Vitamin D Status, Vitamin D Receptor Gene Variants, and Hypertension Risk

本K99/R 00提案的目标是为申请人建立一个指导和独立的研究计划 全面调查维生素D在发育过程中的营养、生化和遗传基础， 女性和男性的高血压。寻找预防高血压的新策略， 慢性病在美国，对公众健康至关重要越来越多的证据表明维生素 维生素D是一种很有前途的预防高血压的营养剂。然而，对维生素D的流行病学研究， 与高血压的关系仍然有限。很少有前瞻性研究考察了 基线循环25（OH）-维生素D（25（OH）D），维生素D状态的生化标志物， 随后发生高血压的风险。迄今为止，遗传流行病学研究只测试了少数几个 在维生素D途径的许多基因中，维生素D受体（VDR）基因的多态性， 与血压（BP）或高血压相关。此外，循环维生素C和维生素E之间的潜在相互作用 维生素D和维生素D途径基因多态性对高血压风险的影响在很大程度上尚未探索。我们将 因此，在两个大型前瞻性队列中调查这些关联：妇女健康研究和 医生的健康研究。该奖项的申请人具有扎实的教育和培训背景， 心血管疾病（CVD）流行病学，并有机会获得丰富的研究，设施和合作 资源申请人目前的目标是提高她在遗传流行病学方面的知识和技能 research.她的长期目标是成为一名独立的流行病学家，研究生物化学 和遗传标记相关的代谢和功能的营养因素的发展， 高血压和其他心血管疾病相关的结果。在K99阶段，申请人将获得 通过教学课程、指导研究、参加研讨会进行遗传流行病学培训， 技能练习。申请方还将对血浆25（OH）D和维生素D的遗传变异进行初步分析。 D途径（候选基因包括VDR、CYP 27 B1、CYP 24 A1、GC、RXRA、RXRB和RXRG） 血压和高血压在R 00阶段，申请人将进一步扩大她的研究，以两个具体的 设计的高血压嵌套病例对照研究，评估基线水平与 血浆25（OH）D和随后的高血压风险，研究潜在的机制，以及 探索潜在的基因-生物标志物相互作用。这项研究的结果将大大提高我们的 了解维生素D在高血压发展中的作用，并帮助优化干预措施 高血压预防策略。与此同时，集中培训和研究将提供 申请人有一个独特的机会，将遗传流行病学与她目前在心血管疾病方面的研究相结合， 营养流行病学，极大地促进了她的职业发展，成为一个独立的调查员， 营养、代谢和遗传在高血压和心血管疾病的发展中的作用。

The goal of this K99/R00 proposal is to build a mentored and independent research program for the applicant to comprehensively investigate the nutritional, biochemical, and genetic basis for vitamin D in the development of hypertension in women and men. Finding novel strategies to prevent hypertension, the most prevalent chronic disease in the U.S., is of critical public health importance. Accumulating evidence suggest that vitamin D is a promising nutritional agent for hypertension prevention. However, epidemiologic studies of vitamin D in relation to hypertension remain limited. Few prospective studies have examined the association between baseline circulating 25(OH)-vitamin D (25(OH)D), the biochemical marker of vitamin D status, and the subsequent risk of developing hypertension. Genetic epidemiologic studies to date have only tested a few polymorphisms in the vitamin D receptor (VDR) gene, among many genes in the vitamin D pathway, for association with blood pressure (BP) or hypertension. Moreover, the potential interaction of circulating vitamin D and vitamin D pathway gene polymorphisms on the risk of hypertension is largely unexplored. We will therefore investigate these associations in two large prospective cohorts: the Women's Health Study and the Physicians' Health Study. The applicant of this award has solid education and training background in cardiovascular disease (CVD) epidemiology and has access to rich research, facilities, and collaboration resources. The current goal of the applicant is to advance her knowledge and skills in genetic epidemiology research. Her long-term goal is to become an independent epidemiologist that investigates the biochemical and genetic markers relevant to the metabolism and functionality of nutritional factors in the development of hypertension and other CVD-related outcomes. During the K99 phase, the applicant will receive focused training in genetic epidemiology through didactic coursework, mentored research, seminars participation, and skill practice. The applicant will also conduct initial analyses of plasma 25(OH)D and genetic variants in vitamin D pathway (candidate genes including VDR, CYP27B1, CYP24A1, GC, RXRA, RXRB, and RXRG) in relation to BP and hypertension. During the R00 phase, the applicant will further extend her research to two specifically designed nested case-control studies of hypertension, assess prospective association between baseline plasma 25(OH)D and subsequent risk of hypertension, investigate the underlying mechanisms, as well as explore the potential gene-biomarker interactions. Findings from this study will substantially improve our understanding on the role of vitamin D in the development of hypertension and help optimize intervention strategy for hypertension prevention. Meanwhile the focused training and research together will offer the applicant a unique opportunity to integrate genetic epidemiology with her current research in CVD and nutritional epidemiology and greatly foster her career development to become an independent investigator on nutrition, metabolism, and genetics in the development of hypertension and CVD.