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

描述(申请人提供)：这项K99/R00提案的目标是为申请人建立一个有指导和独立的研究计划，全面调查维生素D在女性和男性高血压发展中的营养、生化和遗传基础。寻找新的策略来预防高血压，这是美国最常见的慢性病，对公共卫生至关重要。越来越多的证据表明，维生素D是一种很有前途的预防高血压的营养剂。然而，维生素D与高血压相关的流行病学研究仍然有限。很少有前瞻性研究考察基线循环25(OH)-维生素D(25(OH)D)--维生素D状态的生化标记物--与随后发展为高血压的风险之间的关系。到目前为止，遗传流行病学研究只测试了维生素D受体(VDR)基因的少数几个多态性，该基因是维生素D途径中的许多基因，与血压(BP)或高血压有关。此外，循环中的维生素D和维生素D途径基因多态性对高血压风险的潜在交互作用在很大程度上还没有被探索。因此，我们将在两个较大的前瞻性队列中调查这些相关性：妇女健康研究和医生健康研究。该奖项的申请者在心血管疾病(CVD)流行病学方面拥有坚实的教育和培训背景，并拥有丰富的研究、设施和合作资源。申请者目前的目标是提高她在遗传流行病学研究方面的知识和技能。她的长期目标是成为一名独立的流行病学家，研究与高血压和其他心血管疾病相关结果中营养因素的新陈代谢和功能相关的生化和遗传标记。在K99阶段，申请者将通过授课课程、指导性研究、研讨会参与和技能练习，接受有针对性的遗传流行病学培训。申请者还将进行与血压和高血压相关的血浆25(OH)D和维生素D途径的遗传变异(候选基因包括VDR、CYP27B1、CYP24A1、GC、RXRA、RXRB和RXRG)的初步分析。在R00阶段，申请者将进一步将她的研究扩展到两个专门设计的高血压嵌套病例对照研究，评估基线血浆25(OH)D与随后的高血压风险之间的预期关联，调查潜在的机制，以及探索潜在的基因-生物标记物相互作用。这项研究的结果将大大提高我们对维生素D在高血压发病中的作用的理解，并有助于优化高血压预防的干预策略。同时，集中的培训和研究将为申请者提供一个独特的机会，将遗传流行病学与她目前在心血管疾病和营养流行病学方面的研究相结合，并极大地促进她的职业发展，成为高血压和心血管疾病发展中的营养、代谢和遗传学的独立研究员。 公共卫生相关性：拟议的研究项目将大大提高我们对维生素D在高血压发展中的作用的理解，有助于识别高危人群和优化干预策略，并为公共卫生建议高血压和其他心血管疾病相关结果的一级预防的最佳维生素D状态提供基础。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The proposed research project will substantially improve our understanding regarding the role of vitamin D in the development of hypertension, help identify high risk population and optimize intervention strategy, and provide basis for public health recommendations on the optimal vitamin D status for primary prevention of hypertension and other cardiovascular disease-related outcomes.