Luminal Lipid Exposure, Genetics and Colon Cancer Risk

腔内脂质暴露、遗传学和结肠癌风险

• 批准号: 6919197
• 负责人: IKUKO KATO
• 金额: $ 38.22万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-05 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6919197
• 关键词: apolipoprotein E; cancer risk; cholanate compound; clinical research; colon neoplasms; dietary calcium; dietary fiber; dietary iron; dietary lipid; gastrointestinal absorption /transport; gene environment interaction; genetic polymorphism; genetic susceptibility; genotype; high throughput technology; human middle age (35-64); human old age (65+); human subject; lipid metabolism; neoplasm /cancer epidemiology; neoplasm /cancer genetics; nutrition related neoplasm /cancer; patient oriented research; secretion; transport proteins

DESCRIPTION (provided by applicant): The long-term goal of the proposed study is to provide the scientific basis for public health strategies to reduce incidence of and mortality from colorectal cancer. Several lines of evidence suggest that a high fat diet increases the risk of colorectal cancer. While ecologic studies and earlier case-control studies demonstrated a strong association with high fat intake, the results from cohort studies and recent case-control studies have rather been inconsistent. These discrepancies may indicate some genetic susceptibility that modify the effects of a high fat diet. One of the major mechanistic bases for the roles of fat in colorectal carcinogenesis is intracolonic exposure to potentially carcinogenic substances which are generated from lipid and its metabolites with fecal bacterial activities. In this context fat absorption may play a key role in determining the effects of a high fat diet on colorectal cancer risk via modifying the levels of luminal exposure to potentially carcinogenic metabolites. Recently, two common genetic polymorphisms (FABP2 and Apo E) that affect intestinal fat absorption and bile acid secretion have been reported and associated with risks of cardiovascular diseases, diabetes and dementia. We hypothesize that individuals with genotypes for lower intestinal absorption, which results in more intracolonic exposure to potentially carcinogenic substances, have a higher risk of developing colorectal cancer in relation to a high fat diet. To test this hypothesis, we propose to conduct a population-based case-control study in Metropolitan Detroit taking an advantage of the SEER Cancer Registry. We plan to interview 2000 cases and 2000 controls for their usual diet to estimate fat and other nutrient intake and collect blood or buccal cell specimens for genotyping assays. Specific aims of the study are (1) To determine whether the genotype, FABP2 A54, Apo E2/E3 or a combination of these, is associated with risk of colorectal cancer; (2) To determine whether the effect of a high fat diet on colorectal cancer risk is more pronounced in the subjects with these genotypes; and (3) To determine if the above interactions are modified by intake of other dietary components, such as fiber, calcium and iron, which affect luminal lipid metabolism. The results from the proposed study would provide useful information for effective dietary modification in primary prevention for colorectal cancer. In addition, accumulated dietary data and biological specimens will serve as an important resource for future research on other nutrient-gene interactions.

描述（由申请人提供）：拟议研究的长期目标是为公共卫生策略提供科学依据，以降低结直肠癌的发病率和死亡率。几条证据表明，高脂肪饮食会增加患结肠直肠癌的风险。虽然生态学研究和早期的病例对照研究表明，高脂肪摄入与高脂肪摄入有很强的相关性，但队列研究和最近的病例对照研究的结果并不一致。这些差异可能表明某些遗传易感性改变了高脂肪饮食的影响。脂肪在结直肠癌发生中的作用的主要机制基础之一是结肠内暴露于具有粪便细菌活性的脂质及其代谢产物产生的潜在致癌物质。在这种情况下，脂肪吸收可能通过改变管腔暴露于潜在致癌代谢物的水平，在确定高脂肪饮食对结直肠癌风险的影响方面发挥关键作用。最近，两种常见的影响肠道脂肪吸收和胆汁酸分泌的遗传多态性（FABP 2和Apo E）已被报道，并与心血管疾病，糖尿病和痴呆症的风险相关。我们假设，具有较低肠道吸收基因型的个体，其导致更多的结肠内暴露于潜在致癌物质，与高脂肪饮食相关的结直肠癌的风险更高。为了验证这一假设，我们建议在底特律大都市进行一项基于人群的病例对照研究，利用SEER癌症登记。我们计划采访2000例病例和2000例对照，了解他们的日常饮食，以估计脂肪和其他营养素的摄入量，并收集血液或口腔细胞标本进行基因分型分析。本研究的具体目的是（1）确定基因型、FABP 2 A54、Apo E2/E3或这些基因型的组合是否与结直肠癌的风险相关;（2）确定高脂肪饮食对结直肠癌风险的影响是否在具有这些基因型的受试者中更显著;以及（3）确定上述相互作用是否被影响管腔脂质代谢的其他膳食组分（如纤维、钙和铁）的摄入所改变。本研究的结果将为大肠癌的一级预防提供有效的饮食调整信息。此外，积累的饮食数据和生物标本将成为未来研究其他营养素-基因相互作用的重要资源。