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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.

矿物质代谢异常一直与心血管和骨骼疾病有关，在慢性肾病患者和普通人群中。然而，不知道是否矿物质代谢生物标志物本身代表并发症的因果过程，肾功能如何影响这些过程，以及哪种生物标志物（如果有的话）可能是最有希望的干预靶点。孟德尔随机化（MR）采用遗传变异作为感兴趣暴露的无混淆代理来估计它对结果的因果影响。我们现在已经揭示了与以下疾病密切相关的遗传变异：循环水平的矿物质代谢标志物，并将利用这些发现，在MR的框架内，提高对矿物质代谢标志物在心血管和骨骼疾病中的因果作用的认识。 MR方法的最新发展也可以使我们能够检查相互作用并揭示其异质性。新疗法的治疗效果或功效。MR可以提供关键证据，以优先考虑进一步的研究，临床应用，或者同样重要的是，不鼓励将额外的资源分配给非因果性路径。该应用程序的目标是全面评估矿物之间的因果关系代谢物、肾功能、治疗策略以及心血管疾病的临床和亚临床表型和骨骼疾病。我们将使用基因组数据进行分析，基于孟德尔随机化技术，并将利用公开的全基因组关联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）。利用新的技术和资源，我们将1）评估矿物质代谢产物对心血管和骨骼疾病的因果作用; 2）研究肾功能在这些关联中的相互作用;以及3）评估常用处方的可能影响药物和潜在的药物靶点对慢性肾脏疾病心血管和骨骼事件的影响。在一起，这些互补的方法将提高对与矿物质代谢有关的病理学的理解干扰，并将提供一个启动点，为确定新的药物和疗法，以防止心血管和骨骼疾病。