title: Myosin IXB variant increases the risk of celiac disease and points toward a primary intestinal barrier defect.
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 factor. 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 x 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. Individuals homozygous with respect to the at-risk allele have a 2.3-times higher risk of celiac disease (P = 1.55 x 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.
authors.affiliation: Complex Genetics Section, DBG-Department of Medical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
authors.forename: Alienke J
authors.initials: AJ
authors.lastname: Monsuur
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.forename: Behrooz Z
authors.initials: BZ
authors.lastname: Alizadeh
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zhernakova
authors.forename: Marianna R
authors.initials: MR
authors.lastname: Bevova
authors.forename: Eric
authors.initials: E
authors.lastname: Strengman
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.forename: Ruben
authors.initials: R
authors.lastname: van't Slot
authors.forename: Martine J
authors.initials: MJ
authors.lastname: van Belzen
authors.forename: Ineke C M
authors.initials: IC
authors.lastname: Lavrijsen
authors.forename: Begoña
authors.initials: B
authors.lastname: Diosdado
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: Chris J J
authors.initials: CJ
authors.lastname: Mulder
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Mearin
authors.forename: Jos W R
authors.initials: JW
authors.lastname: Meijer
authors.forename: Gerrit A
authors.initials: GA
authors.lastname: Meijer
authors.forename: Erica
authors.initials: E
authors.lastname: van Oort
authors.forename: Martin C
authors.initials: MC
authors.lastname: Wapenaar
authors.forename: Bobby P C
authors.initials: BP
authors.lastname: Koeleman
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
mesh_terms: D000595:Amino Acid Sequence; D002446:Celiac Disease / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007421:Intestine, Small / Q000503:physiopathology; D007438:Introns / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D009218:Myosins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: C113469:myosin IXB; D009218:Myosins