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

功能性维生素 D 受体基因变异与种族/民族癌症差异

• 批准号: 7385292
• 负责人: Robin Taylor Wilson
• 金额: $ 14.75万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7385292
• 关键词: Address; African; African American; Age; Alleles; American; Amino Acids; Apoptosis; Autoimmune Process; Base Pairing; Binding; Biological Assay; Blood specimen; Bone Density; Breast; CYP3A4 gene; Cancer Patient; Caucasians; Caucasoid Race; Cell Cycle Arrest; Cell Line; Childhood Leukemia; Chronic; Co-Immunoprecipitations; Colon; Colorectal; Complex; Condition; Confidence Intervals; DNA; DNA Binding; Data; Diabetes Mellitus; Diagnosis; Dietary intake; Division of Cancer Epidemiology and Genetics; Electrophoretic Mobility Shift Assay; Environment; Enzymes; Epidemiologic Studies; Epidemiologist; Epitopes; Ethnic Origin; Ethnic group; Etiology; Exons; Faculty; Female; Gel; Genes; Genetic; Genetic Polymorphism; Genetic Population Study; Genetic Variation; Genotype; Genus Cola; Goals; H1299; High Prevalence; Incidence; Initiator Codon; Institutes; Interdisciplinary Study; Investigation; Kidney; Lead; Linkage Disequilibrium; Liver; Lymphocyte; MCF7 cell; Male Adolescents; Malignant Neoplasms; Malignant neoplasm of kidney; Malignant neoplasm of prostate; Maps; Mediating; Melanins; Melanocytic nevus; Messenger RNA; Metabolic Pathway; Metabolism; Minority Groups; Mixed Function Oxygenases; Mole the mammal; Molecular; Molecular Epidemiology; Osteocalcin; Participant; Pathway interactions; Patient Self-Report; Phenotype; Pilot Projects; Plague; Plasmids; Play; Polymerase Chain Reaction; Population; Population Heterogeneity; Positioning Attribute; Postdoctoral Fellow; Prevalence; Process; Promoter Regions; Prostate; Public Health; Publishing; RXR; RXRA gene; Race; Receptor Gene; Recruitment Activity; Renal Cell Carcinoma; Renal carcinoma; Renal pelvis; Reporter; Research; Risk; Robin bird; Role; SEER Program; Sampling; Seasons; Serum; Serum Calcium Level; Signal Transduction; Site; Skin; Source; Standards of Weights and Measures; Statistical Models; Stratification; Students; Sunlight; Techniques; Testing; Transactivation; Transfection; United States; United States National Institutes of Health; Variant; Vertebral column; Vitamin D; Vitamin D Deficiency; Vitamin D Response Element; Vitamin D3 Receptor; Vitamins; Work; aged; cancer health disparity; cancer risk; cancer site; career; case control; design; early onset; gene environment interaction; genetic variant; health disparity; improved; indexing; leukemia; malignant breast neoplasm; member; men; mortality; novel; prevent; programs; protein protein interaction; racial and ethnic; racial/ethnic difference; receptor; receptor binding; restriction enzyme; sex; trend

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.

描述（由申请人提供）：非洲裔美国人的癌症健康差异正在增加。怀疑维生素D在几种癌症和其他慢性病中发挥作用，非洲裔美国人的发生率更高。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响应基因的启动子区域中的维生素D反应元件（VDRE）来促进或预防下游基因信号传导。流行病学研究受VDR SNP的未知功能的限制，它们与VDRE中的变体的关系可能因种族/种族而异。流行病学研究集中在VDR上，尽管代谢途径中的其他基因可能很重要。我们已经确定了一种新型的多态性变体，该变体发生在一个24-羟化酶的VDRE中，这是维生素D的主要分解代谢酶，以及在健康的非裔美国人样本中（人口15％的人口流行）中，这是维生素D的主要分解代谢酶和最高VDR诱导的基因。使用凝胶换档测定法，我们已经证明了这种VDRE多态性消除了VDR结合。其他VDRE基因中可能出现身份不明的SNP。因此，我们提出以下特定目的：1）在维生素D反应元件（VDRE）内和附近进行SNP发现，位于涉及维生素D代谢的基因启动子区域（VDR，CYP24A1和CYP3A4）； 2）单独表征VDRE多态性变体，并与VDR-Short和VDR-Long多态性变体结合使用； 3）流行病学表征了VDRE多态性变体，并与VDR-Short和VDR-Long形式相对于血清维生素D的作用。我们将检验以下假说：VDR和VDRE基因型与血清维生素D独立相关，与年龄，性别，性别，性别，性别，性别，性，季节，饮食，饮食狂热（旋律），crace necentake confection，crace tracky（scrace）调整了年龄，Sunlight Sunlight Sugnake confectect confectect（sunevence confectect）。通过了解VDR/VDR/VDRE遗传变异，遗传血统和对血清维生素D水平的环境贡献者的独立贡献，这项研究将有助于减少与维生素D的维生素D缺乏症和健康差异。我们的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：在强大的跨学科交流环境中制定繁荣的分子流行病学研究计划。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师。该提案与NIH路线图呼吁跨学科研究团队和NCI优先级降低癌症差异并提高分子流行病学一致。