Association of Toll-like receptor 10 and susceptibility to Crohn's disease independent of NOD2

Abstract

Impaired innate inflammatory response has a key role in the Crohn's disease (CD) pathogenesis. The aim of this study was to investigate the possible role of the TLR10-TLR1-TLR6 gene cluster in CD susceptibility. A total of 508 CD patients (284, cohort 1 and 224, cohort 2) and 576 controls were included. TLR10-TLR1-TLR6 cluster single-nucleotide polymorphisms genotyping, NOD2 mutations and TLR10 mRNA quantification were performed using TaqMan assays. Nucleotide-binding oligomerization domain containing 2 (NOD2) and Toll-like receptor (TLR) loci interaction was analyzed by logistic regression and multifactor-dimensionality reduction (MDR). Entropy-based analysis was used to interpret combination effects. One TLR10 haplotype (TLR10 GGGG ) was found associated with CD susceptibility in both cohorts, individuals with two copies had approximately twofold more risk of CD susceptibility than individuals having no copies (odds ratio ¼ 1.89, P-value ¼ 0.0002). No differences in the mRNA levels were observed among the genotypes. The strongest model for predicting CD risk according to the MDR analysis was a two-locus model including NOD2 mutations and TLR10 GGGG haplotype (P c o0.0001). The interaction gain attributed to the combination of both genes was negative (IG ¼ À2.36%), indicating redundancy or independent effects. Our results support association of the TLR10 gene with CD susceptibility. The effect of TLR10 would be independent of NOD2, suggesting different signaling pathways for both genes.

Genetic variation within TLR10 is associated with Crohn's disease in a New Zealand population

“…As such, to confirm the role of TLR10 in CD susceptibility as reported by Abad et al [8], we performed an independent association study in a New Zealand case-control sample set. We were able to demonstrate evidence of association for four individual SNPs and three haplotypes with CD.…”

“…Several studies have reported association of CD susceptibility with TLRs, such as TLR4 [5] and TLR9 [6,7]. Recently the first association of TLR10 with CD was reported [8].…”

Convergent evolution in European and Rroma populations reveals pressure exerted by plague on Toll-like receptors

“…Genetic variation in TLR7 and TLR8 has been shown to protect against viral infections (25), while predisposing some to autoimmune diseases (4). Similarly, TLR1 or TLR10 polymorphisms can protect against infections, while being associated with autoinflammatory diseases such as sarcoidosis (28) and Crohn's disease (29). Although the differences in cytokine production induced by Y. pestis in individuals with various TLR1, TLR6, or TLR10 polymorphisms are moderate from an immunological point of 5 /mL).…”

Gene/environment interactions in the pathogenesis of autoimmunity: New insights on the role of Toll-like receptors

“…An association of TLR10 and susceptibility to CD has been described in two cohorts of 284 and 224 CD patients [193]. Furthermore genetic variations in TLR10 play a role in interindividual differences in CD susceptibility and clinical outcome in a New…”

“…MG [85] nr CD [193]; CD susceptibility and clinical outcome in a New Zealand population [194]. [83]); RA [67]; RA in European Caucasian [135], Korean [136], Tunisian [137] and Japanese populations [138];…”