Genome-Wide Predictors of Plasma Folate and Homocysteine

描述（由申请人提供）： 叶酸和同型半胱氨酸是一碳代谢的重要组成部分。叶酸减少和同型半胱氨酸血浆水平升高与结直肠癌（CRC）和乳腺癌有关，特别是在那些摄入中到高水平酒精的人中，这会干扰一碳代谢。血浆叶酸和血浆同型半胱氨酸的遗传水平的遗传变异不到10%可以解释。因此，我们建议在国家癌症研究所赞助的癌症易感性遗传标记项目中，对1,629名妇女的血浆叶酸和同型半胱氨酸水平的全基因组数据进行具有成本效益的多阶段分析，基于单倍型结构进行250万个SNP插补，并将这些数据与来自国家心肺和血液研究所的FractionalSNP参与者的数据结合联合收割机，健康协会资源研究。这一建议包括对常见遗传变异的系统关联测试，包括已知关联和识别新途径。我们将在960名女性中复制来自初始分析中产生的假设的最高等级SNP的子集，并探索最有希望的SNP与CRC和腺瘤（CRA）风险的关联。作为血浆叶酸和同型半胱氨酸的第一个全基因组关联研究，这些数据将提供一个综合的研究范式，综合全基因组分析方法和代谢谱，为理解基因-营养关系及其与CRC和CRA的潜在关联提供信息平台。我们对血浆叶酸和同型半胱氨酸水平遗传变异的经验表征将为癌症预防策略提供见解，并阐明哪些人群亚群可能因B族维生素代谢或吸收的遗传变异而从额外的叶酸摄入或补充中获益最多。

DESCRIPTION (provided by applicant): Folate and homocysteine are essential components of one-carbon metabolism. Diminished folate and increased homocysteine plasma levels are associated with colorectal cancer (CRC) and breast cancer particularly among those who consume moderate to high levels of alcohol, which interferes with one-carbon metabolism. Less than 10% of the genetic variance in the heritable levels of plasma folate and plasma homocysteine can be explained. Therefore we propose to conduct a cost-effective multistage analysis of genome-wide data on plasma folate and homocysteine levels among 1,629 women in the National Cancer Institute sponsored Cancer Genetic Markers of Susceptibility project, perform 2.5 million SNP imputations based on haplotype structure and combine these data with data from participants in the National Heart Lung and Blood Institute's Framingham SNP-Health Association Resource study. This proposal incorporates systematic association testing of common genetic variation including known associations and identifying novel pathways. We will replicate a subset of the highest-ranking SNPs from the hypotheses generated in the initial analysis in 960 women and explore the most promising SNP associations with risk of CRC and adenoma (CRA). As the first genome-wide association study of plasma folate and homocysteine, these data will provide an integrated research paradigm that synthesizes genome-wide analytic approaches and metabolic profiling to offer an informative platform for understanding gene-nutrient relationships and their potential association with CRC and CRA. Our empirical characterization of genetic variation in plasma levels of folate and homocysteine will provide insight for cancer prevention strategies and elucidate which population subgroups may benefit most from additional folate intake or supplementation due to genetic variation in B-vitamin metabolism or absorption.