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Title: A translational genomics approach to dissect mechanisms of heart failure and recovery
Author: Pesce, Francesco
ISNI:       0000 0004 7656 7599
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Dilated cardiomyopathy (DCM) is a progressive disease of heart muscle leading to end-stage heart failure (HF). In this study I used a novel RNA-Sequencing (RNA-Seq) dataset derived from left ventricle (LV) of a large cohort (n = 126) of patients with this condition. Different bioinformatics approaches were applied to combine data from cases, controls, in vivo and cell-based experimental models of fibrosis, as well as genetic data, in order to investigate pathways underlying end-stage HF in DCM, the potential for recovery and mechanisms resulting from Titin (TTN) truncating mutations in these patients. Multiple and functionally heterogeneous gene co-expression networks (n = 48) were identified in DCM, of which 26 were disease specific. Further prioritization of the networks focused on fibrosis as key process occurring in the LV of these patients. Finally, a Systems Genetics framework was implemented and identified the gene WW Domain Containing E3 Ubiquitin Protein Ligase 2 (WWP2) as a genetic regulator of a disease specific fibrosis-related network. In a second phase, I investigated the differences in the expression profile of DCM patients who received a left ventricular assist device (LVAD) (n = 61) compared to those who underwent elective heart transplant (n = 58). The results showed in the first group a prominence of mechanisms driven by cytokines and the role of a specific pattern of coordinated genes related to contractile function. Analysis of a subset of LVAD implanted patients who subsequently recovered function was limited by sample size. Likewise, testing whether truncating mutations in TTN, the single most common genetic cause of DCM, perturb downstream pathways lacked power. Based on comprehensive and unbiased analyses centered on RNA-Seq, these findings are unique in defining the transcriptional landscape of LV in end-stage HF due to DCM. In particular, Systems Genetics proved to be a useful translational framework having pointed towards WWP2 as novel candidate target gene for fibrosis in these patients.
Supervisor: Barton, Paul ; Cook, Stuart Sponsor: European Union
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral