Dietary Calcium and Magnesium, Genetics, and Colorectal Adenoma

描述（由申请人提供）： 项目摘要：关于钙和镁摄入对结直肠癌和腺瘤的保护作用的结果不一致。我们最近在田纳西州结直肠息肉研究 (TCPS; P50CA95103) 中发现，钙或镁的摄入量与结直肠腺瘤和增生性息肉风险之间的关联可能因 TRPM7 基因常见的 Thr1482Ile 多态性而不同，该基因涉及钙和镁的再（吸收）和体内平衡。我们的发现可能部分解释了先前关于钙和镁的研究的不一致。此外，我们发现，对于腺瘤性息肉和增生性息肉，钙镁摄入量的比例与 Thr1482Ile 多态性显着相互作用。为了响应 PAR-07-377，我们基于我们有希望的数据提出了一项临床流行病学研究，以使用作为 TCPS（一项正在进行的大型结直肠腺瘤分子流行病学病例对照研究）一部分收集的数据和生物样本来测试有关基因-营养相互作用的几个新假设。具体来说，我们将 1）在独立组中确认我们的试点发现； 2) 进行两阶段研究，评估参与镁和钙（再）吸收、调节和平衡的 14 个候选基因的其他多态性与结直肠腺瘤风险之间的关系；并研究钙和镁的摄入量或钙镁摄入量的比例与结直肠腺瘤风险之间的关联是否因14个基因的基因型或单倍型而异。 该研究的第一阶段将包括 1200 个病例和 2400 个对照，以全面研究有希望的多态性及其与营养素的相互作用。所有有希望的变异都将在一组独立的 800 个病例和 1600 个对照中进行重新评估，以验证已确定的关联或营养基因相互作用。拟议的两阶段研究设计将使我们能够有效解决潜在的假阳性结果（I 型错误），这是低外显率遗传因素关联研究中最严重的问题之一，并使我们能够增强评估基因-基因和基因-营养相互作用的统计能力。我们的研究结果将有助于识别结直肠腺瘤的高风险人群，并制定饮食改变或营养强化的个性化策略，以预防结直肠腺瘤的发生，从而预防结直肠癌。在美国普通人群中，每 18 个人中就有 1 人在一生中会患上结直肠癌，40% 的人将在诊断后五年内死亡，这主要是由于诊断已属晚期。因此，制定结直肠癌的一级预防策略非常关键。我们的研究结果将有助于识别结直肠腺瘤的高风险人群，并制定个性化策略，通过饮食改变或营养强化来预防结直肠腺瘤的发生，从而预防结直肠癌。

DESCRIPTION (provided by applicant): Project Summary: Results have been inconsistent on the protective effect of calcium and magensium intake on colorectal cancer and adenoma. We found very recently in the Tennessee Colorectal Polyp Study (TCPS; P50CA95103) that the associations between intake of calcium or magnesium and risk of colorectal adenoma and hyperplastic polyps may differ by the common Thr1482Ile polymorphism of the TRPM7 gene, a gene involved in calcium and magnesium re(absorption) and homeostasis. Our finding may partially explain the inconsistency in previous studies on calcium and magnesium. In addition, we found that the ratio of calcium to magnesium intake significantly interacted with the Thr1482Ile polymorphism in relation to both adenomatous and hyperplastic polyps. In response to PAR-07-377, we propose a clinical epidemiologic study, based on our promising data, to test several novel hypotheses regarding gene-nutrition interactions using data and biological samples collected as part of the TCPS, a large on-going molecular epidemiologic case-control study of colorectal adenoma. Specifically, we will 1) confirm our pilot finding in an independent set; and 2) conduct a two-phase study to evaluate the relationships between other polymorphisms in 14 candidate genes involved in magnesium and calcium (re)absorption, regulation and balance and risk of colorectal adenoma; and investigate whether the associations between intake of calcium and magnesium or the ratio of calcium to magnesium intake and risk of colorectal adenoma differs by the genotypes or haplotypes in the 14 genes. The first phase of the study will include 1200 cases and 2400 controls to comprehensively investigate promising polymorphisms and their interactions with nutrients. All promising variants will be re-evaluated in an independent set of 800 cases and 1600 controls to validate the identified associations or nutrient-gene interactions. The proposed two-phase study design will allow us to effectively address potential false positive findings (Type I error), one of the most serious concerns regarding association studies of low-penetrance genetic factors and will allow us to enhance the statistical power for evaluation of gene-gene and gene-nutrition interactions. The results from our study will help to identify people at a high risk of colorectal adenoma and to develop personalized strategies of dietary changes or nutritional fortication to prevent occurrence of colorectal adenoma, and, thus, colorectal cancer. In the general US population, 1 in 18 individuals will develop colorectal cancer over their lifetime and forty percent will die within five years of diagnosis, mainly due to diagnosis at a late stage. Therefore, development of primary preventive strategies for colorectal cancer is very critical. The results from our study will help to identify people at a high risk of colorectal adenoma and to develop personalized strategies to prevent occurrence of colorectal adenoma, and, thus, colorectal cancer through dietary changes or nutritional fortification.