Influence of Dietary Pattern and Race on Metabolic and Epigenetic Alterations Associated with Cancer Development

摘要 非洲裔美国人患胃肠癌的风险存在差异，从病因上讲，胃肠癌与 发炎。饮食和其他行为因素，而不是遗传因素，可能在解释 这种差异，因为胃肠道癌症的发病率在非洲农村人中要低得多。美国的素食主义者 基督复临安息日健康研究-2(AHS-2)队列研究发现，结直肠癌和胃肠道疾病的风险降低 相对于杂食动物的巨蟹座。此外，素食者的炎性细胞因子浓度较低， 和更高水平的抗炎生物活性化合物。因此，习惯性素食和杂食性饮食 模式可能会不同地调节炎症。然而，有必要确定其他饮食- 影响炎症和癌症的相关代谢物和分子过程。 代谢组和DNA甲基组在癌症中发生了深刻的变化，并且也受到SELECT的影响 食物或饮食条件。然而，目前还不清楚他们是如何受到以下饮食模式的影响的 食用植物性或动物性食物。非裔美国人，他们往往营养状况较差， 饮食行为，具有不同于高加索人的代谢和表观遗传特征。因此，这些 差异可以部分地用饮食来解释。次生多酚和其他植物来源的代谢物可以 预防炎症，而氧化和与能量相关的代谢物随着摄入 动物性食物可能会促进慢性炎症。这些不同的代谢物图谱可能是 甲基化的特点是反对影响基因组稳定性和基因稳定性的甲基化的全局或基因特异性变化 癌症相关基因的表达。甲基供体代谢产物(叶酸、胆碱和蛋氨酸) 有各种各样的食物会影响癌症，但研究结果并不一致。看似合理的是， 甲基供体和其他代谢物的精确甲基化活性在很大程度上取决于炎症状态， 它本身已被发现调节甲基化，并由饮食模式定义。 使用AHS-2队列中素食者和杂食者的血液样本，特定的目标将检查 饮食结构和种族对血浆代谢物和基因甲基化的独立影响 确定饮食模式对这些生物标志物图谱的影响在非裔美国人亲属中是否不同 敬高加索人。此外，先验候选者、饮食相关代谢物和基因之间的相关性 与炎症和癌症相关的内容将会被检查。拟议项目将在以下方面提供新的培训 分子流行病学、基因组学和健康差距研究。培训活动包括讲习班、 会议、短期课程和研讨会，以及拨款撰写课程和工作小组。研究将会 在实验营养学和代谢组学方面经验丰富的导师的帮助下，统计 方法论和流行病学，癌症生物学和健康差异，以及合作 在生物信息学和表观遗传学方面拥有额外专业知识的科学家。

Abstract African Americans suffer disparities in risk of gastrointestinal cancers, which are etiologically linked with inflammation. Dietary and other behavioral factors, rather than genetic, likely play a dominant role in explaining the disparity, as incidence of gastrointestinal cancers is much lower in rural Africans. Vegetarians in the Adventist Health Study-2 (AHS-2) cohort were found to have decreased risk for colorectal and gastrointestinal cancers relative to omnivores. Additionally, vegetarians have lower concentrations of inflammatory cytokines, and higher levels of anti-inflammatory bioactive compounds. Thus, habitual vegetarian and omnivorous dietary patterns may differentially regulate inflammation. However, there is a need for identification of other diet- related metabolites and molecular processes that influence inflammation and consequently cancer. The metabolome and DNA methylome are profoundly altered in cancer and also impacted by select foods or dietary conditions. However, it is unclear how they are influenced by dietary patterns characterized by consumption of plant- or animal-based foods. African Americans, who tend to have poorer nutrient profiles and dietary behaviors, have different metabolic and epigenetic signatures from Caucasians. Thus, these differences could be partly explained by diet. Secondary polyphenol and other plant-derived metabolites may prevent inflammation, while oxidative and energy-related metabolites that accumulate with consumption of animal-based foods may promote chronic inflammation. These different metabolite profiles may be characterized by opposing global or gene-specific alterations in methylation that influence genome stability and expression of cancer-relevant genes. Methyl-donating metabolites (folate, choline, and methionine) associated with a wide variety of foods influence cancer, but findings have not been consistent. It is plausible that the precise methylation activity of methyl donor and other metabolites is largely dependent on inflammatory status, which itself has been found to regulate methylation, and is defined by dietary pattern. Using blood samples from vegetarians and omnivores in the AHS-2 cohort, specific aims will examine the independent influences of dietary pattern and race on plasma metabolites and gene methylation, and determine if the effect of dietary patterns on these biomarker profiles is different in African Americans relative to Caucasians. In addition, correlations between a priori candidate, diet-associated metabolites and genes relevant to inflammation and cancer will be examined. The proposed project will provide new training in molecular epidemiology, genomics, and health disparities research. Activities for training include workshops, conferences, short courses, and seminars, along with grant writing classes and working groups. Research will be facilitated by the expertise of mentors experienced in experimental nutrition and metabolomics, statistical methodology and epidemiology, and cancer biology and health disparities, in conjunction with collaborating scientists with additional expertise in bioinformatics and epigenetics.