Vitamin D related genes and developmental origins of cardiometabolic risk

描述(申请人提供)：此K01申请书是对“促进教师多元化/重返生物医学研究的导师职业发展奖”(RFA-HL-10-012)的回应。申请人寻求发展一个跨学科的研究生涯，侧重于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，直接基于他以前在心血管、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，维生素D水平低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水平低的后代差异表达的基因变异是否在一定程度上解释了成人心脏代谢风险的发育起源，在很大程度上尚不清楚。申请者将使用来自两个具有良好特征的研究人群(NIH资助的耶路撒冷围产期研究和Omega研究)的母子双胞胎的生物标本、临床和检查数据来检查与维生素D代谢相关的遗传变异和心脏代谢风险。申请者将使用Tag-SNPs评估先验确定的维生素D代谢5个候选基因(LRP2、CUBN、CYP27B1、GC和VDR)的常见变异与出生体重、心脏代谢风险因素(包括肥胖、胰岛素抵抗、脂蛋白和脂蛋白以及年轻人高血压)的相关性。在一项试验性的全球全血基因表达研究中，申请人将使用1)脐带血和2)维生素D水平高/低的后代的外周血，确定一组与维生素D代谢相关的脂肪酸和葡萄糖代谢途径的新候选基因。然后，申请者将检查这些新的候选基因在母亲和后代中的变异与后代出生体重和年轻人心脏代谢风险的关系。其次，申请者将评估候选/新基因的变异是否改变了25-羟基维生素D的相关性，以检验一组涉及维生素D代谢相关遗传风险因素和心脏代谢风险的发育起源的假说。候选人还建立了一个指导框架，在与他的研究议程相关的领域拥有专业知识，将通过开展与心脏代谢疾病的基因-环境(营养)相互作用和发育起源有关的高质量和高影响的跨学科研究，帮助候选人发展做出独特贡献所需的能力，这些研究涉及心脏代谢风险水平。总而言之，这些研究的结果将使候选人能够检验一套涉及维生素D代谢相关遗传风险因素和心脏代谢风险的发育起源的假说。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，将通过开展与心脏代谢性疾病的基因-环境(营养)相互作用和发育起源相关的高质量和高影响的跨学科研究，帮助候选人发展做出独特贡献所需的能力。 公共卫生相关性：虽然成人心脏代谢风险与低维生素D水平之间的关联已经被很好地记录下来，但与维生素D代谢相关的基因变异在心脏代谢风险的发育起源中的作用在很大程度上是未知的。在两个特征明确的研究中，通过基因分型、生物标记物和基因表达测量，我们建议调查维生素D相关的遗传变异和心脏代谢风险。研究心脏代谢风险发育起源的因素，而指导框架将加强少数人的准备，使其成为学术界独立的心血管疾病流行病学家，具备进一步研究成人心脏代谢风险发育起源的技能和能力。这些发现将解决和/或产生涉及维生素D相关遗传风险的可检验假说。(摘要结束)

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)