TY - JOUR
T1 - A Non-Synonymous Coding Variant (L616F) in the TLR5 Gene Is Potentially Associated with Crohn's Disease and Influences Responses to Bacterial Flagellin
AU - Sheridan, Jared
AU - Mack, David R.
AU - Amre, Devendra K.
AU - Israel, David M.
AU - Cherkasov, Artem
AU - Li, Huifang
AU - Grimard, Guy
AU - Steiner, Theodore S.
PY - 2013/4/11
Y1 - 2013/4/11
N2 - 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.
AB - 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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U2 - 10.1371/journal.pone.0061326
DO - 10.1371/journal.pone.0061326
M3 - Article
C2 - 23593463
AN - SCOPUS:84876098777
SN - 1932-6203
VL - 8
JO - PloS one
JF - PloS one
IS - 4
M1 - e61326
ER -