A Non-Synonymous Coding Variant (L616F) in the TLR5 Gene Is Potentially Associated with Crohn's Disease and Influences Responses to Bacterial Flagellin

Jared Sheridan, David R. Mack, Devendra K. Amre, David M. Israel, Artem Cherkasov, Huifang Li, Guy Grimard, Theodore S. Steiner

Research output: Contribution to journalArticle

Abstract

Background and Objectives: 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. Methods and Principal 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.

Original languageEnglish (US)
Article numbere61326
JournalPLoS One
Volume8
Issue number4
DOIs
StatePublished - Apr 11 2013
Externally publishedYes

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Flagellin
flagellin
Crohn disease
Crohn Disease
Genes
Single Nucleotide Polymorphism
Haplotypes
genes
haplotypes
Alleles
alleles
inflammation
Genome-Wide Association Study
Linkage Disequilibrium
linkage disequilibrium
Polymorphism
single nucleotide polymorphism
pathogenesis
Nucleotides
Ligands

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

A Non-Synonymous Coding Variant (L616F) in the TLR5 Gene Is Potentially Associated with Crohn's Disease and Influences Responses to Bacterial Flagellin. / Sheridan, Jared; Mack, David R.; Amre, Devendra K.; Israel, David M.; Cherkasov, Artem; Li, Huifang; Grimard, Guy; Steiner, Theodore S.

In: PLoS One, Vol. 8, No. 4, e61326, 11.04.2013.

Research output: Contribution to journalArticle

Sheridan, Jared ; Mack, David R. ; Amre, Devendra K. ; Israel, David M. ; Cherkasov, Artem ; Li, Huifang ; Grimard, Guy ; Steiner, Theodore S. / A Non-Synonymous Coding Variant (L616F) in the TLR5 Gene Is Potentially Associated with Crohn's Disease and Influences Responses to Bacterial Flagellin. In: PLoS One. 2013 ; Vol. 8, No. 4.
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