Incorporating intermediate biomarkers of folate with colorectal cancer

描述（由申请人提供）：“阐明叶酸与结肠直肠癌的中间生物标志物”该提案的目标是测量中间生物标志物，并用设计用于阐明结肠直肠癌的潜在病因机制的统计方法评价这些生物标志物。该提案利用了结肠癌家族登记处（Colon CFR）内进行的研究的现有遗传数据，该登记处是一个由NCI支持的联盟，成立于1997年，致力于为结直肠癌遗传学和遗传流行病学的跨学科研究建立全面的合作基础设施。受试者包括在FOCM途径基因（RO 1CA 112237）的候选基因研究中基因分型的1,531名对照，以及在结肠CFR病例的全基因组关联研究（U 01 CA 122839）中基因分型的999名对照。在这些受试者中，我们将评价单碳代谢内的血浆指标（血浆叶酸、维生素B2、B6、B12、蛋氨酸、甲基丙二酸、肌酐、血浆总Hcy（tHcy）和循环淋巴细胞（PBL）中的DNA甲基化）。此外，我们建立在我们以前的工作中开发的统计方法，在假定的疾病途径的遗传关联建模。这些模型将不同水平的数据（例如基因型、基因表达、生物标志物和外源性暴露）与先验信息相结合，以构建更全面的统计模型，从而更好地确定遗传效应的优先级、估计和表征。 公共卫生相关性：本提案的总体目标是进一步深入了解结直肠癌的潜在病因机制。我们将通过首先测量具有来自基于相关候选基因通路和全基因组关联研究（GWAS）的现有基因型数据的受试者中与叶酸相关的一碳代谢相关的中间生物标志物来实现这一点。然后，使用新的统计方法，我们将调查SNP-生物标志物，SNP-疾病和通路-疾病的关联，以提供更多的了解叶酸对结直肠致癌过程的复杂影响。

DESCRIPTION (provided by applicant): "Incorporating intermediate biomarkers of folate with colorectal cancer" The goal of this proposal is to measure intermediate biomarkers and to evaluate these with statistical methods designed to elucidate the underlying etiologic mechanism of colorectal cancer. The proposal leverages existing genetic data from studies conducted within the Colon Cancer Family Registry (Colon CFR), an NCI-supported consortium initiated in 1997 and dedicated to the establishment of a comprehensive collaborative infrastructure for interdisciplinary studies in the genetics and genetic epidemiology of colorectal cancer. The subjects include 1,531 controls genotyped in a candidate gene study of FOCM pathway genes (RO1CA112237), and 999 controls genotyped in a genome wide association study of colon CFR cases (U01CA122839). In these subjects, we will evaluate plasma measures within one carbon metabolism (plasma folate, vitamins B2, B6, B12, methionine, methyl malonic acid, creatinine, plasma total Hcy (tHcy), and DNA methylation in circulating lymphocytes (PBL)). In addition, we build upon our previous work in developing statistical methods for modeling genetic associations in putative disease pathways. These models integrate various levels of data, e.g. genotypes, gene expression, biomarkers, and exogenous exposures, with prior information to build more comprehensive statistical models for better prioritization, estimation, and characterization of genetic effects. PUBLIC HEALTH RELEVANCE: The overall goal of this proposal is to gain further insight into the underlying etiologic mechanism of colorectal cancer. We will accomplish this by first measuring intermediate biomarkers relevant to folate associated one- carbon metabolism in subjects with existing genotype data from a related candidate gene pathway-based and genome-wide association studies (GWAS). Then using novel statistical methods, we will investigate SNP- biomarker, SNP-disease, and pathway-disease associations to provide more insight into the complex effects of folate on the colorectal carcinogenic process.