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

Discipline of Nutrition, The University of Auckland, Auckland, New Zealand.
Human immunology (Impact Factor: 2.28). 02/2012; 73(4):416-20. DOI: 10.1016/j.humimm.2012.01.015
Source: PubMed

ABSTRACT Toll-like receptors (TLRs) play an important role in the induction and regulation of the innate immune system and have been implicated in both infectious and inflammatory diseases. Recently the first association of TLR10 with Crohn's disease (CD) was reported. Here, we attempted to validate this association, using a candidate gene single nucleotide polymorphism (SNP) study of TLR10 in CD. We identified tagging SNPs, and genotyped these SNPs in a Caucasian New Zealand dataset consisting of 406 CD patients and 638 controls. In this sample, we were able to demonstrate an association between CD and several different TLR10 SNPs and haplotypes. Phenotypic analysis showed an association with early age at first diagnosis, inflammatory and ileocolonic CD behavior, requirement of bowel resection, and extra intestinal manifestations. This study provides evidence to suggest that genetic variation in TLR10 plays a role in interindividual differences in CD susceptibility and clinical outcome.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Toll-like receptors (TLRs) play key roles in innate immune recognition of pathogen-associated molecular patterns of invading microbes. Among the 10 TLR family members identified in humans, TLR10 remains an orphan receptor without known agonist or function. TLR10 is a pseudogene in mice and mouse models are noninformative in this regard. Using influenza virus infection in primary human peripheral blood monocyte-derived macrophages and a human monocytic cell line, we now provide previously unidentified evidence that TLR10 plays a role in innate immune responses following viral infection. Influenza virus infection increased TLR10 expression and TLR10 contributed to innate immune sensing of viral infection leading to cytokine induction, including proinflammatory cytokines and interferons. TLR10 induction is more pronounced following infection with highly pathogenic avian influenza H5N1 virus compared with a low pathogenic H1N1 virus. Induction of TLR10 by virus infection requires active virus replication and de novo protein synthesis. Culture supernatants of virus-infected cells modestly up-regulate TLR10 expression in nonvirus-infected cells. Signaling via TLR10 was activated by the functional RNA-protein complex of influenza virus leading to robust induction of cytokine expression. Taken together, our findings identify TLR10 as an important innate immune sensor of viral infection and its role in innate immune defense and immunopathology following viral and bacterial pathogens deserves attention.
    Proceedings of the National Academy of Sciences 02/2014; DOI:10.1073/pnas.1324266111 · 9.81 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Innate and adaptive immune responses in humans have evolved as protective mechanisms against infectious microorganisms. Toll-like receptors (TLRs) have an important role in the recognition of invading microorganisms. TLRs are the first receptors to detect potential pathogens and to initiate the immune response, and they form the crucial link between the innate and adaptive immune responses. TLRs also have an important role in the pathophysiology of infectious and inflammatory diseases. Increasing data suggest that the ability of certain individuals to respond properly to TLR ligands may be impaired by single-nucleotide polymorphisms (SNPs) within TLR genes, resulting in an altered susceptibility to infectious or inflammatory disease that might contribute to the pathogenesis of complex diseases such as cancer. The associations between diseases and SNPs are in the early stage of discovery. Important clinical insights are emerging, and these polymorphisms provide new understanding of common diseases. This review summarizes and discusses the studies that shed light on the relevance of these polymorphisms in human infectious and inflammatory diseases and cancer.Genes and Immunity advance online publication, 13 March 2014; doi:10.1038/gene.2014.10.
    Genes and immunity 03/2014; DOI:10.1038/gene.2014.10 · 3.79 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Graves' disease (GD) is postulated to be caused by the combined effects of susceptibility genes and environmental triggers. Toll-like receptors (TLRs) play a role in the activation of innate and adaptive immune responses in mammalians. The aim of this study was to evaluate the potential association of polymorphisms in TLR1, TLR6 and TLR10 genes with GD in Chinese Cantonese population. Seven single nucleotide polymorphisms (i.e. rs4833095 and rs5743565 in TLR1; rs5743808 in TLR6; and rs4504265, rs11466655, rs11096957 and rs10856839 in TLR10) were evaluated in 332 GD patients and 351 unrelated controls from Chinese Cantonese population. SNP rs5743565 in TLR1 conferred a protective effect against GD. The minor allele G of rs5743565 decreased the risk of GD in all cases (odds ratio; ORG vs. A = 0.72 (0.58-0.91); p = 0.005; ptrend = 0.004) and early onset patients (ORG vs. A = 0.72 (0.56-0.91); p = 0.007; ptrend = 0.006). This study provided evidence that genetic variation rs5743565 in TLR1 might be associated with the decreased susceptibility of GD.
    Autoimmunity 07/2014; DOI:10.3109/08916934.2014.939269 · 2.75 Impact Factor