PhD studentship: mining large international genetic datasets to identify new therapeutic targets in giant cell arteritis through innovative genetic methodology
Giant cell arteritis (GCA) is the commonest primary systemic vasculitis, occurring exclusively after 50 years of age. Irreversible ischaemic complications, including blindness, occur in 19% of UK patients, despite prompt treatment. Ongoing vascular inflammation in the extracranial and large vessels leads to late vascular stenoses and has a 17 fold increased incidence of thoracic aortic aneurysms. Most patients commence glucocorticoid monotherapy and there is a high relapse rate with 50% remaining glucocorticoid dependent 2-3 years later. This is in marked contrast with other systemic inflammatory disorders where early immunosuppressive therapy leads to improved patient outcomes and reduced tissue damage.
We hypothesise that major pathogenic pathways active in GCA can be identified through the analysis of polygenic risk scores and protein quantitative trait loci (pQTL) derived from relevant immunological, vascular or tissue remodelling datasets
- Well-phenotyped GCA cohorts with genome-wide genotypic data, histological data and associated sample collections for proteomic analysis will be used, combined with publicly accessible data of traits related to immune and vascular function and matrix turnover
- In conjunction with the SCALLOP Consortium, pQTL and polygenic scores for selected immunological, vascular, tissue remodelling and clinical traits will be derived
- The influence of these loci and scores on disease susceptibility, selected clinical and histological phenotypes and outcome in GCA and thoracic aortic aneurysm cohorts will be analysed
- Genetic data and plasma protein data will be combined and measured on a subset of GCA patients to identify clinical subtypes and examine associations with outcome in GCA
- Opportunities for the therapeutic targeting of key pathogenic pathways associated with GCA or selected phenotypic subgroups (ischaemic complications, thoracic aortic aneurysms) using computational biology and pharmacological compound profiling tools will be explored
You will join existing MRC and EU-funded international programmes of research.
- Professor Ann Morgan is a practicing clinician and the PI of the MRC TARGET (Treatment According to Response in Giant cEll arteritis) Partnership. This TARGET research network holds regular project meetings and an annual scientific meeting where you would be invited to present.
- Professor Jenny Barrett is a statistical geneticist; she runs an MSc module in genetic epidemiology at the University of Leeds, which is frequently taken as a training module by PhD students.
- Dr Anders Mälarstig (Associate Researcher, Karolinska Institute, Sweden) is the PI of the EU-funded SCALLOP Consortium. Furthermore, he is the Director of Human Genetics and Computational Biomedicine at Pfizer Research & Development, bringing unique insights into drug target selection and validation from the Pharmaceutical Industry.
The Leeds-based supervisors have recently been awarded a EU Horizon 2020 Innovative Training Network in vasculitis (HELICAL) that will commence for 4 years in 2019, comprising 16 PhD students across Europe. A proportion of the ITN training will be delivered by teams in Leeds and will be available to the student.
The student will also have the opportunity to work with international collaborators in the SCALLOP consortium during a placement at the Karolinska Institute and will also have an opportunity to visit our industrial collaborator Olink, in Upsala, Sweden. We will also explore a placement in Pfizer.
To apply for this post, please follow this link.