Characterization and functional investigation of single nucleotide polymorphisms (SNPs) in the human TLR5 gene

Merx, Sabine; Zimmer, Wilma; Neumaier, Michael; Ahmad-Nejad, Parviz

doi:10.1002/humu.9409

Cited by 34 publications

(19 citation statements)

References 15 publications

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“…Because allele T has been shown by our group (Fig. 2) and others (30)(31)(32) to be associated with significantly impaired flagellin responsiveness, we predicted that CF patients carrying the T allele would have improved clinical outcomes due to the endogenous anti-inflammatory effects of this TLR5 variant.…”

Section: Discussionmentioning

confidence: 94%

“…Allele T is found in 6.1% of Canadian CF patients and acts in a dominant fashion with respect to allele C to significantly reduce flagellin responsiveness (30)(31)(32). Consequently, through determining the disease-modifying effects of the TLR5 c.1174C.T SNP, we were able to examine the impact of reduced TLR5 responsiveness on the health of a large cohort of Canadian CF patients.…”

Section: Stopmentioning

confidence: 99%

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TLR5 as an Anti-Inflammatory Target and Modifier Gene in Cystic Fibrosis

Blohmke

Park

Hirschfeld

et al. 2010

The Journal of Immunology

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New treatments are needed to improve the health of people with cystic fibrosis (CF). Reducing lung-damaging inflammation is likely to be beneficial, but specific anti-inflammatory targets have not been identified. By combining cellular immunology with a population-based genetic modifier study, we examined TLR5 as an anti-inflammatory target and modifier gene in CF. Using two pairs of human CF and control airway epithelial cells, we demonstrated that the TLR5–flagellin interaction is a major mediator of inflammation following exposure to Pseudomonas aeruginosa. To validate TLR5 as an anti-inflammatory target, we analyzed the disease modifying effects of the TLR5 c.1174C>T single nucleotide polymorphism (rs5744168) in a large cohort of CF patients (n = 2219). rs5744168 encodes a premature stop codon and the T allele is associated with a 45.5–76.3% reduction in flagellin responsiveness (p < 0.0001). To test the hypothesis that reduced TLR5 responsiveness would be associated with improved health in CF patients, we examined the relationship between rs5744168 and two clinical phenotypes: lung function and body weight. Adults with CF carrying the TLR5 premature stop codon (CT or TT genotype) had a higher body mass index than did CF patients homozygous for the fully functional allele (CC genotype) (p = 0.044); however, similar improvements in lung function associated with the T allele were not statistically significant. Although follow-up studies are needed to confirm the impact of TLR5 on nutritional status, this translational research provides evidence that genetic variation in TLR5 resulting in reduced flagellin responsiveness is associated with improved health indicators in adults with CF.

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Section: Discussionmentioning

confidence: 94%

Section: Stopmentioning

confidence: 99%

TLR5 as an Anti-Inflammatory Target and Modifier Gene in Cystic Fibrosis

Blohmke

Park

Hirschfeld

et al. 2010

The Journal of Immunology

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“…11,21 The TLR4 Asp299Gly variant has been related to hyporesponsiveness to inhaled endotoxins in humans 12,20 and with several infectious and inflammatory conditions. 14,17,9 The TLR5 Arg392Stop variant in the ligand-binding domain abolished flagellin-induced signalling in CHO-K1 cells 57 and was associated with the susceptibility to Legionnaire's disease 15 and systemic Lupus erythematosus. 58 The TLR9 À1237T4C variant was associated with asthma in a European-American study population and in conjunction with the À1486T4C polymorphism differentiates between the most frequent haplotypes.…”

Section: Selection Of Polymorphismsmentioning

confidence: 99%

Gene polymorphisms in Toll-like receptors, interleukin-10, and interleukin-10 receptor alpha and lymphoma risk

et al. 2006

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Interactions between environment and immune system play an essential role in the aetiology of immunopathologies, including lymphomas. Toll-like receptors (TLR) belong to a group of pattern recognition receptors, with importance for innate immune response and inflammatory processes. Interleukin-10 (IL-10) is a key regulatory cytokine and has been implicated in lymphomagenesis. Functional polymorphisms in these inflammation-associated genes may affect the susceptibility towards lymphoma. To test this hypothesis, we have genotyped DNA of 710 lymphoma cases and 710 controls within the context of a population-based epidemiological study for 11 functionally important single-nucleotide polymorphisms in TLR1, À2, À4, À5, À9, IL10 and IL10 receptor (IL10RA). The IL10RA Ser138Gly variant was underrepresented among lymphoma cases (odds ratio (OR) ¼ 0.81, 95 per cent confidence interval (95% CI) ¼ 0.65-1.02), mainly owing to an inverse association with Hodgkin's lymphoma (HL). The TLR2 À16933T4A variant was associated with a 2.8-fold increased risk of follicular lymphoma (95% CI ¼ 1.43-5.59) and a decreased risk of chronic lymphocytic leukaemia (OR ¼ 0.61, 95% CI ¼ 0.38-0.95). Furthermore, the TLR4 Asp299Gly variant was positively associated with the risk of mucosa-associated lymphoid tissue lymphoma (OR ¼ 2.76, 95% CI ¼ 1.12-6.81) and HL (OR ¼ 1.80, 95% CI ¼ 0.99-3.26). In conclusion, this study suggests an effect of polymorphisms in factors of the innate immune response in the aetiology of some lymphoma subtypes.

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“…To date, several studies have demonstrated that some naturally occurring TLR variants enhance the risk of severe infections in humans, mice, and most recently, domestic cattle (23)(24)(25)(26). In addition to the emerging molecular and population-based casecontrol data, bovine health-related quantitative trait loci (QTL) have been localized to genomic regions either proximal to or directly overlapping one or more TLR loci, and at least two healthrelated QTL are proximal to PGLYRP1 (25)(26)(27)(28)(29)(30)(31).…”

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confidence: 99%

Diversity and evolution of 11 innate immune genes in Bos taurus taurus and Bos taurus indicus cattle

Seabury

Seabury²,

Decker³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

100

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The Toll-like receptor (TLR) and peptidoglycan recognition protein 1 (PGLYRP1) genes play key roles in the innate immune systems of mammals. While the TLRs recognize a variety of invading pathogens and induce innate immune responses, PGLYRP1 is directly microbicidal. We used custom allele-specific assays to genotype and validate 220 diallelic variants, including 54 nonsynonymous SNPs in 11 bovine innate immune genes (TLR1-TLR10, PGLYRP1) for 37 cattle breeds. Bayesian haplotype reconstructions and median joining networks revealed haplotype sharing between Bos taurus taurus and Bos taurus indicus breeds at every locus, and we were unable to differentiate between the specialized B. t. taurus beef and dairy breeds, despite an average polymorphism density of one locus per 219 bp. Ninety-nine tagSNPs and one tag insertion-deletion polymorphism were sufficient to predict 100% of the variation at all 11 innate immune loci in both subspecies and their hybrids, whereas 58 tagSNPs captured 100% of the variation at 172 loci in B. t. taurus. PolyPhen and SIFT analyses of nonsynonymous SNPs encoding amino acid replacements indicated that the majority of these substitutions were benign, but up to 31% were expected to potentially impact protein function. Several diversitybased tests provided support for strong purifying selection acting on TLR10 in B. t. taurus cattle. These results will broadly impact efforts related to bovine translational genomics.peptidoglycan recognition protein | bovine translational genomics | bovine Toll-like receptors | single nucleotide polymorphism

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Characterization and functional investigation of single nucleotide polymorphisms (SNPs) in the human TLR5 gene

Cited by 34 publications

References 15 publications

TLR5 as an Anti-Inflammatory Target and Modifier Gene in Cystic Fibrosis

TLR5 as an Anti-Inflammatory Target and Modifier Gene in Cystic Fibrosis

Gene polymorphisms in Toll-like receptors, interleukin-10, and interleukin-10 receptor alpha and lymphoma risk

Diversity and evolution of 11 innate immune genes in Bos taurus taurus and Bos taurus indicus cattle

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