Abstract
It is increasingly evident that different inflammatory disorders show some overlap in their pathological features, concurrence in families and individuals, and shared genetic factors. This might also be true for coeliac disease, a chronic inflammatory disorder of the gastrointestinal system, which shares two linkage regions with inflammatory bowel disease: on chromosome 5q31 (CELIAC2 and IBD5) and 19p13 (CELIAC4 and IBD6). We hypothesised that these regions contain genes that contribute to susceptibility to both disorders. The overlapping 5q31 region contains only five positional candidate genes, whereas the overlapping 19p13 region has 141 genes. As the common disease gene probably plays a role in inflammation, we selected five functional candidate genes from the 19p13 region. We studied these 10 positional and functional candidate genes in our Dutch coeliac disease cohort using 44 haplotype tagging single-nucleotide polymorphisms. Two genes from 19p13 showed a small effect on familial clustering: the cytochrome P450 F3 gene CYP4F3 (Pnominal 0.0375, odds ratio (OR) 1.77) and CYP4F2 (Pnominal 0.013, OR 1.33). CYP4F3 and CYP4F2 catalyse the inactivation of leukotriene B4 (LTB4), a potent mediator of inflammation responsible for recruitment and activation of neutrophils. The genetic association of LTB4-regulating gene variants connects the innate immune response of neutrophil mobilisation with that of the established Th1 adaptive immunity present in coeliac disease patients. The findings in coeliac disease need to be replicated. Expanding genetic association studies of these cytochrome genes to other inflammatory conditions should reveal whether their causative influence extends beyond coeliac disease.
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Acknowledgements
We thank all the patients, their physicians, pathologists and the Dutch Coeliac Disease Foundation for participating in this study. We thank Jackie Senior for critically reading the manuscript. This study was supported by grants from the Netherlands Organisation for Scientific Research (Grant 912-02-028), the Dutch Digestive Diseases Foundation (Grants 97-44 and 03-06) and the Coeliac Disease Consortium, an Innovative Cluster approved by the Netherlands Genomics Initiative and partially funded by the Dutch Government (Grant BSIK03009). JDR was supported by grants from the American National Institute of Diabetes and Digestive and Kidney Diseases and the Crohn's and Colitis Foundation of America.
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Curley, C., Monsuur, A., Wapenaar, M. et al. A functional candidate screen for coeliac disease genes. Eur J Hum Genet 14, 1215–1222 (2006). https://doi.org/10.1038/sj.ejhg.5201687
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DOI: https://doi.org/10.1038/sj.ejhg.5201687
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