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Yang, I.A. et al. Toll-like receptor 4 polymorphism and severity of atopy in asthmatics. Genes Immun. 5, 41−45

Asthma Genetics Laboratory, Division of Human Genetics and Infection, University of Southampton, Southampton, UK.
Genes and Immunity (Impact Factor: 3.79). 01/2004; 5(1):41-5. DOI: 10.1038/sj.gene.6364037
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ABSTRACT Endotoxin exposure may have a protective effect against asthma and atopy. An Asp299Gly polymorphism in the Toll-like receptor 4 (TLR4) gene reduces responsiveness to endotoxin. This study determined the effect of TLR4 polymorphism on the risk and severity of asthma and atopy. In all, 336 UK Caucasian families with > or = 2 affected sibs (physician's diagnosis of asthma and current medication use) and 179 Caucasians without asthma or a family history of asthma were genotyped using ARMS-PCR. No association of the TLR4 polymorphism was found with the risk of developing asthma, either in parent-affected sibling trios, or in case-control analyses (P>0.05). In the first affected asthmatic siblings, the atopy severity score (based on size and number of positive skin-prick tests and specific IgE) was higher in those with the Asp/Gly or Gly/Gly genotypes (mean 1.8, s.d. 1.1, n=39) compared to those with the Asp/Asp genotype (mean 1.2, s.d. 1.0, n=279) (P=0.003, t-test). No associations were found with total IgE, FEV(1) % predicted, slope of FEV(1) response to methacholine or asthma severity score (P>0.05). This study confirms the previously observed lack of association of TLR4 polymorphisms with asthma. In contrast, the findings suggest that genetically determined hyporesponsiveness to endotoxin may increase atopy severity.

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    • "The majority of previous studies have analysed the relationship between asthma and the TLR4 polymorphism, rs4986790. One study of Swedish children reported that rs4986790 was associated with a 4-fold higher prevalence of asthma (36); however, an Egyptian study reported no significant association of this marker with childhood asthma (37), and a further study the British showed no association of rs4986790 with asthma development (38). However, this polymorphism is not informative in some Asian populations. "
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    ABSTRACT: The risk of asthma has been increasing in parallel with use of acetaminophen, which is a potential source of oxidative stress. Toll-like receptor 4 (TLR4) plays a critical role not only in innate immunity, but also in mediating reactive oxygen species induced inflammation. Therefore, we investigated associations between acetaminophen usage and TLR4 polymorphism on asthma and bronchial hyperresponsiveness (BHR). The number of 2,428 elementary school children in Seoul and Jeongeup cities was recruited. Subjects who used acetaminophen with a family history of asthma had an increased risk of both asthma diagnosis ever and current asthma. Individuals with CT+TT genotypes at the TLR4 polymorphism, in combination with acetaminophen usage, also demonstrated an increased risk of asthma diagnosis ever (aOR, 2.08; 95% confidence interval [CI], 1.10-3.92). Family history of asthma and acetaminophen usage were risk factors for BHR. Although TLR4 was not an independent risk factor for BHR, individuals with CT+TT genotypes at the TLR4 polymorphism had an increased risk of BHR when combined with acetaminophen usage (aOR, 1.74; 95% CI, 1.03-2.94). In conclusion, acetaminophen usage may be associated with asthma and BHR in genetically susceptible subjects. This effect may be modified by polymorphism at TLR4. Graphical Abstract
    Journal of Korean Medical Science 05/2014; 29(5):662-8. DOI:10.3346/jkms.2014.29.5.662 · 1.25 Impact Factor
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    • "In a study conducted by Saçkesen et al. on heterozygous Turkish children the TLR4 polymorphism was reported to be related with mild asthma and may protect against severe asthma [13]. On the other hand, other studies have failed to find a correlation between common TLR4 mutations (especially Asp299Gly) and asthma or atopy [8,41,43,44], the severity of asthma may have been a confounding factor in these analyses [41]. Nevertheless TLR4 polymorphism was more closely related to the moderate and severe atopic asthma group than the mild atopic asthma group For the Asp299Gly polymorphism the Asp allele was associated with mild atopic asthma and the Gly allele with moderate and severe asthma [8]. "
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    ABSTRACT: Endotoxins stimulate T helper 1 cell maturation and send a negative signal to T helper 2 polarisation. This causes a decrease IgE levels and prevents atopy (Hygiene hypothesis). It is shown that this response is under genetic control by polymorphisms in CD14 and TLR4 genes in some researchs. We aimed to investigate the effects of genetic variants of CD14 (-) and TLR4 (Asp299Gly, Thr399Ile) genes on asthma phenotypes in adults with asthma. Asthma patients (n = 131) and healthy control cases (n = 75) were included in the study. Relations between CD14 C-159 T, TLR4 299 and TLR4 399 genotypes and duration of asthma history of allergic rhinitis-dermatitis, total IgE, eosinophil, skin prick test, forced expiratory volume 1 (FEV1) and severity of disease were evaluated. Real time PCR (RT-PCR) was used for genotyping. For CD14-159, presence of the C allele (CC + CT) was more frequent among those with low median log (logarithm) IgE levels, but no statistically significant difference in all asthma group (p = 0.09). C allele was significantly correlated with low total IgE levels and T allele with high total IgE levels in atopics (p = 0.04). CC + CT genotype was more frequent in moderate and severe asthma group in atopics (p = 0.049). TLR4 299 and TLR4 399 genotypes and asthma phenotypes were not found to be significantly correlated (p > 0.05). Total IgE levels were found to be low among patients with the CC + CT genotype, and high among patients with the TT genotype contrary to the results of many other studies, which is therefore an important finding. Another important finding was that the C allele is a risk factor for moderate and severe asthma.
    BMC Pulmonary Medicine 02/2014; 14(1):20. DOI:10.1186/1471-2466-14-20 · 2.49 Impact Factor
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    • "Childhood asthma in relation to polymorphisms in TLRs was addressed in 19 studies [21,25-28,34,38,39,41,43-45,55-61]. The age of the population in these studies ranged from 0 to 18 years with 31 to 644 cases and 184 to 2927 controls. "
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    ABSTRACT: The aetiology of childhood asthma is complex. An early dysfunction in the immunological development of the innate immune system in combination with environmental factors possibly triggers asthma. CD14 and toll-like receptors are important components of the innate immune system. The aim of this systematic review was to obtain a better insight into the relation between CD14 and toll-like receptors and childhood asthma in Caucasians. We searched PubMed and EMBASE for relevant articles. 44 articles were included. The quality of the selected studies was independently assessed by the first two authors using the Newcastle-Ottawa quality assessment scale. Toll-like receptor 2, toll-like receptor 6, toll-like receptor 9, and toll-like receptor 10 appear to have some association with childhood asthma in Caucasians. The evidence for a relation of CD14 with childhood asthma is limited. In conclusion, there is no convincing evidence yet for a role of CD14 and toll-like receptors in relation to childhood asthma. Future studies should include haplotype analysis and take environmental factors into account to further clarify the role of CD14 and toll-like receptors on childhood asthma.
    Allergy Asthma and Clinical Immunology 03/2013; 9(1):10. DOI:10.1186/1710-1492-9-10
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