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Haplotypes in the CTLA4 region are associated with coeliac disease in the Irish population

Genes & Immunity volume 7, pages 19–26 (2006)Cite this article

Abstract

Chromosomal region 2q33 encodes the immune regulatory genes, CTLA4, ICOS and CD28, which are involved in regulation of T-cell activity and has been studied as a candidate gene locus in autoimmune diseases, including coeliac disease (CD). We have investigated whether an association exists between this region and CD in the Irish population using a comprehensive analysis for genetic variation. Using a haplotype-tagging approach, this gene cluster was investigated for disease association in a case–control study comprising 394 CD patients and 421 ethnically matched healthy controls. Several SNPs, including CTLA4_CT60, showed association with disease; however, after correction for multiple-testing, CTLA4−658C/T was the only polymorphism found to show significant association with disease when allele, genotype, or carrier status frequency were analysed (carrier status (Allele C), P=0.0016). Haplotype analysis revealed a haplotype incorporating the CD28/CTLA4 and two 5′ ICOS polymorphisms to be significantly associated with disease (patients 24.1%; controls 31.5%; P=0.035), as was a shorter haplotype composed of the CTLA4 markers only (30.9 vs 34.9%; P=0.042). The extended haplotype incorporating CD28/CTLA4 and 5′ ICOS is more strongly associated with disease than haplotypes of individual genes. This suggests a causal variant associated with this haplotype may be associated with disease in this population.

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Acknowledgements

We thank all volunteers who donated samples, Megan Dring (Clinical Medicine and DMMC, Trinity College, Dublin) and Cathal O’Brien (Immunology and DMMC, Trinity College, Dublin) for useful discussion and advice. The financial support of the Higher Education Authority and Hitachi Europe Ltd is gratefully acknowledged. RMM is a Wellcome Trust/HRB Lecturer.

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Authors and Affiliations

  1. Department of Clinical Medicine, Trinity College, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland

    K Brophy, A W Ryan, J M Thornton, N P Kennedy, D Kelleher & R McManus

  2. Dublin Molecular Medicine Centre, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland

    K Brophy, A W Ryan, J M Thornton, C Feighery, D Kelleher & R McManus

  3. Department of Immunology, Trinity College, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland

    M Abuzakouk & C Feighery

  4. The Haughton Institute, St James's Hospital, Dublin, Ireland

    A P Fitzgerald

  5. Department of Clinical Medicine, Trinity College, Trinity Centre for Health Sciences, The Adelaide & Meath Hospital Dublin, Incorporating The National Children's Hospital, Tallaght, Dublin, Ireland

    R M McLoughlin & C O'Morain

  6. Department of Medicine, National University of Ireland, Galway, Ireland

    F M Stevens

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Correspondence to R McManus.

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Brophy, K., Ryan, A., Thornton, J. et al. Haplotypes in the CTLA4 region are associated with coeliac disease in the Irish population. Genes Immun 7, 19–26 (2006). https://doi.org/10.1038/sj.gene.6364265

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