Dietary Calcium and Magnesium, Genetics, and Colorectal Adenoma

描述(由申请人提供)：项目摘要：关于钙和镁摄取对结直肠癌和腺瘤的保护作用的结果一直不一致。我们最近在田纳西州大肠息肉研究(TCPS；P50CA95103)中发现，钙或镁的摄入与结直肠腺瘤和增生性息肉风险之间的关联可能因TRPM7基因共同的Thr1482Ile多态性而不同，TRPM7基因参与钙和镁的重新吸收和体内平衡。我们的发现可能在一定程度上解释了之前关于钙和镁的研究的不一致。此外，我们发现钙镁摄入量的比例与Thr1482Ile基因多态显著相关，这与腺瘤性息肉和增生性息肉有关。为了响应PAR-07-377，我们提出了一项临床流行病学研究，基于我们有希望的数据，使用作为TCPS的一部分收集的数据和生物样本来验证几个关于基因-营养相互作用的新假说。TCPS是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。具体地说，我们将1)在一个独立的集合中确认我们的初步发现；2)进行一项分两个阶段的研究，以评估14个候选基因中与镁和钙(再)吸收、调节和平衡相关的其他多态与结直肠腺瘤风险之间的关系；并调查14个基因中的不同基因型或单倍型是否与钙和镁的摄入量或钙/镁摄入量的比例与结直肠腺瘤的风险之间的关系不同。第一阶段的研究将包括1200例病例和2400名对照，以全面调查有希望的多态性及其与营养物质的相互作用。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地解决潜在的假阳性发现(类型I错误)，这是对低外显性遗传因素关联研究最严重的问题之一，并将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危人群，并制定个性化的饮食改变或营养强化策略，以预防结直肠腺瘤的发生，从而预防结直肠癌的发生。在普通美国人中，每18个人中就有一个人会在一生中患上结直肠癌，40%的人将在确诊后五年内死亡，主要是由于在晚期确诊。因此，发展结直肠癌的初级预防策略是非常关键的。我们的研究结果将有助于识别结直肠腺瘤的高危人群，并制定个性化的策略，通过改变饮食或营养强化来预防结直肠腺瘤的发生，从而预防结直肠癌的发生。

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.