1227 - Evidence of Genetic Overlap Between Ankylosing Spondylitis and Crohn's Disease

Monday, October 19, 2009: 4:45 PM
Auditorium (Pennsylvania Convention Center)
Patrick Danoy, Diamantina Institute, University of Queensland, Brisbane, Queensland, Australia
Presentation Number: 1227

P Danoy1, K Pryce1, J Hadler1, TASC2, M Ward3, M Weisman4, JD Reveille5, BP Wordsworth6, M Stone7, MA Brown1,6.

1Diamantina Institute of Cancer, Immunology and Metabolic Medicine, University of Queensland, AUS. 2The Australo-Anglo-American Spondyloarthritis Consortium (TASC). 3National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, USA. 4Department of Medicine/Rheumatology, Cedars-Sinai Medical Centre, Los Angeles, USA. 5Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, USA. 6Botnar Research Centre, University of Oxford, UK. 7Royal National Hospital for Rheumatic Diseases NHS Foundation Trust and University of Bath, UK.

Purpose: Inflammatory bowel disease (IBD) occurs in ~10% of AS cases and 70% of AS cases have subclinical terminal ileitis. Spondyloarthritis is also common in patients with IBD.  We sought to test whether genes involved in Crohn’s disease (CD) are also associated with ankylosing spondylitis (AS), potentially explaining the co-occurrence of the two conditions.

Method: Using Taqman and Sequenom technologies, we genotyped 1262 US and UK AS cases of white European descent for 37 established CD loci. Because 3 loci were in strong candidates, genes were typed using tagSNPs across all exons.  Control genotypes were obtained from a white European ancestry historical dataset (n=1295, from the 1958 British Birth Cohort, typed by the Wellcome Trust Case Control Consortium), and imputation was carried out using MACH whenever control marker data was unavailable. Statistical analysis was carried out using a Cochran-Armitage test for trend and all associated markers (P<0.1) were genotyped on US and UK cases (n=854) and controls (n=858) for replication on the OpenArray platform (AB).  P-values for the combined analysis are presented.

Results: Out of 62, 26 markers (P<0.1) were taken for genotyping in the 2nd phase and 9 achieved association (P<0.05) in the replication phase with P values ranging from 0.01 to 7.7x10-29 in the combined analysis. Association was confirmed for IL23R (rs11465804, P=1.0x10-4) and MHC (rs3763313, P=7.7x10-29). Outside the MHC, strongest association was detected at chromosome 1q32.1 (rs11584383, P=8.2x10-8), in an intergenic region.  Association was also confirmed for 3 markers in STAT3 (rs6503695, P=5.7x10-3; rs4103200, P=1.1x10-2; rs744166, P=1.5x10-3). Finally, association was identified in both datasets for markers in MST1 (rs3924462, P=2.7x10-3), CDKAL1 (rs6908425, P=1.4x10-3), and LRRK2/MUC19 (rs11175593, P=3.6x10-3).  These associations did not significantly change when AS cases with clinical IBD were excluded.

Conclusion: Evidence has been demonstrated for strong association with an intergenic region on chromosome 1q32.1, and with STAT3. STAT3 is a key gene involved in Th17 lymphocyte differentiation, and further enhances the case for a major role of this T-lymphocyte subset in AS pathogenesis.  Finally these findings suggest a common aetiopathogenesis for AS and CD and further highlight the involvement of common risk variants across multiple diseases.

Keywords: ankylosing spondylitis (AS) and inflammatory bowel disease (IBD)

Disclosure: P. Danoy, None.