Periodic Reporting for period 4 - inHForm (Integrative omics of heart failure to inform discovery of novel drug targets and clinical biomarkers)
Periodo di rendicontazione: 2020-10-01 al 2021-03-31
Heart failure is a leading cause of morbidity and mortality in the aging European populations. This condition represents the end-stage of myocardial and valvular disease, arising from loss of viable or functional muscle cells in the heart. Therapy is complicated by the multitude of causes and comorbidities of heart failure. New therapeutic targets and clinical biomarkers to individually tailor therapy (‘precision medicine’) are greatly needed. This research program aims to realize the promise of precision medicine for heart failure by application of an integrated proteomic, genomic and epidemiological approach.
First, the research group has established heritability of several subphenotypes in heart failure, supporting the hypothesis that systematic genetic studies may uncover molecular pathways underlying such subphenotypes. Second, we have conducted genome-wide genotyping in >40 000 subjects from two large population cohorts from Sweden, and conducted genetic analyses of heart failure and related subphenotypes. The research group has further contributed towards the establishment, design and conduct of large, international meta-analyses including multiple cohorts for heart failure, subphenotypes and endophenotypes, identifying dozens of genetic loci with several additional analyses ongoing. Third, mechanisms linking such genetic loci to heart failure have been explored using experimental pipelines which have been established in the laboratory of the principal investigator, and large numbers of human heart tissues have been collected for this purpose. The research group has developed methods to improve resolution of transcriptional profiles of non-cardiomyocyte cells through single-cell sequencing of human heart tissue, which has previously not been possible, and are currently applying such methods in scale to collected hearts, for integration with whole-genome resequencing data which have been generated in the same hearts. Several promising therapeutic targets have been identified. Fourth, large-scale proteomic and metabolomic characterization of plasma has also been undertaken in population-based cohorts and heart failure cases, and identified several promising proteins showing association with heart failure which are currently further being explored in experimental, genetic and transcriptional analyses. The research group has developed an ultrasensitive assay to measure the gene product from one of the identified genetic loci in human plasma. Biomarkers strongly associated with congestion, cardiac hemodynamics and adverse prognosis have been brought forward for evaluation in a precision medicine context in clinical studies, and two such clinical studies are currently ongoing or in preparation. Results have been presented at international conferences and congresses and published in peer reviewed journals.
Our results have provided highly novel insights into plasma proteome and metabolome dynamics in the general population and in relation to heart failure, the genetic determinants of such profiles and of heart failure, and on cellular individuality in the heart and the cell type specific transcriptional regulation of the implicated genes. Several promising therapeutic targets have been identified which will be further studied in experimental models towards application, and clinical studies are ongoing or in planning to evaluate clinical benefits of a precision medicine approach in heart failure, informed by our global plasma profiling experiments.