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Cell/molecular biology posters 336–351
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336 A GENETIC ANALYSIS OF COELIAC DISEASE

S. Popat, N. Hearle, S. Bevan, G.K.T. Holmes, P.D. Howdle, L. Hogberg, C.P. Braegger, D. O'Donoghue, K. Falth-Magnusson, H. Jenkins, S. Johnston, N.P. Kennedy, P. Kumar, R.F.A. Logan, M.N. Marsh, C.J. Mulder, K. Sjoberg, L. Stenhammar, J.R.F. Walters, D.P. Jewell, R.S. Houlston. Section of Cancer Genetics, Institute of Cancer Research, Sutton, UK

Background and Aims: A genetic susceptibility to coeliac disease is well recognised. Although a strong association is seen between HLA DQ2 and coeliac disease, this does not entirely account for the observed familial risk. In order to assess the contribution of HLA to coeliac disease and to identify non-HLA linked coeliac disease susceptibility genes, 3 complimentary strategies were adopted.

Methods: (1) Allele sharing across HLA was calculated by non-parametric linkage analysis. (2) A genome-wide linkage search for non-HLA linked susceptibility loci was performed on 24 multiplex families using ∼240 microsatellite markers. (3) Analysis of candidate genes was undertaken by linkage, allelic association, and/or direct mutational analysis. Candidate loci tested were TGM2 (encoding tissue transglutaminase) and CTLA4-CD28 (on chromosome 2q33, implicated in a number of autoimmune diseases).

Results: (1) The HLA locus only accounts for ∼40% of the familial risk of coeliac disease. (2) In addition to linkage to HLA, there was evidence of linkage to chromosomes 19p13.3 (p=0.02) and 4p14 (p=0.03). No significant linkage was observed at candidate regions proposed in other reported linkage searches. (3) Mutational analysis of TGM2 did not show any disease causing mutations. Analysis of the CTLA4-CD28 gene region showed evidence for linkage (p=0.004) and association (p=0.039). Pooling these findings with published analyses through a meta-analysis showed significant evidence for linkage (p=0.0008) and association (p=0.0006). Mutational analysis of both CTLA4 and CD28 did not show any disease-causing mutations

Conclusions: Non-HLA gene(s) are likely to be a stronger determinant …

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