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Genome Wide Association scan in Ulcerative Colitis: characterizing genetic determinants of susceptibility and disease phenotype

Christopher Mathew

Miles Parkes, Jeffrey Barrett, Jack Satsangi.

The inflammatory bowel diseases, ulcerative colitis and Crohn's disease, are common causes of chronic gastrointestinal disease affecting 400/100 000 of the UK population. Ulcerative colitis is more prevalent in adults (250/100 000) than Crohn's disease and has high morbidity; its effects on growth, education, employment and social wellbeing have lifelong implications. Severe disease has a significant associated mortality.

Indirect and direct costs of healthcare are high. Current therapeutic options are limited and unsatisfactory, aimed at minimizing symptoms and establishing remission rather than cure. Medical therapies, involving corticosteroids and immunosuppressive agents have limited efficacy and appreciable toxicity. The consequence of failure of medical therapy is surgery in the form of colectomy, with associated physical and psychological morbidity.

Advances in patient management will follow directly from progress in understanding disease pathogenesis. Epidemiological data provide clear evidence of a genetic basis to ulcerative colitis. The recent success in identifying genetic determinants in Crohn's disease in the Wellcome Trust Case Control Consortium Study has already produced some insight in to the pathogenesis of ulcerative colitis, and provided the catalyst for the present study.

Epidemiological, clinical, and molecular data provides strong evidence that the inflammatory bowel diseases are related but distinct polygenic disorders. Genome-wide scanning has been successfully applied in Crohn's disease (CD) as part of WTCCC1 by the applicants. A genome-wide association study is now proposed in ulcerative colitis (UC) in the UK population, using a similar design. DNA from 2,000 unrelated UK Caucasian patients has been collected for genotyping, and full phenotypic data are available using strict criteria for diagnosis and sub-phenotyping. Genotypes will be compared with those from 3000 UK population controls. Markers showing strong association will be tested for replication in 2,000 independent cases of UC and 2,000 controls.

Analyses will be carried out in parallel with data available from Crohn's disease and proposed psoriasis and ankylosing spondylitis scans. The study will allow insight into the pathogenesis of ulcerative colitis, its relationship with Crohn's disease, and common pathways involved in chronic inflammatory disorders affecting gut, skin and joints.