Vitamin D metabolism related genetic variations and developmental origins of card

维生素D代谢相关遗传变异及发育起源证

• 批准号: 8127729
• 负责人: Daniel Asmamaw Enquobahrie
• 金额: $ 13.22万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8127729
• 关键词: Academia; Accounting; Address; Adult; Area; Biological Markers; Biomedical Research; Birth Weight; Candidate Disease Gene; Cardiovascular Diseases; Cardiovascular system; Clinical; DNA; Data; Development; Disease; Early Diagnosis; Early treatment; Environment; Epidemiologist; Faculty; Fatty Acids; Funding; Gene Expression; Gene-Modified; Genes; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genotype; Hypertension; Insulin Resistance; Interdisciplinary Study; K-Series Research Career Programs; Lipids; Lipoproteins; Measurement; Mentors; Metabolism; Mothers; Obesity; Pathway interactions; Perinatal; Perinatal Epidemiology; Population Study; Preparation; Prevention; Research; Risk; Risk Factors; Role; Serum; Specimen; Sum; Tissue-Specific Gene Expression; Training; Umbilical Cord Blood; Underrepresented Minority; United States National Institutes of Health; Variant; Vitamin D; Whole Blood; abstracting; career; experience; genetic epidemiology; genetic risk factor; glucose metabolism; novel; nutrition; nutritional epidemiology; obesity risk; offspring; peripheral blood; public health relevance; reproductive epidemiology; response; skills; young adult

DESCRIPTION (provided by applicant): This K01 application is in response to the "Mentored Career Development Award to Promote Faculty Diversity/Re-entry in Biomedical Research" (RFA-HL-10-012). The applicant seeks to develop an inter-disciplinary research career focused on the role of genetic susceptibility and environment in the developmental origins of adult cardiometabolic risk, building directly upon his previous training/experience in cardiovascular, reproductive, perinatal, nutritional and genetic epidemiology. Mounting evidence supports the developmental origins of cardiometabolic risk. Additionally, low vitamin D levels are associated with cardiometabolic risk factors. However, whether variations in vitamin D metabolism related genes and/or variations in genes differentially expressed in offspring with low vitamin D levels, account, in part, for the developmental origins of adult cardiometabolic risk is largely unknown. The applicant will use biologic specimens, clinical and examination data from mother and offspring diads from two well characterized study populations (the NIH funded Jerusalem Perinatal Study and the Omega Study) to examine vitamin D metabolism related genetic variations and cardiometabolic risk. Using tag-SNPs, the applicant will evaluate associations of common variations in a priori identified 5 candidate genes in vitamin D metabolism (LRP2, CUBN, CYP27B1, GC and VDR) with birth weight, and cardiometabolic risk factors, including obesity, insulin resistance, lipids and lipoproteins, and high blood pressure in young adults. In a pilot global whole blood gene expression study, using 1) cord blood and 2) peripheral blood from offspring with high/low vitamin D levels, the applicant will identify a set of novel candidate genes in fatty acid and glucose metabolism pathways related to vitamin D metabolism. The applicant then will examine associations of variations in these novel candidate genes in mothers and offspring with offspring birth weight and cardiometabolic risk in young adults. Secondarily, the applicant will evaluate whether variations in candidate/novel genes modify the associations of 25-hydroxy vitamin D to examine a set of hypothesis involving vitamin D metabolism related genetic risk factors and developmental origins of cardiometabolic risk. The candidate also has developed a mentoring framework with expertise in areas relevant to his research agenda that will help the candidate develop the capabilities needed to make unique contributions by conducting high quality and high impact interdisciplinary research related to gene-environment (nutrition) interactions and developmental origins of cardiometabolic diseases, levels with cardiometabolic risk. In sum, the findings from these studies will allow the candidate to examine a set of hypothesis involving vitamin D metabolism related genetic risk factors and developmental origins of cardiometabolic risk. The candidate also has developed a mentoring framework with expertise in areas relevant to his research agenda that will help the candidate develop the capabilities needed to make unique contributions by conducting high quality and high impact interdisciplinary research related to gene-environment (nutrition) interactions and developmental origins of cardiometabolic diseases. PUBLIC HEALTH RELEVANCE: While associations of adult cardiometabolic risk with low vitamin D levels have been well documented, the role of vitamin D metabolism related genetic variations in developmental origins of cardiometabolic risk is largely unknown. Among mother and offspring pairs of two well characterized studies, using genotyping, biomarker and gene expression measurements, we propose to investigate vitamin D related genetic variations and cardiometabolic risk. Study factors of developmental origins of cardiometabolic risk while the mentoring framework will enhance preparations of an underrepresented minority to become an independent cardiovascular disease epidemiologist in academia with the skills and capabilities to address further the developmental origins of adult cardiometabolic risk. Findings will address and/or generate testable hypothesis involving vitamin D related genetic risk. (End of Abstract)

描述（由申请人提供）：此 K01 申请是为了响应“促进教师多样性/重新进入生物医学研究的指导职业发展奖”(RFA-HL-10-012)。申请人寻求发展跨学科的研究生涯，重点关注遗传易感性和环境在成人心脏代谢风险的发育起源中的作用，直接建立在他之前在心血管、生殖、围产期、营养和遗传流行病学方面的培训/经验的基础上。越来越多的证据支持心脏代谢风险的发育起源。此外，维生素 D 水平低与心脏代谢危险因素有关。然而，维生素 D 代谢相关基因的变化和/或维生素 D 水平低的后代中差异表达的基因的变化是否在一定程度上解释了成人心脏代谢风险的发育起源，目前尚不清楚。申请人将使用来自两个特征明确的研究人群（NIH 资助的耶路撒冷围产期研究和 Omega 研究）的母亲和后代二胎的生物标本、临床和检查数据来检查维生素 D 代谢相关的遗传变异和心脏代谢风险。使用标签-SNP，申请人将评估先验确定的维生素 D 代谢中的 5 个候选基因（LRP2、CUBN、CYP27B1、GC 和 VDR）的常见变异与出生体重和心脏代谢危险因素（包括肥胖、胰岛素抵抗、血脂和脂蛋白以及年轻人高血压）的关联。在一项全球全血基因表达试点研究中，申请人将使用 1) 脐带血和 2) 来自维生素 D 水平高/低的后代的外周血，在与维生素 D 代谢相关的脂肪酸和葡萄糖代谢途径中鉴定出一组新的候选基因。然后，申请人将检查母亲和后代中这些新候选基因的变异与后代出生体重和年轻人心脏代谢风险的关联。其次，申请人将评估候选/新基因的变异是否会改变25-羟基维生素D的关联，以检验涉及维生素D代谢相关遗传风险因素和心脏代谢风险的发育起源的一组假设。候选人还制定了一个指导框架，在与其研究议程相关的领域拥有专业知识，这将帮助候选人发展所需的能力，通过开展与基因-环境（营养）相互作用和心脏代谢疾病的发育起源、心脏代谢风险水平相关的高质量和高影响力的跨学科研究来做出独特的贡献。 总之，这些研究的结果将使候选人能够检验一系列涉及维生素 D 代谢相关遗传风险因素和心脏代谢风险发育起源的假设。候选人还制定了一个指导框架，在与其研究议程相关的领域拥有专业知识，这将帮助候选人发展所需的能力，通过开展与基因-环境（营养）相互作用和心脏代谢疾病的发育起源相关的高质量和高影响力的跨学科研究来做出独特的贡献。 公众健康相关性：虽然成人心脏代谢风险与低维生素 D 水平之间的关联已得到充分证明，但维生素 D 代谢相关的遗传变异在心脏代谢风险发育起源中的作用在很大程度上尚不清楚。在两项特征明确的研究中，我们利用基因分型、生物标志物和基因表达测量，研究了与维生素 D 相关的遗传变异和心脏代谢风险。研究心脏代谢风险的发育起源因素，而指导框架将加强代表性不足的少数群体的准备工作，使其成为学术界独立的心血管疾病流行病学家，拥有进一步解决成人心脏代谢风险的发育起源的技能和能力。研究结果将解决和/或产生涉及维生素 D 相关遗传风险的可检验假设。 （摘要完）