Integrating urinary and plasma omics to identify markers and therapeutic targets for cardiac disease

IntroductionUrinary breakdown products, representing kidney regulated filtration of metabolism end products, contain cardiac disease biomarkers such as NT-proBNP. We set out to integrate plasma proteins with metabolism pathways, as reflected by urinary breakdown products, to identify potentially druggable metabolism pathways for cardiac disease. MethodsData was leveraged from a genome-wide association study (GWAS) on 954 urinary breakdown products. Mendelian randomisation was used to identify urinary breakdown products associating with atrial fibrillation (AF), heart failure (HF), dilated cardiomyopathy (DCM), or hypertrophic cardiomyopathy (HCM). By interrogating eight independent plasma protein GWAS, jointly including 92,277 participants and 1,562 unique proteins, we identified druggable plasma proteins with a directionally concordant effect on urinary breakdown products and cardiac outcomes. ResultsIn total, 38 unique urinary breakdown products associated with cardiac disease, predominantly covering breakdown products from amino acid metabolism (n=12), xenobiotic metabolism (n=5), and unclassified metabolism origins (n=16). Subsequently, we identified 32 druggable proteins expressed in cardiac tissue, which had a directionally concordant association with the identified urinary breakdown products and cardiac outcomes. This included positive control findings, for example higher values of AT1B2 (targeted by digoxin) decreased the risk of HCM, which we were able to link to a novel unclassified urinary breakdown product (X-15497). Additionally, we showed that increased plasma RET values, a mediator of GDF-15 signalling, reduced the risk of HF, and linked this to the novel unclassified urinary breakdown product X-23776. ConclusionWe have identified amino acid, xenobiotic and unclassified metabolism as important pathways contributing to cardiac disease and prioritised 32 druggable proteins as potential therapeutic targets.