Abstract
Celiac disease is probably the best-understood immune-related disorder. The disease presents in the small intestine and results from the interplay between multiple genes and gluten, the triggering environmental factor1. Although HLA class II genes explain 40% of the heritable risk, non-HLA genes accounting for most of the familial clustering have not yet been identified. Here we report significant and replicable association (P = 2.1 × 10−6) to a common variant located in intron 28 of the gene myosin IXB (MYO9B), which encodes an unconventional myosin molecule that has a role in actin remodeling of epithelial enterocytes2,3. Individuals homozygous with respect to the at-risk allele have a 2.3-times higher risk of celiac disease (P = 1.55 × 10−5). This result is suggestive of a primary impairment of the intestinal barrier in the etiology of celiac disease, which may explain why immunogenic gluten peptides are able to pass through the epithelial barrier.
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Acknowledgements
We thank the affected individuals, their physicians and the Dutch Celiac Disease Foundation for participating in this study; C. Gouw, A. Bardoel and H. van Someren for practical assistance and J. Senior for critically reading the manuscript. This study was supported by grants from The Netherlands Organization for Scientific Research, the Dutch Digestive Disease Foundation and the Celiac Disease Consortium.
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Supplementary information
Supplementary Fig. 1
Study design. (PDF 102 kb)
Supplementary Fig. 2
Detailed picture of MYO9B and the location of all the SNPs studied in this region. (PDF 483 kb)
Supplementary Fig. 3
Linkage disequilibrium (LD) plot of the five associated SNPs from the random screen and the one associated SNP from the tag screen showing D' values. (PDF 473 kb)
Supplementary Fig. 4
Detailed picture of MYO9B and the location of all 35 SNPs currently to be found in HapMap in this region. (PDF 739 kb)
Supplementary Table 1
Baseline demographics of the cohorts. (PDF 53 kb)
Supplementary Table 2
Overview of all the random SNPs tested in and around MYO9B, including the details of the tag SNPs used in the comprehensive screen in this region. (PDF 77 kb)
Supplementary Table 3
Comprehensive screen: statistics of the screen and results of the association study on Set 2 supplemented with cases from Set 1, using tag SNPs. (PDF 117 kb)
Supplementary Table 4
Sequence analysis of MYO9B. (PDF 95 kb)
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Monsuur, A., Bakker, P., Alizadeh, B. et al. Myosin IXB variant increases the risk of celiac disease and points toward a primary intestinal barrier defect. Nat Genet 37, 1341–1344 (2005). https://doi.org/10.1038/ng1680
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DOI: https://doi.org/10.1038/ng1680
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