Skip to main content
  • Invited speaker presentation
  • Open access
  • Published:

Patient stratification and genomics: flares, fizzlers and foxes

Diseases have traditionally been defined predominantly by clinical criteria, sometimes with the assistance of “conventional” laboratory data. Recent advances in genomic technology have begun to find previously undiscovered sub-divisions within what were thought to be single diagnoses, sometimes with significant clinical implications. This talk will discuss the potential for such technologies to redefine the classification and treatment of autoimmune diseases, using two recent examples from Cambridge.

The first is the use of a Genome Wide Association Study to determine the genetic underpinning of ANCA-associated Vasculitis (AAV). This study has confirmed a genetic component to AAV pathogenesis, and demonstrated that the AAV clinical syndromes granulomatosis with polyangiitis (GPA: formerly Wegener’s) and microscopic polyangiitis (MPA) are genetically distinct diseases better defined by ANCA specificity for proteinase-3 (PR3) or myeloperoxidase (MPO) rather than clinical syndrome. In addition the response against the autoantigen PR3 (encoded by PRTN3) was found to be a central etiological feature of PR3-ANCA associated vasculitis. Thus PR3- and MPO-ANCA-associated vasculitis must be considered as distinct autoimmune syndromes [1].

The second example will describe the use of whole genome transcriptome analysis of purified CD8 T cells to define two sub-groups within patients with a number of inflammatory diseases (including SLE, AAV, Crohn’s disease and ulcerative colitis). These otherwise “invisible” groups have markedly different long term outcomes [2, 3]. This has implications for therapy, and has led to the development of a biomarker now entering clinical trials. Follow-up studies have led to the discovery of a new inflammatory pathway controlling TNFα and IL-10 production that might drive this difference in outcome.


  1. Lyons PA, Rayner TF, Trivedi S, Holle JU, Watts RA, Jayne DRW, Baslund B, Brenchley P, Bruchfeld A, Chaudhry AN, Cohen Tervaert JW, Deloukas P, Feighery C, Gross WL, Guillevin L, Gunnarsson I, Harper L, Hrušková Z, Little MA, Martorana D, Neumann T, Ohlsson S, Padmanabhan S, Pusey CD, Salama AD, Sanders J-S F, Savage CO, Segelmark M, Stegeman CA, Tesař V, Vaglio A, Wieczorek S, Wilde B, Zwerina J, Rees AJ, Clayton DG, Smith KGC: Genetically distinct subsets within ANCA-associated vasculitis. N Engl J Med. 2012, 367: 214-223. 10.1056/NEJMoa1108735.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. McKinney EF, Lyons PA, Carr EJ, Hollis JL, Jayne DRW, Willcocks LC, Koukoulaki M, Hatton A, MacAry PA, Brazma A, Chaudhry AN, Smith KGC: A CD8+ memory T cell transcription signature predicts prognosis in autoimmune diseases. Nature Medicine. 2010, 16: 586-589. 10.1038/nm.2130.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Lee JC, Lyons PA, McKinney EF, Sowerby JM, Carr EJ, Bredin F, Rickman HM, Ratlamwala H, Hatton A, Rayner TF, Parkes M, Smith KGC: Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis. J Clin Invest. 2011, 121: 4170-4179. 10.1172/JCI59255.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations


Rights and permissions

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and permissions

About this article

Cite this article

Smith, K.G. Patient stratification and genomics: flares, fizzlers and foxes. J Transl Med 10 (Suppl 3), I5 (2012).

Download citation

  • Published:

  • DOI: