Investigating causality between abnormalities of mineral metabolism and kidney, cardiovascular and bone disease

研究矿物质代谢异常与肾脏、心血管和骨骼疾病之间的因果关系

基本信息

批准号：
9978786
负责人：
Cassianne Robinson-Cohen
金额：
$ 38.25万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-16 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9978786
关键词：
25-hydroxyvitamin D Adverse drug effect Adverse event Albuminuria Area Biological Biological Markers Biological Process Bone Density Bone Diseases Calcitriol Calcium Calcium-Sensing Receptors Cardiovascular Diseases Cardiovascular system Chronic Kidney Failure Clinical Complex Coronary Arteriosclerosis DNA Data Development Disease Drug Targeting Etiology Event Fracture General Population Genes Genetic Glomerular Filtration Rate Goals Heart failure Heterogeneity Impairment Individual Intervention Investigation Kidney Diseases Knowledge Lead Left Ventricular Mass Metabolism Methodology Methods Minerals Morbidity - disease rate Observational Study Outcome PTH gene Pathologic Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Phenotype Phosphorus Play Process Proxy Randomized Renal function Research Resource Allocation Resources Role Techniques Tissues Treatment Efficacy Tumor necrosis factor receptor 11b United States Variant Veterans Vitamin D Vitamin D3 Receptor alpha-Fetoproteins base biobank bone bone metabolism cardiovascular risk factor carotid intima-media thickness cinacalcet clinical application clinical phenotype clinically relevant drug candidate drug development epidemiologic data experimental study fibroblast growth factor 23 genetic predictors genetic variant genome wide association study genomic data genomic locus improved interest mortality novel novel therapeutics osteoporosis with pathological fracture phenome pleiotropism prevent programs randomized trial treatment effect treatment strategy

项目摘要

Abnormalities in mineral metabolism have consistently been associated with cardiovascular and bone disease, among individuals with chronic kidney disease and in the general population. However, it is unknown whether mineral metabolism biomarkers themselves represent causal processes for complications, how kidney function impacts these processes, and which biomarker, if any, may be the most promising interventional target. Mendelian Randomization (MR) employs genetic variants as unconfounded proxies of an exposure of interest to estimate its causal effect on an outcome. We have now revealed genetic variants robustly associated with circulating levels of mineral metabolism markers and will employ these findings, within the framework of MR, to advance knowledge of the causal roles of mineral metabolism marker in cardiovascular and bone disease. Recent developments in MR methods can also enable us to examine interactions and uncover heterogeneity of treatment effect or efficacy of new therapies. MR can provide critical evidence to prioritize further research and clinical applications, or just as importantly, to discourage additional resource allocation towards non-causal pathways. The goal of this application is to comprehensively evaluate causal relationships between mineral metabolites, kidney function, treatment strategies and clinical and subclinical phenotypes of cardiovascular and bone disease. We will conduct analyses using genomic data, based on Mendelian Randomization techniques, and will leverage publicly available genome-wide association data and two of the largest practice-based biobanks in the world: Vanderbilt’s BioVU and the Million Veteran Program (MVP). Using novel techniques and resources, we will 1) evaluate the causal effect of mineral metabolites on cardiovascular and bone disease; 2) investigate the interplay of kidney function in these associations; and 3) assess the likely effect of commonly prescribed medications and potential drug targets on cardiovascular and bone events in chronic kidney disease. Together, these complementary approaches will improve understanding of pathologies related to mineral metabolism disturbances and will provide a launch point for the identification of novel drugs and therapies to prevent cardiovascular and bone disease.

矿物代谢异常一直与心血管和骨骼疾病有关，在患有慢性肾脏疾病和普通人群的个体中。但是，未知是否矿物质代谢生物标志物本身代表并发症的毒液过程，肾功能如何影响这些过程，哪种生物标志物（如果有）可能是最有承诺的介入目标。 Mendelian随机分组（MR）员工遗传变异是不受关注的不符代理估计其因果关系对结果的影响。我们现在已经揭示了与循环矿物代谢标志物的水平，并将在MR框架内采用这些发现提前了解矿物质代谢标记在心血管和骨骼疾病中的因果作用。 MR方法的最新发展还可以使我们能够检查相互作用和发现的异质性新疗法的治疗效果或有效性。 MR可以提供关键证据以优先考虑进一步的研究和临床应用，或同样重要的是，以劝阻其他资源分配给非因果途径。该应用的目的是全面评估次要的因果关系心血管的代谢物，肾功能，治疗策略以及临床和亚临床表型和骨骼疾病。我们将基于Mendelian随机化技术使用基因组数据进行分析，并将利用全基因组公开可用的整个基因组协会数据和两个最大的基于实践的生物库世界：范德比尔特的Biovu和百万退伍军人计划（MVP）。使用新颖的技术和资源，我们将1）评估矿物代谢产物对心血管和骨骼疾病的因果影响； 2）调查肾功能在这些关联中的相互作用； 3）评估常规规定的可能影响慢性肾脏疾病中心血管和骨骼事件的药物以及潜在的药物靶标。一起，这些完成方法将提高人们对与密尔代谢相关的病理的理解干扰，将为识别新型药物和疗法提供一个发射点，以防止心血管和骨骼疾病。