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dc.contributor.authorHadinnapola, Charaka Mayura Bandara
dc.date.accessioned2019-10-15T10:51:56Z
dc.date.available2019-10-15T10:51:56Z
dc.date.issued2019-10-01
dc.date.submitted2018-09-12
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/297849
dc.description.abstractIdiopathic and heritable pulmonary arterial hypertension (PAH) are rare diseases with a poor prognosis. There is significant heterogeneity in clinical features at diagnosis, and in a proportion of patients there is a genetic cause of the disease. This clinical and genetic heterogeneity has hindered accurate risk stratification and the development of personalised treatments. The National Institute of Health Research BioResource – Rare Diseases PAH Study and the Medical Research Council / British Heart Foundation National Cohort Study of Idiopathic and Heritable PAH were established to investigate disease pathogenesis through whole genome sequencing and deep phenotyping. One thousand and seventy patients were sequenced and 391 clinical variables were captured for each patient. In patients with idiopathic PAH the age at diagnosis, gender, right atrial pressure and the transfer coefficient for carbon monoxide were identified as independent prognostic variables. However, the presence of rare and predicted deleterious variants in BMPR2 was not of prognostic significance. Variants in genes previously associated with disease pathogenesis were identified in 204 patients (19 %). Patients with variants in BMPR2 were younger at diagnosis and had more severe pulmonary haemodynamic impairment compared to patients with idiopathic PAH. Novel associations between BMPR2 variant status and both haemoglobin concentration and white blood cell count were observed. Four patients carried variants in both SMAD9 and either BMPR2 or EIF2AK4. The clinical significance of this requires further study. Unexpectedly, biallelic variants in EIF2AK4 were identified in patients with a clinical diagnosis of idiopathic PAH. These patients had a significantly worse prognosis compared to patients with idiopathic PAH. The spectrum of phenotypic, radiological and histological changes associated with biallelic EIF2AK4 variants was broader than previously recognised. As these datasets mature, further analyses assessing the response to specific treatments and the outcomes of specific subgroups will be possible.
dc.description.sponsorshipNIHR RD TRC
dc.language.isoen
dc.rightsAll rights reserved
dc.rightsAll Rights Reserveden
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved/en
dc.subjectPulmonary arterial hypertension
dc.subjectPulmonary veno-occlusive disease
dc.subjectBMPR2
dc.subjectEIF2AK4
dc.titlePhenotype – genotype associations in a large cohort of patients with pulmonary arterial hypertension
dc.typeThesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnameDoctor of Philosophy (PhD)
dc.publisher.institutionUniversity of Cambridge
dc.publisher.departmentClinical Medicine
dc.date.updated2019-08-06T14:54:28Z
dc.identifier.doi10.17863/CAM.44903
dc.contributor.orcidHadinnapola, Charaka Mayura Bandara [0000-0002-7794-3432]
dc.publisher.collegeSelwyn
dc.type.qualificationtitlePhD in Medicine
cam.supervisorMorrell, Nicholas
cam.supervisorStefan, Graf
cam.supervisor.orcidMorrell, Nicholas [0000-0001-5700-9792]
cam.supervisor.orcidStefan, Graf [0000-0002-1315-8873]
cam.thesis.fundingfalse


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