Abstract
Celiac disease is an inflammatory enteropathy caused by intolerance to gluten. Previous linkage studies in the Dutch, Finnish and Hungarian populations have revealed a locus on chromosome 6q21-22 conferring susceptibility to celiac disease. This locus has previously been implicated in susceptibility to other autoimmune diseases such as Crohn's disease and type 1 diabetes. We performed fine mapping on 446 independent individuals with celiac disease and 641 controls of Dutch origin, testing 872 tagging SNPs in a 22 Mb region of chromosome 6. The 12 most promising SNPs were followed up in 2071 individuals from 284 Finnish and 357 Hungarian celiac disease families to identify risk variants in this region. Multiple markers in the region were significantly associated with celiac disease in the Dutch material. Two SNPs, rs9391227 and rs4946111, were significantly associated with celiac disease in the Finnish population. The association to rs9391227 represents the strongest association signal found in the Finnish (P=0.003, OR 0.66) as well as the combined Dutch, Finnish and Hungarian populations (P=3.6 × 10−5, OR 0.76). The rs9391227 is situated downstream of the HECT domain and ankyrin repeat containing, E3 ubiquitin protein ligase 1 (HACE1) gene and is contained within a region of strong linkage disequilibrium enclosing HACE1. Two additional, independent, susceptibility variants in the 6q21-22 region were also found in a meta-analysis of the three populations. The 6q21-22 region was confirmed as a celiac disease susceptibility locus and harbors multiple independent associations, some of which may implicate ubiquitin-pathways in celiac disease susceptibility.
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Acknowledgements
All the study subjects are thanked for participating in the study. We thank the Dutch Celiac Disease Foundation for participating in this study, and H van Someren and F Mulder for clinical database. We thank Wieke HM Verbeek for help in sample collection and Jackie Senior for critical reading of the manuscript. We thank Hanne Ahola and Anne Heimonen for excellent technical assistance and Erzsébet Szathmári, Judit BKovács, Margit Lörincz and Anikó Nagy for their work with the Hungarian families. We thank Carolien de Kovel at UMC Utrecht for providing unpublished data on the population structure of the Dutch cohort. We acknowledge funding from the Coeliac Disease Consortium (an innovative cluster approved by the Netherlands Genomics Initiative and partly funded by the Dutch Government, grant BSIK03009 to CW), the Netherlands Organization for Scientific Research (VICI grant 918.66.620 to CW) and the Dutch Digestive Disease Foundation. This work has been funded by the EU Commission through a Marie Curie Excellence Grant (FP6 contract MEXT-CT-2005-025270 to PS), by the Academy of Finland, the Hungarian Scientific Research Fund (contract OTKA 61868), the University of Helsinki Funds, Biocentrum Helsinki, the Competitive Research Funding of the Tampere University Hospital, and the Foundation of Pediatric Research and the Sigrid Juselius Foundation.
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Einarsdottir, E., Bevova, M., Zhernakova, A. et al. Multiple independent variants in 6q21-22 associated with susceptibility to celiac disease in the Dutch, Finnish and Hungarian populations. Eur J Hum Genet 19, 682–686 (2011). https://doi.org/10.1038/ejhg.2011.2
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DOI: https://doi.org/10.1038/ejhg.2011.2
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