Vitamin D related genes and developmental origins of cardiometabolic risk

描述（由申请人提供）：此K 01应用程序是响应“指导职业发展奖，以促进教师多样性/重新进入生物医学研究”（RFA-HL-10-012）。申请人旨在发展一个跨学科的研究生涯，重点是遗传易感性和环境在成人心脏代谢风险的发展起源中的作用，直接建立在他以前在心血管，生殖，围产期，营养和遗传流行病学方面的培训/经验。越来越多的证据支持心脏代谢风险的发育起源。此外，低维生素D水平与心脏代谢风险因素有关。然而，维生素D代谢相关基因的变异和/或维生素D水平低的后代中差异表达的基因的变异是否部分地解释了成人心脏代谢风险的发育起源在很大程度上是未知的。申请方将使用来自两个充分表征的研究人群（NIH资助的耶路撒冷围产期研究和Omega研究）的母亲和后代二联体的生物标本、临床和检查数据，以检查维生素D代谢相关的遗传变异和心脏代谢风险。使用tag-SNP，申请方将评估先验确定的维生素D代谢中的5个候选基因（LRP 2、CUBN、CYP 27 B1、GC和VDR）中的常见变异与出生体重和心脏代谢风险因素（包括肥胖、胰岛素抵抗、脂质和脂蛋白以及年轻人的高血压）的相关性。在一项初步全球全血基因表达研究中，使用1）来自高/低维生素D水平后代的脐带血和2）外周血，申请人将在与维生素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成人心脏代谢风险的关联。其次，申请方将评价候选/新基因的变异是否改变25-羟基维生素D的相关性，以检查一组涉及维生素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。候选人还开发了一个指导框架，在与他的研究议程相关的领域具有专业知识，这将帮助候选人发展所需的能力，通过进行与基因-环境（营养）相互作用和心脏代谢疾病的发展起源相关的高质量和高影响力的跨学科研究，做出独特的贡献，具有心脏代谢风险的水平。 总之，这些研究的结果将允许候选人检查一组假设，涉及维生素D代谢相关的遗传风险因素和心脏代谢风险的发育起源。候选人还开发了一个指导框架，在与他的研究议程相关的领域具有专业知识，这将帮助候选人发展所需的能力，通过进行与基因-环境（营养）相互作用和心脏代谢疾病的发展起源相关的高质量和高影响力的跨学科研究做出独特的贡献。 公共卫生相关性：虽然成人心脏代谢风险与低维生素D水平的相关性已得到充分证明，但维生素D代谢相关的遗传变异在心脏代谢风险的发育起源中的作用在很大程度上尚不清楚。在两个良好表征的研究中，使用基因分型，生物标志物和基因表达测量的母亲和后代对中，我们建议调查维生素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展起源因素，而指导框架将加强代表性不足的少数民族的准备，成为学术界的独立心血管疾病流行病学家，具有进一步解决成人心脏代谢风险的发展起源的技能和能力。研究结果将解决和/或产生涉及维生素D相关遗传风险的可验证假设。(End摘要）

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)