Vitamin D and colorectal cancer risk: an integrated molecular and genetic epidemiologic study

项目摘要 K99/R 00职业发展奖将为申请人Warren Andersen博士提供研究 经验和培训，以推动她成为一个独立的研究人员在遗传和 分子流行病学，重点是种族，可改变的风险因素和遗传因素之间的相互作用。 癌症风险和结果的决定因素。该研究计划使用孟德尔随机化方法， 评估循环和生物可利用的维生素D水平与降低 结直肠癌风险。孟德尔随机化（MR）方法可用于评估关联 通过使用遗传变异作为工具变量， 暴露。沃伦·安德森博士还将评估维生素D结合蛋白是否会改变这种联系 维生素D和结直肠癌风险之间的关系。该项目将利用三个已建立的 流行病学联盟（结肠直肠跨学科研究（CORECT）联盟，一项结肠直肠癌 非裔美国人和亚洲结直肠癌全基因组关联研究联盟 Consortium）和南方社区队列研究，以评估大样本中的相关性，包括 欧洲人、亚洲人和非洲人后裔。沃伦·安德森博士将创造种族特异性基因 评分代表循环维生素D和维生素D结合蛋白。将进行精细映射， 确定潜在的因果变异，包括在维生素D遗传评分。这些基因分数将 然后评估与总体结直肠癌风险的相关性，并将结直肠癌风险分层 肿瘤的特定特征，如考克斯-2表达、PIK 3CA突变状态和分期。期间 职业发展奖沃伦·安德森博士将获得遗传分析方面的额外技能， 结直肠癌生物学知识和健康差异。该研究项目的结果将是 用于在职业发展奖完成之前开发并提交两个R 01级别的项目。 从这个职业发展奖获得的额外经验将准备博士.沃伦·安德森 癌症遗传和分子流行病学领域的领导者，在结直肠癌方面具有专长 病因学、遗传和癌症流行病学以及疾病风险种族差异的根本原因。这 研究课题意义重大，正如医学研究所2010年的报告所述， 维生素D与总体癌症和特定部位癌症之间的因果关系是一项重要的研究需求。的 MR和分子流行病学方法的使用应该为以下问题提供更明确的答案： 结肠直肠癌风险与循环维生素D、生物可利用维生素D和维生素D的关系 结合蛋白这项研究将提供深入了解结直肠癌病因和潜在的确定亚组 从维生素D补充中获益最多的人。

PROJECT ABSTRACT This K99/R00 Career Development Award will provide the applicant, Dr. Warren Andersen, with the research experience and training to propel her into a career as an independent investigator in the field of genetic and molecular epidemiology with a focus on the interplay between race, modifiable risk factors, and the genetic determinants of cancer risk and outcomes. The research plan uses Mendelian randomization methods to evaluate the hypothesis that circulating and bioavailable vitamin D levels are associated with decreased colorectal cancer risk. Mendelian randomization (MR) methods can be used to evaluate the associations between long-term exposures and diseases by using genetic variants as instrumental variables in place of exposures. Dr. Warren Andersen will also assess whether vitamin D binding protein modifies the association between vitamin D and colorectal cancer risk. The project will leverage resources from three established epidemiologic consortia (the ColoRectal Transdisciplinary Study (CORECT) consortium, a colorectal cancer genome-wide association study consortium among African Americans, and the Asia Colorectal Cancer Consortium) and the Southern Community Cohort Study to evaluate associations in large samples including individuals of European, Asian and African descent. Dr. Warren Andersen will create race-specific genetic scores to represent circulating vitamin D and vitamin D binding protein. Fine-mapping will be conducted to identify potentially causal variants to be included in the vitamin D genetic scores. These genetic scores will then be assessed for associations with overall colorectal cancer risk, and colorectal cancer risk stratified by specific characteristics of the tumor such as COX-2 expression, PIK3CA mutation status, and stage. During the Career Development Award Dr. Warren Andersen will gain additional skills in genetic analysis and increase her knowledge in colorectal cancer biology and health disparities. The findings from this research project will be used to develop and submit two R01 level projects before the completion of the Career Development Award. The additional experience gained from this Career Development Award will prepare Dr. Warren Andersen to be a leader in the field of genetic and molecular epidemiology of cancer, with expertise in colorectal cancer etiology, genetic and cancer epidemiology, and the root causes of racial differences in disease risk. This research topic is of much significance, as the Institute of Medicine's 2010 Report stated, investigation into the causal relationships between vitamin D and total and site-specific cancers is an important research need. The use of MR and molecular epidemiologic methods should provide a more definitive answer to the questions of the relationships of colorectal cancer risk with circulating vitamin D, bioavailable vitamin D and vitamin D binding protein. This study will provide insight into colorectal cancer etiology and potentially identify subgroups of individuals who may benefit the most from vitamin D supplementation.