The effect of polymorphisms at the CD14 promoter and the TLR4 gene on asthma phenotypes in Turkish children with asthma (original) (raw)
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Endotoxins, asthma, and allergic immune responses
Toxicology, 2000
Asthma severity depends to a great extent on the levels of endotoxin present in the microenvironment. Although favouring a Th1 cytokine response that could be beneficial to the asthmatic, lipopolysaccharide (LPS) aggravates bronchopulmonary inflammation by several mechanisms. These include neutrophil and eosinophil recruitment, and release by activated macrophages of pro-inflammatory cytokines and nitric oxide. LPS exerts its biological actions through its interaction with CD14. The genetic locus of CD14 is close to the genomic region controlling levels of IgE. A polymorphism in the CD14 promoter region seems to favour high serum IgE levels. Genetic influences may thus control circulating levels of sCD14 and by this mechanism modulate Th1/Th2 balance and IgE synthesis. LPS exposure, although hazardous to the asthmatic, seems to exert a role in the maturation of the immune system in children towards a Th1-skewed pattern.
Polymorphisms in Toll-Like Receptor 4 Are Not Associated with Asthma or Atopy-related Phenotypes
American Journal of Respiratory and Critical Care Medicine, 2002
Toll-like receptor 4 (TLR4) is the principal receptor for bacterial cant interindividual variability in response to endotoxin has endotoxin recognition, and functional variants in the gene confer long been recognized (4, 5). Arbour and colleagues have endotoxin-hyporesponsiveness in humans. Furthermore, there is recently demonstrated that common polymorphisms in the evidence that endotoxin exposure during early life is protective coding region of the TLR4 gene are responsible for a substanagainst the development of atopy and asthma, although this relatial portion of this variability (6). Specifically, a substitution tionship remains poorly understood. It is therefore possible that of glycine for asparginine at amino acid position 259 (D259G) genetic variation in the TLR4 locus contributes to asthma susceptiresults in reduction in cell surface expression of TLR4 and bility. In this study we characterize the genetic diversity in the TLR4 subsequent disruption of LPS-mediated signaling. Furtherlocus and test for association between the common genetic variants more, subjects heterozygous for D259G demonstrate a blunted and asthma-related phenotypes. In a cohort of 90 ethnically diverse bronchoconstrictor response to inhaled LPS, suggesting a subjects, we resequenced the TLR4 locus and identified a total of dominant genetic effect. A second amino acid variant, a sub-29 single nucleotide polymorphisms. We assessed five common stitution of threonine for isoleucine at position 359 (T359I), polymorphisms for evidence of association with asthma in two large which is in tight linkage disequilibrium (LD) with D259G, family-based cohorts: a heterogeneous North American cohort (589 also demonstrated in vitro LPS-hyporesponsive effects. There families), and a more homogenous population from northeastern is evidence that these functional variants are important deter-Quebec, Canada (167 families). Using the transmission-disequilibminants of health and disease, including sepsis susceptibility rium test, we found no evidence of association for any of the polymorphisms tested, including two functional variants. Furthermore, and atherogenesis (7, 8). Smirnova and colleagues have resewe found no evidence for association between the TLR4 variants quenced the complete coding region of TLR4 in 348 individuand four quantitative intermediate asthma-and atopy-related pheals of diverse ethnic origin and identified 10 additional amino notypes. Based on these results, we found no evidence that genetic acid variants of extremely low frequency (9). Although funcvariation in TLR4 contributes to asthma susceptibility. tional data regarding these rare variants is currently unavailable, this excess number of rare variants suggests that weakly purifying selective forces influence variation at the TLR4 netic association cohort of 499 infants at high risk of developing asthma dem-Recherche sur la Nature et les Technologies du Québec. C.G. is a Chercheur onstrated that higher household endotoxin levels were associ-Boursier of the Fonds pour la Recherche en Santé du Québec. ated with an increased risk of persistent wheeze during the Correspondence and requests for reprints should be addressed to Benjamin A. first year of life (16). Household endotoxin level is also sig-Raby, M.D., Channing Laboratory, Brigham and Women's Hospital, 181 Longnificantly associated with asthma severity among dust mitesensitive children (17). The role of endotoxin in the develop-
Pediatric Allergy and Immunology, 2014
Background: We investigated the interaction between genetic variants in endotoxin signalling pathway and domestic endotoxin exposure in relation to asthma presence, and amongst children with asthma, we explored the association of these genetic variants and endotoxin exposure with hospital admissions due to asthma exacerbations. Methods: In a case-control study, we analysed data from 824 children (417 asthmatics, 407 controls; age 5-18 yr). Amongst asthmatics, we extracted data on hospitalization for asthma exacerbation from medical records. Endotoxin exposure was measured in dust samples collected from homes. We included 26 single-nucleotide polymorphisms (SNPs) in the final analysis (5 CD14, 7LY96 and 14 TLR4). Results: Two variants remained significantly associated with hospital admissions with asthma exacerbations after correction for multiple testing: for CD14 SNP rs5744455, carriers of T allele had decreased risk of repeated hospital admissions compared with homozygotes for C allele [OR (95% CI), 0.42 (0.25-0.88), p = 0.01, False Discovery Rate (FDR) p = 0.02]; for LY96 SNP rs17226566, C-allele carriers were at a lower risk of hospital admissions compared with T-allele homozygotes [0.59 (0.38-0.90), p = 0.01, FDR p = 0.04]. We observed two interactions between SNPs in CD14 and LY96 with environmental endotoxin exposure in relation to hospital admissions due to asthma exacerbation which remained significant after correction for multiple testing (CD14 SNPs rs2915863 and LY96 SNP rs17226566). Conclusion: Amongst children with asthma, genetic variants in CD14 and LY96 may increase the risk of hospital admissions with acute exacerbations. Polymorphisms in endotoxin pathway interact with domestic endotoxin exposure in further modification of the risk of hospitalization.
Toll-like receptor 4 polymorphism and severity of atopy in asthmatics
Genes and Immunity, 2004
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 Z2 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 (P40.05). 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, n¼39) compared to those with the Asp/Asp genotype (mean 1.2, s.d. 1.0, n¼279) (P¼0.003, t-test). No associations were found with total IgE, FEV 1 % predicted, slope of FEV 1 response to methacholine or asthma severity score (P40.05). 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.
The role of endotoxin and its receptors in allergic disease
Annals of Allergy, Asthma & Immunology, 2005
Objective-To summarize the existing literature on the association of endotoxin with respiratory diseases and allergic sensitization and to review the potentially modifying effects of endotoxin receptor polymorphisms.
BMC Pulmonary Medicine, 2014
Background: 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. Methods: 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.
Journal of Allergy and Clinical Immunology, 2009
Background: Toll-like receptor 4 (TLR4) variants have been shown to reduce the respiratory responses to inhaled LPS in controlled experiments among healthy volunteers. Objective: We sought to investigate whether naive subjects with TLR4 variants showed reduced respiratory response to a complex aerosol including endotoxin as a major constituent. Methods: Twenty-nine nonsmoking, nonatopic healthy subjects with TLR4 299/399 polymorphisms and 29 age-and sexmatched, wild-type TLR4 control subjects were exposed for 5 hours each in a noncontaminated environment (baseline day) and in a swine confinement facility (exposure day). There were 16 men and 13 women in each of the 2 age-and sex-matched groups. Results: TLR4 polymorphic subjects who were exposed to high endotoxin levels ($1550 EU/m 3 ) had less reduction in the percentage across-shift change in FEV 1 from baseline than did wild-type subjects exposed to similar endotoxin levels. Among subjects exposed to higher endotoxin levels, the mean differences in the percentage across-shift changes between baseline and exposure days were significantly less in TLR4 polymorphic subjects compared with those seen in wild-type subjects in FEV 1 (28.48% 6 1.52% [mean 6 SE] vs 211.46% 6 1.79%, P 5 .001), forced expiratory flow between 25% and 75% of forced vital capacity (218.30% 6 1.99% vs 224.14% 6 3.28%, P 5 .009), and FEV 1 /forced vital capacity ratio (25.40% 6 0.56% vs 28.53% 6 1.51%, P 5 .04). These patterns were not observed in IL-6 levels from serum and nasal lavage fluid, IL-8 levels from nasal lavage fluid, white blood cell counts, or blood differential counts. Conclusion: The association between TLR4 variants and reduced airway responsiveness to inhaled particulate was observed at high endotoxin concentrations, creating the possibility of certain threshold phenomena for the apparent protective effect of TLR4 variants. (J Allergy Clin Immunol 2009;123:1034-40.)