Functional Vitamin D Receptor Gene Variants and Racial/Ethnic Cancer Disparities

描述（由申请人提供）：非裔美国人之间的癌症健康差距正在扩大。维生素D被怀疑在非裔美国人中发病率较高的几种癌症和其他慢性疾病中发挥作用。维生素D的作用是通过维生素D受体（VDR）介导的。VDR通过位于维生素D应答基因启动子区域的维生素D应答元件（VDRE）促进或阻止下游基因信号传导。流行病学研究受到VDR snp未知功能的限制，以及它们与VDRE变异的关系可能因种族/民族而异。流行病学研究的重点是VDR，尽管代谢途径中的其他基因可能也很重要。我们在健康的非裔美国人样本（15%人群患病率）中发现了一种新的多态变异，发生在24-羟化酶的一个VDRE中，24-羟化酶是维生素D的主要分解代谢酶，也是最易诱导vdr的基因。使用凝胶转移试验，我们已经证明这种VDRE多态性消除了VDR结合。可能在其他VDRE基因中也存在未识别的snp。因此，我们提出以下具体目标：1)在维生素D代谢相关基因（VDR、CYP24A1和CYP3A4）启动子区域的维生素D应答元件（VDRE）内部和附近进行SNP发现；2)对VDRE多态性变异单独及与VDR-short和VDR-long多态性变异联合进行分子表征；3)在流行病学上单独表征VDRE多态性变异，并结合VDR-短型和VDR-长型与血清维生素D的关系。我们将检验VDR和VDRE基因型与血清维生素D独立相关的假设，调整年龄、性别、阳光照射、季节、饮食摄入、遗传血统、皮肤反射率（黑色素指数）。通过了解VDR/VDRE遗传变异、遗传祖先和环境因素对血清维生素D水平的独立贡献，本研究将有助于重要的公共卫生工作，以减少维生素D缺乏症和与维生素D相关的健康差异。我们还将推进对基因多态性影响的理解，并通过加强分子生物学家之间的合作，提高流行病学研究的解释力。癌症健康差异和维生素D工作组的生物化学家和流行病学家。职业目标：在跨学科交流的环境中发展一个蓬勃发展的分子流行病学研究项目。威尔逊博士是NCI癌症流行病学和遗传学部门的前博士后研究员，目前是宾夕法尼亚州立大学的终身教职员工。该提案与NIH路线图呼吁跨学科研究团队和NCI优先减少癌症差异和推进分子流行病学的要求是一致的。

DESCRIPTION (provided by applicant): Cancer health disparities among African Americans are increasing. Vitamin D is suspected to play a role in several cancers and other chronic conditions with a higher incidence among African Americans. The actions of vitamin D are mediated through the vitamin D receptor (VDR). VDR acts to promote or prevent downstream gene signaling through vitamin D response elements (VDRE) located in the promoter region of vitamin D-responsive genes. Epidemiologic studies are limited by the unknown function of VDR SNPs, and their relation to variants within VDRE that may differ by race/ethnicity. Epidemiologic research has focused on VDR, although other genes within the metabolic pathway are likely important. We have identified a novel polymorphic variant occurring in one VDRE of 24-hydroxylase, the main catabolic enzyme of vitamin D and most highly VDR-inducible gene in a sample of healthy African Americans (15% population prevalence). Using a gel-shift assay, we have demonstrated that this VDRE polymorphism eliminates VDR binding. It is likely that unidentified SNPs occur in other VDRE genes. Therefore, we propose the following specific aims: 1) Conduct SNP discovery within and near Vitamin D Response Elements (VDRE) located in the promoter region of genes involved in vitamin D metabolism (VDR, CYP24A1 and CYP3A4); 2) Molecularly characterize VDRE polymorphic variants alone and in combination with VDR-short and VDR-long polymorphic variants; and 3) Epidemiologically characterize VDRE polymorphic variants alone and in combination with VDR-short and VDR-long forms in relation to serum vitamin D. We will test the hypothesis that VDR and VDRE genotypes are independently associated with serum vitamin D, adjusting for age, sex, sunlight exposure, season, dietary intake, genetic ancestry, skin reflectance (melanin index). By understanding the independent contribution of VDR/VDRE genetic variants, genetic ancestry, and environmental contributors to serum vitamin D levels, this research will assist important public health efforts to reduce vitamin D deficiency and health disparities related to vitamin D. We will also advance the understanding of the influence of gene polymorphisms and improve the interpretive power of epidemiologic studies by increasing collaborative efforts between molecular biologists, biochemists, and epidemiologists in our Cancer Health Disparities and Vitamin D Working Group. Career Goal: Develop a thriving molecular epidemiologic research program in an environment of strong interdisciplinary exchange. Dr. Wilson is a former post-doctoral research fellow with the NCI Division of Cancer Epidemiology and Genetics and is currently a tenure-track faculty member at Penn State. This proposal is consistent with the NIH Road Map's call for interdisciplinary research teams and NCI priorities to reduce cancer disparities and advance molecular epidemiology.