title: A non-synonymous coding variant (L616F) in the TLR5 gene is potentially associated with Crohn's disease and influences responses to bacterial flagellin.
abstract: OBJECTIVE
  Although numerous studies have implicated TLR5, or its ligands, bacterial flagellins, in the pathogenesis of Crohn's disease (CD), genome-wide association studies (GWAS) have not reported associations with the TLR5 gene. We aimed to examine potential CD-associated TLR5 variants and assess whether they modified inflammatory responses to bacterial flagellins.
  
  
  RESULTS
  A two-stage study was carried out. In stage 1, we genotyped tagging single-nucleotide polymorphisms (tag-SNPs) in the TLR5 gene in a sample of CD cases (<20 years of age, N = 566) and controls (N = 536). Single SNP and haplotype analysis was carried out. In Stage 2, we assessed the functional significance of potential CD-associated variant(s) vis-à-vis effects on the inflammatory response to bacterial flagellin using HEK293T cells. We observed marginal association between a non-synonymous coding SNP rs5744174 (p = 0.05) and CD. Associations between SNP rs851139 that is in high linkage disequilibrium (LD) with SNP rs5744174 were also suggested (p = 0.07). Haplotype analysis revealed that a 3 marker haplotype was significantly associated with CD (p = 0.01). Functional studies showed that the risk allele (616F) (corresponding to the C allele of SNP rs5744174) conferred significantly greater production of CCL20 in response to a range of flagellin doses than the comparator allele (616L).
  
  
  CONCLUSIONS
  Our findings suggest that a non-synonymous coding variation in the TLR5 gene may confer modest susceptibility for CD.
authors.affiliation: Division of Infectious Diseases, Vancouver Hospital and University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jared
authors.initials: J
authors.lastname: Sheridan
authors.forename: David R
authors.initials: DR
authors.lastname: Mack
authors.forename: Devendra K
authors.initials: DK
authors.lastname: Amre
authors.forename: David M
authors.initials: DM
authors.lastname: Israel
authors.forename: Artem
authors.initials: A
authors.lastname: Cherkasov
authors.forename: Huifang
authors.initials: H
authors.lastname: Li
authors.forename: Guy
authors.initials: G
authors.lastname: Grimard
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Steiner
mesh_terms: D002170:Canada; D016022:Case-Control Studies; D054418:Chemokine CCL20 / Q000276:immunology; D003424:Crohn Disease / Q000235:genetics* / Q000276:immunology; D005408:Flagellin / Q000276:immunology*; D055106:Genome-Wide Association Study; D005838:Genotype; D057809:HEK293 Cells; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D051198:Toll-Like Receptor 5 / Q000235:genetics*
chemical_list: C108355:CCL20 protein, human; D054418:Chemokine CCL20; C495346:TLR5 protein, human; D051198:Toll-Like Receptor 5; D005408:Flagellin