Myosin IXB variant increases the risk of celiac disease and points toward a primary intestinal barrier defect

Alienke J Monsuur¹, Paul I W de Bakker², Behrooz Z Alizadeh¹, Alexandra Zhernakova¹, Marianna R Bevova¹, Eric Strengman¹, Lude Franke¹, Ruben van't Slot¹, Martine J van Belzen^1, 7, Ineke C M Lavrijsen¹, Begoña Diosdado¹, Mark J Daly², Chris J J Mulder³, M Luisa Mearin⁴, Jos W R Meijer⁵, Gerrit A Meijer⁶, Erica van Oort¹, Martin C Wapenaar¹, Bobby P C Koeleman¹ & Cisca Wijmenga¹

¹  Complex Genetics Section, DBG-Department of Medical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.

²  Broad Institute of Harvard and MIT, 320 Charles St., Cambridge, Massachusetts 02141, USA; and Center for Human Genetics Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.

³  Department of Gastroenterology, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.

⁴  Department of Pediatrics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, and VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.

⁵  Department of Pathology, Rijnstate Hospital, P.O. Box 9555, 6800 TA Arnhem, The Netherlands.

⁶  Department of Pathology, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.

⁷  Present address: Laboratory of DNA Diagnostics, Leiden University Medical Center, P.O. Box 9503, 2300 RA Leiden, The Netherlands.

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 enterocytes^{2, 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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