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Genome Wide Association Studies in Ankylosing Spondylitis

Matthew Brown

Paul Wordsworth, Millicent Stone, David Evans.

Ankylosing spondylitis (AS) is a common inflammatory arthritis, affecting 4/1000 white Europeans, which causes pain and stiffness predominantly of the spine, and can lead to inexorable progressive fusion (ankylosis) of the spine and other affected joints. There is a strong genetic component in the risk of developing the condition, with heritability of 97%. The severity of disease is also largely genetically determined, with heritability of disease activity, functional impairment and radiographic disease extent estimated at 51%, 76%, and 62% respectively. Treatment options for the condition are very limited, and there are no treatments yet known to induce remission in the condition, or to significantly retard the progression of joint fusion. There is also currently only limited ability to predict the likely disease course in AS.

Genetic studies of AS in the Wellcome Trust Case Control Consortium have identified two major genes for the disease, IL23R and ARTS1. These findings have rapidly stimulated research into the disease, including development of therapies against IL23 and Th17 cytokines. The association with ARTS1, which encodes a peptidase potentially influencing the repertoire of peptides available for binding to HLA-B27, has informed a novel area of research in AS. It is likely that many other genes involved in the disease have yet to be identified. The success of the preliminary WTCCC studies indicates that AS is a condition in which, like Crohn's disease with which it is aetiopathogenically related, linkage disequilibrium mapping is likely to produce major advances. This study aims to identify further genes directly involved in AS pathogenesis by studying genetic associations with disease-susceptibility and severity.

The main aim of this study is to identify genes that affect the risk of developing AS. The secondary aim is to identify genes involved in severity of AS, with respect to structural damage, spinal fusion, high disease activity levels and functional impairment. We will compare genetic findings in 2000 British Caucasian AS cases, recruited by two centres (Nuffield Orthopaedic Centre, Oxford; Royal National Hospital for Rheumatic Diseases, Bath), with those from previously genotyped healthy controls. AS will be defined according to the modified New York Criteria, which require clinical and x-ray evidence of disease, and are considered the gold standard for diagnosis. The severity of AS will be evaluated using internationally accepted and valid tools. For x-ray damage and fusion we will use the modified Stoke Ankylosing Spondylitis Severity Score; for disease activity and functional impairment we will use the Bath Indices. We will also investigate genetic associations with eye inflammation complicating AS, and age of AS-onset as both of these factors have been associated with worse outcomes in prior studies.