Incorporating intermediate biomarkers of folate with colorectal cancer

描述（由申请人提供）：“将叶酸的中间生物标志物与结直肠癌结合”本提案的目标是测量中间生物标志物，并用统计学方法对其进行评估，旨在阐明结直肠癌的潜在病因机制。该提案利用了结肠癌家族登记处（Colon CFR）开展的现有遗传数据，结肠癌家族登记处是一个由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一个全面的协作基础设施。研究对象包括1531名在FOCM途径基因候选基因研究（RO1CA112237）中分型的对照，以及999名在结肠CFR病例全基因组关联研究（U01CA122839）中分型的对照。在这些受试者中，我们将评估一种碳代谢的血浆测量（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DNA甲基化（PBL））。此外，我们建立在我们以前的工作，在开发统计方法建模遗传关联在假定的疾病途径。这些模型整合了不同层次的数据，如基因型、基因表达、生物标志物和外源暴露，以及先验信息，以建立更全面的统计模型，以便更好地确定遗传效应的优先级、估计和表征。

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.