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

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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.