCC 1，ERCC 5和其他几个基因。将使用多变量非条件logistic回归模型分析所得数据。将特别注意识别潜在的基因-基因，基因-生活方式和基因-表型相互作用。

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.