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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.

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