MRC DiMeN Doctoral Training Partnership: 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 50yrs. 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.

Objectives
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 also matrix turnover.

• In conjunction with the SCALLOP Consortium, derive pQTL and polygenic scores for selected immunological, vascular, tissue remodelling and clinical traits
• Analyse the influence of these loci and scores on disease susceptibility, selected clinical and histological phenotypes and outcome in GCA and thoracic aortic aneurysm cohorts
• Combine genetic data with plasma protein data measured on a subset of GCA patients to identify clinical subtypes and examine associations with outcome in GCA
• Explore 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

Training
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.
https://medicinehealth.leeds.ac.uk/medicine/staff/2614/professor-ann-morgan
This TARGET research network holds regular project meetings and an annual scientific meeting where you would be invited to present.
https://lida.leeds.ac.uk/target

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.
https://medicinehealth.leeds.ac.uk/medicine/staff/112/professor-jenny-barrett


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.
www.scallop-consortium.com

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 O’link, in Upsala, Sweden.
https://www.olink.com/
We will also explore a placement in Pfizer.

Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website:
http://www.dimen.org.uk/