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被怀疑在几种癌症和其他慢性病中发挥作用，在非裔美国人中发病率较高。维生素D的作用是通过维生素D受体(VDR)来实现的。VDR通过位于维生素D反应基因启动子区域的维生素D反应元件(VDRE)促进或阻止下游基因信号转导。流行病学研究受到VDR SNPs未知功能的限制，以及它们与VDRE中可能因种族/民族而异的变异的关系。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。我们在一个健康的非裔美国人(15%的人口患病率)样本中发现了一种新的多态变异，发生在24-羟基酶的一个VDRE中，24-羟基酶是维生素D的主要分解代谢酶，也是最高VDR诱导基因。使用凝胶位移分析，我们已经证明了这种VDRE多态消除了VDR结合。可能在其他VDRE基因中也存在未识别的SNPs。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)启动子区的维生素D反应元件(VDRE)内及其附近发现SNP；2)单独研究VDRE的多态变异，并与VDR-Short和VDR-Long的多态变异相结合；3)流行病学研究VDRE基因多态变异与血清维生素D的关系。我们将检验VDR和VDRE基因与血清维生素D独立相关的假设，调整年龄、性别、日照、季节、饮食摄入量、遗传血统、皮肤反射率(黑色素指数)。通过了解VDR/VDRE基因变异、遗传祖先和环境因素对血清维生素D水平的独立贡献，这项研究将有助于重要的公共卫生努力，以减少与维生素D相关的维生素D缺乏和健康差距。我们还将通过加强我们的癌症健康差距和维生素D工作组分子生物学家、生物化学家和流行病学家之间的合作，促进对基因多态影响的理解，并提高流行病学研究的解释力。职业目标：在跨学科交流强烈的环境中发展蓬勃发展的分子流行病学研究项目。威尔逊博士是美国国家癌症研究所癌症流行病学和遗传学分部的前博士后研究员，目前是宾夕法尼亚州立大学终身教职的教员。这一建议与NIH路线图呼吁跨学科研究团队和NCI优先事项一致，以减少癌症差异和推进分子流行病学。

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.