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Ena-DATASET-UCAM-GEL-05-07-2017-12:00:41:588-300 - samples

ABSTRACT: Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within genes encoding components of the transforming growth factor-ÃƒÂŸ pathway underlie the majority of heritable forms of PAH. Identifying the missing genetic contribution is challenging, even with genes of large effect size, since it likely involves mutations in genes confined to small numbers of PAH cases. In this study, we performed whole genome sequencing, comparing 1038 PAH index cases to 6385 subjects with other rare diseases. Rare variant analysis identified mutations in novel causal genes, namely ATP13A3, AQP1 and SOX17, and provided independent validation of a critical role for GDF2 in PAH. We detected mutations predicted to be disruptive of function in most, but not all, previously reported PAH genes. Taken together these findings provide new insights into the molecular basis of PAH, and support a central role for endothelial dysregulation in disease pathogenesis.

PROVIDER: EGAD00001003423 | EGA |

REPOSITORIES: EGA

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Project description:Abstract: Right ventricular failure (RVF) remains the leading cause of death in pulmonary arterial hypertension (PAH). We investigated the transcriptomic signature of RVF in hemodynamically well-phenotyped monocrotaline (MCT)-treated, male, Sprague-Dawley rats with severe PAH and decompensated RVF (increased right ventricular (RV) end diastolic volume (EDV), decreased cardiac output (CO), tricuspid annular plane systolic excursion (TAPSE) and ventricular-arterial decoupling). RNA sequencing revealed 2547 differentially regulated transcripts in MCT-RVF RVs. Multiple enriched gene ontology (GO) terms converged on mitochondria/metabolism, fibrosis, inflammation, and angiogenesis. The mitochondrial transcriptomic pathway is the most affected in RVF, with 413 dysregulated genes. Downregulated genes included tfam (−0.45-fold), suggesting impaired mitochondrial biogenesis, Cyp2e1 (−3.8-fold), a monooxygenase which when downregulated increases oxidative stress, dehydrogenase/reductase 7C (Dhrs7c) (−2.8-fold), consistent with excessive autonomic activation, and polypeptide N-acetyl-galactose-aminyl-transferase 13 (Galnt13), a known pulmonary hypertension (PH) biomarker (−2.7-fold). The most up-regulated gene encodes Periostin (Postn; 4.5-fold), a matricellular protein relevant to fibrosis. Other dysregulated genes relevant to fibrosis include latent-transforming growth factor beta-binding protein 2 (Ltbp2), thrombospondin4 (Thbs4). We also identified one dysregulated gene relevant to all disordered transcriptomic pathways, Annexin A1. This anti-inflammatory, phospholipid-binding mediator, is a putative target for therapy in RVF-PAH. Comparison of expression profiles in the MCT-RV with published microarray data from the RV of pulmonary artery-banded mice and humans with bone morphogenetic protein receptor type 2 (BMPR2)-mutations PAH reveals substantial conservation of gene dysregulation, which may facilitate clinical translation of preclinical therapeutic and biomarkers studies. Transcriptomics reveals the molecular fingerprint of RVF to be heavily characterized by mitochondrial dysfunction, fibrosis and inflammation.

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Ena-DATASET-UCAM-GEL-05-07-2017-12:00:41:588-300 - samples

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