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: 7906795
• 负责人: Robin Taylor Wilson
• 金额: $ 15.31万
• 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/7906795
• 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; 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; Gene Activation; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; 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 prostate; Maps; Mediating; Melanins; 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; Population; Population Heterogeneity; Population Study; 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; Statistical Models; Stratification; Students; Sun Exposure; 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; 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; working group

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）：非裔美国人之间的癌症健康差距正在增加。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未知功能及其与VDRE内可能因种族/民族而异的变异体的关系的限制。流行病学研究主要集中在VDR上，尽管代谢途径中的其他基因可能也很重要。我们已经确定了一种新的多态性变异发生在一个VDRE的24-羟化酶，维生素D的主要分解代谢酶和最高度的VDR诱导基因的健康非洲裔美国人的样本（15%的人口患病率）。使用凝胶迁移试验，我们已经证明，这种VDRE多态性消除VDR结合。可能在其他VDRE基因中存在未识别的SNP。因此，我们提出了以下具体目标：1）在维生素D代谢相关基因启动子区的维生素D反应元件（VDRE）内及其附近进行SNP发现2）分子表征单独的VDRE多态性变体和与VDR-短和VDR-长多态性变体组合的VDRE多态性变体;和3）流行病学上表征单独的VDRE多态性变体以及与VDR-短形式和VDR-长形式组合的VDRE多态性变体与血清维生素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，这项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。我们还将推进基因多态性的影响的理解，并通过增加我们的癌症健康差异和维生素D工作组的分子生物学家，生物化学家和流行病学家之间的合作努力，提高流行病学研究的解释力。职业目标：在强大的跨学科交流环境中发展蓬勃发展的分子流行病学研究计划。Wilson博士曾是NCI癌症流行病学和遗传学部门的博士后研究员，目前是宾夕法尼亚州立大学的终身教职员工。这一建议与NIH路线图呼吁跨学科研究团队和NCI优先考虑减少癌症差异和推进分子流行病学的要求一致。

项目成果

Ancestry-Adjusted Vitamin D Metabolite Concentrations in Association With Cytochrome P450 3A Polymorphisms.

祖先调整的维生素 D 代谢物浓度与细胞色素 P450 3A 多态性相关。

• DOI: 10.1093/aje/kwx187
• 发表时间: 2018
• 期刊: American journal of epidemiology
• 影响因子: 5
• 作者: Wilson,RobinTaylor;Masters,LorenD;Barnholtz-Sloan,JillS;Salzberg,AnnaC;Hartman,TerrylJ
• 通讯作者: Hartman,TerrylJ

Vitamin D and family history of hypertension in relation to hypertension status among college students.

• DOI: 10.1038/s41371-021-00577-6
• 发表时间: 2022-09
• 期刊: JOURNAL OF HUMAN HYPERTENSION
• 影响因子: 2.7
• 作者: Cuffee, Yendelela L.;Wang, Ming;Geyer, Nathaniel R.;Saxena, Sangeeta;Akuley, Suzanne;Jones, Lenette;Wilson, Robin Taylor
• 通讯作者: Wilson, Robin Taylor

Lead, calcium uptake, and related genetic variants in association with renal cell carcinoma risk in a cohort of male Finnish smokers.

• DOI: 10.1158/1055-9965.epi-11-0670
• 发表时间: 2012-01
• 期刊: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
• 作者: Southard EB;Roff A;Fortugno T;Richie JP Jr;Kaag M;Chinchilli VM;Virtamo J;Albanes D;Weinstein S;Wilson RT
• 通讯作者: Wilson RT

Genetic and environmental influences on plasma vitamin D binding protein concentrations.

遗传和环境对血浆维生素 D 结合蛋白浓度的影响。

• DOI: 10.1016/j.trsl.2014.08.003
• 发表时间: 2015
• 期刊: Translational research : the journal of laboratory and clinical medicine
• 作者: Wilson,RobinTaylor;BortnerJr,JamesD;Roff,Alanna;Das,Arunangshu;Battaglioli,EricJ;RichieJr,JohnP;Barnholtz-Sloan,Jill;Chinchilli,VernonM;Berg,Arthur;Liu,Guodong;Salzberg,AnnaC;El-Bayoumy,Karam
• 通讯作者: El-Bayoumy,Karam

Genetic Ancestry, Skin Reflectance and Pigmentation Genotypes in Association with Serum Vitamin D Metabolite Balance.

与血清维生素 D 代谢平衡相关的遗传祖先、皮肤反射率和色素沉着基因型。

• DOI: 10.1515/hmbci.2011.021
• 发表时间: 2011
• 期刊: Hormone molecular biology and clinical investigation
• 影响因子: 1
• 作者: Wilson,RobinTaylor;Roff,AlannaN;Dai,PJenny;Fortugno,Tracey;Douds,Jonathan;Chen,Gang;Grove,GaryL;Nikiforova,SheilaOngeri;Barnholtz-Sloan,Jill;Frudakis,Tony;Chinchilli,VernonM;Hartman,TerrylJ;Demers,LaurenceM;Shriver,Mark
• 通讯作者: Shriver,Mark