Luminal Lipid Exposure, Genetics and Colon Cancer Risk

描述（由申请人提供）：拟议研究的长期目标是为降低结直肠癌发病率和死亡率的公共卫生策略提供科学依据。多项证据表明，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与高脂肪摄入密切相关，但队列研究和最近的病例对照研究的结果却不一致。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潜在的致癌物质，这些物质是由脂肪及其代谢产物与粪便细菌活性产生的。在这种情况下，脂肪吸收可能通过改变潜在致癌代谢物的肠道暴露水平，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，两种影响肠道脂肪吸收和胆汁酸分泌的常见遗传多态性（FABP2和Apo E）被报道，并与心血管疾病、糖尿病和痴呆的风险相关。我们假设，具有低肠吸收基因型的个体，导致更多的结肠内暴露于潜在的致癌物质，与高脂肪饮食相关，患结直肠癌的风险更高。为了验证这一假设，我们建议利用SEER癌症登记处的优势，在底特律大都会进行一项基于人群的病例对照研究。我们计划采访2000例病例和2000例对照组，了解他们的日常饮食，以估计脂肪和其他营养摄入，并收集血液或口腔细胞标本进行基因分型分析。该研究的具体目的是：(1)确定基因型FABP2 A54、载脂蛋白E2/E3或它们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为明显；(3)确定上述相互作用是否通过摄入其他影响腔内脂质代谢的膳食成分（如纤维、钙和铁）而改变。这项研究的结果将为结肠直肠癌一级预防的有效饮食调整提供有用的信息。此外，积累的饮食数据和生物标本将为未来研究其他营养-基因相互作用提供重要资源。

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.