Identifying genetic drivers of circulating metabolites associated with cardiac risk in pediatric chronic kidney disease

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PROJECT ABSTRACT Cardiovascular death is the number one cause of mortality for children with chronic kidney disease (CKD) once they reach adulthood. There is limited knowledge of the biochemical pathophysiology of left ventricular hypertrophy (LVH) and ventricular dysfunction (VD), prognostic markers of future adverse cardiac outcomes in pediatric CKD, and a dearth of targeted or preventive interventions. Metabolite associations with cardiac outcomes in children with CKD have been identified through plasma untargeted metabolomic profiling in the Chronic Kidney Disease in Children (CKiD) study. Multi-omics investigations can better elucidate pathomechanism and have to led to significant discoveries; however, studies in pediatric CKD have been limited. This proposal builds upon previous metabolomics work by integrating genotyping data to identify causal gene- metabolite axes with left LVH and VD in pediatric CKD. This work seeks to answer two specific aims, 1) if there is genetic variation associated with circulating metabolite levels that have been previously associated with pediatric CKD cardiovascular outcomes and 2) if circulating metabolite levels have causal effects on LVH and VD in pediatric CKD. Circulating metabolite levels' association with single nucleotide polymorphisms (SNPs) will be assessed through metabolomics-genome wide association studies (mGWAS) analyses. Metabolite causality on LVH and VD pathogenesis will be assessed with bidirectional Mendelian randomization, leverage genotype data as instrument variables. Elucidation of pathophysiology of LVH and VD in pediatric CKD may inform continued research investigations and development of therapeutic targets, aiding in the eventual prevention and treatment of cardiac risk factors in this underexamined population in clinical practice. In addition to the scientific pursuits of this career development award, Dr. Arthur Lee will make significant advances toward developing his career as an independent clinician investigator. Dr. Lee's career goals are to 1) extend the science of his R38 metabolomics work through the integration of genomics data, 2) gain skills in biostatistics by working with genomics data and multi-omics analyses, and 3) to continue receiving mentorship and formalized didactical training in large data-based clinical research. Dr. Lee will meet regularly with his primary mentor and two working groups, and will receive feedback from his mentoring committee quarterly. Dr. Lee will pursue a Masters of Science in Translational Research (MSTR), with a concentration in Bioinformatics, which advances future researchers through didactive coursework, a formal mentorship program, research training, professional skills development program, and guidance towards protocol and grant development. Completion of this K38 research will result in abstract submissions to national conferences and first-author manuscripts for each aim. Altogether, this proposal will serve as a bridge leading to a NIH early career funding proposal, analogous to how the R38 served as a pipeline to this K38 application.