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Bioinformatic and functional characterization of genetic variants associated with autoimmune idiopathic inflammatory myopathy

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  • Full or part time
    Dr H Chinoy
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

About This PhD Project

Project Description

Background:

The idiopathic inflammatory myopathies (IIM) are autoimmune disorders characterized by muscle weakness and inflammatory cell infiltrates in muscle. IIM are caused by a combination of genetic and environmental factors. In adults, IIM are clinically heterogeneous and include several subtypes with different myositis-specific autoantibodies.

Through our UK Myositis Network, we have access to clinical, serological and genetic data from >1,300 IIM cases. A further 90 adult samples have been collected as part of our Myositis Research Tissue Bank, including clinical data, DNA, RNA, peripheral blood mononuclear cells, and muscle biopsy samples.

We reported the first Genomewide Association Study of myositis in dermatomyositis patients, and have recently conducted an Immunochip study on ~3,000 cases. This study has identified several genetic variants associated with IIM, and variants specific to the polymyositis and dermatomyositis subgroups.

Hypothesis:

Genetic variants specifically associated with Polymyositis or Dermatomyositis lead to different myositis clinical subtypes through discrete biological pathways.

Aims:

To characterize the role of specific associated genetic variants in polymyositis and dermatomyositis using bioinformatic and functional approaches, to increase understanding of the underlying molecular mechanisms.

Methods:

A variety of bioinformatic and functional approaches will be employed. Initially, analysis of publically available resources will be carried out. Chromosomal interactions involving associated non-coding DNA and/or gene promoters will be screened for using chromosome conformation capture (3C) approaches. Regulatory elements will be investigated to identify active histone marks as a measure of enhancer activity using ChIP-seq. Variant effects on gene expression will be subsequently investigated in skeletal muscle biopsy samples and stimulated and unstimulated primary cells carrying the associated and non-associated alleles via reporter assays.

Potential Outcomes/impact:

This research will lead to increased understanding of the molecular mechanisms underlying development of the different myositis clinical subtypes, and may have relevance for other autoimmune diseases. This may lead to improved treatment, resulting in better health and improved quality of life for individuals affected with myositis.

Skills training/methods/techniques:

Cross-cutting skills training will be provided through the use of computational methodologies, applied to a medical/health problem through e.g. management, analysis and interpretation of large and complex ‘omic’ data sets.

Additional training opportunities will be provided through close links with the ARUK Centre for Excellence in Epidemiology, through dissemination and presentation of data at national and international conferences and our national, EU and US networks, and through public engagement events, such as Scientific Open Days and Science festivals.


This 4-year full-time studentship forms one of our PhD opportunities within the MRC Doctoral Training Partnership (MRC DTP) scheme. Funding provides full support for tuition fees, annual tax-free stipend at Research Council UK rates (currently £13, 863) and conference/travel allowance. The project is due to commence October 2015 and is open to UK/EU nationals only due to the nature of the funding.

Applicants should hold (or expect to obtain) a minimum upper-second honours degree (or equivalent) in Bioinformatics/Genetics or one of the medical/health sciences. A Masters qualification in a similar area would be an advantage.

Please direct applications in the following format to Dr Hector Chinoy ([Email Address Removed])

• Academic CV
• Official academic transcripts
• Contact details for two suitable referees
• A personal statement (750 words maximum) outlining your suitability for the study, what you hope to achieve from the PhD and your research experience to date.

Any enquiries relating to the project and/or suitability should be directed to Dr Hector Chinoy. Applications are invited up to and including 26 November 2014.

Further details on the MRC DTP scheme, shortlisting/interview process and additional PhD project opportunities can be found on our website: www.mhs.manchester.ac.uk/mrcdtp

http://www.manchester.ac.uk/research/hector.chinoy/

www.mhs.manchester.ac.uk/mrcdtp

http://www.mhs.manchester.ac.uk/postgraduate/mhs-graduate-school/


References

Genotyping of immune-related genetic variants identifies TYK2 as a novel associated locus for idiopathic inflammatory myopathies. Jani M, Massey J, Wedderburn LR, Vencovsky J, Danko K, Lundberg IE, Padyukov L, Selva-O'Callaghan A, Radstake T, Platt H, Warren RB, Griffiths CE, Lee A, Gregersen PK, Miller FW, Ollier WE, Cooper RG, Chinoy H, Lamb JA; and EUMYONET. Ann Rheum Dis. 2014. Sep;73(9):1750-2

Miller F.W., Cooper R.G., Vencovsky J., Rider L.G., Danko K., Wedderburn L.R., Lundberg I.E., Pachman L.M., Reed A.M., Ytterberg S.R., Padyukov L., Selva-O’Callaghan A., Radstake T., Isenberg D.A., Chinoy H., Ollier W.E.R., O’Hanlon T.P., Peng B., Lee A., Lamb J.A., Chen W., Amos C.I., Gregersen P.K., Myositis Genetics Consortium. Genome-wide Association Study of Dermatomyositis Reveals Genetic Overlap with other Autoimmune Disorders. Arthritis Rheum. 2013 Dec;65(12):3239-47
Smith SL, Plant D, Eyre S, Barton A. The potential use of expression profiling: implications for predicting treatment response in rheumatoid arthritis. Ann Rheum Dis. 2013 Jul;72(7):1118-24. Epub 2013 Mar 13. Review.

Eyre S, Bowes J, Diogo D, Lee A, Barton A, Martin P, Zhernakova A, Stahl E, Viatte S, McAllister K, Amos CI, Padyukov L, Toes RE, Huizinga TW, Wijmenga C, Trynka G, Franke L, Westra HJ, Alfredsson L, Hu X, Sandor C, de Bakker PI, Davila S, Khor CC, Heng KK, Andrews R, Edkins S, Hunt SE, Langford C, Symmons D; Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate; Wellcome Trust Case Control Consortium, Concannon P, Onengut-Gumuscu S, Rich SS, Deloukas P, Gonzalez-Gay MA, Rodriguez-Rodriguez L, Ärlsetig L, Martin J, Rantapää-Dahlqvist S, Plenge RM, Raychaudhuri S, Klareskog L, Gregersen PK, Worthington J. High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis.
Nat Genet. 2012 Dec;44(12):1336-40.

Chinoy H., Adimulam, S., Marriage F., New P., Vincze M., Zilahi E., Kapitány A.., Gyetvai A., Ekholm L., Novota P., Remakova M., Charles P., McHugh N.J., Padyukov L., Alfredsson L., Vencovsky J., Lundberg I. E., Danko K., Ollier, W.E., Cooper, R.G. The interaction of HLA-DRB1*03 and smoking for the development of anti-Jo-1 antibodies in adult idiopathic inflammatory myopathies: a European-wide case study. Ann Rheum Dis 2012 Jun;71(6):961-5


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