The role of Toll-like receptors and related receptors of the innate immune system in asthma

PURPOSE OF REVIEW: The biology of the innate immunity receptors is of central importance in the host response to the environment. Identifying genetic variants that alter the innate immune response is highly relevant to understanding asthma pathogenesis. This review summarizes recent studies of the role of innate immunity receptors, including Toll-like receptors and CD14, in the pathogenesis of asthma. RECENT FINDINGS: The majority of studies published since 2004 have been genetic association studies in various clinical settings, which have found positive associations of single nucleotide polymorphisms in TLR2, TLR4, TLR6 and TLR10 with asthma or atopy, although the number of studies is small and the results not yet replicated. The designs for CD14 genetic studies have been more sophisticated and have included gene-environment interaction. The results of CD14 gene associations with asthma and atopy are suggestive but have not been fully replicated. Potential reasons for non-replication of TLR and CD14 association studies include insufficient power, type I error, population heterogeneity and different phenotypes studied. In addition, there may be differences in CD14 genetic effects between childhood and adulthood, and between levels of endotoxin exposure. SUMMARY: The evidence is still being accumulated for the role of Toll-like receptor polymorphisms in the pathogenesis of asthma. There is emerging evidence for the role of CD14 polymorphisms in the development of asthma and atopy. Further studies of innate immunity in asthma and allergy are required, using rigorous study design, measurement of environmental exposure and intermediate phenotypes to demonstrate single nucleotide polymorphism functionality.     

Prenatal farm exposure is related to the expression of receptors of the innate immunity and to atopic sensitization in school-age children

BACKGROUND: There is increasing evidence that environmental exposures determining childhood illnesses operate early in life. Prenatal exposure to a farming environment through the mother might also play an important role. OBJECTIVE: We sought to investigate the role of maternal exposures to environments rich in microbial compounds for the development of atopic sensitization, asthma, and corresponding alterations in the innate immune system in offspring. METHODS: In the children of the cross-sectional Prevention of Allergy Risk Factors for Sensitization in Children Related to Farming and Anthroposophic Life Style study, asthma and atopy were assessed by means of standardized questionnaires (n = 8263) and serum IgE measurements (n = 2086). In a subsample (n = 322) gene expression of Toll-like receptors (TLR2 and TLR4) and CD14 was assessed. Maternal exposures were defined through questionnaire information. RESULTS: Both atopic sensitization (adjusted odds ratio, 0.58; 95% CI, 0.39-0.86) and the gene expression of receptors of innate immunity were strongly determined by maternal exposure to stables during pregnancy, whereas current exposures had much weaker or no effects. A dose-response relation was found between the extent of upregulation of these genes and the number of different farm animal species the mother had encountered in her pregnancy. Each additional farm animal species increased the expression of TLR2, TLR4, and CD14 by a factor of 1.16 (95% CI, 1.07-1.26), 1.12 (95% CI, 1.04-1.2), and 1.10 (95% CI, 1.03-1.23), respectively. CONCLUSION: Maternal exposure to an environment rich in microbial compounds might protect against the development of atopic sensitization and lead to upregulation of receptors of the innate immune system. The underlying mechanisms potentially operating through the intrauterine milieu or epigenetic inheritance await further elucidation. CLINICAL IMPLICATIONS: When assessing risk factors of allergies in an infant's medical history, attention must also be paid to environmental exposures affecting the mother.     

Immune‐mediated diseases and microbial exposure in early life

The non‐communicable disease pandemic includes immune‐mediated diseases such as asthma and allergy, which are likely originating in early life where the immature immune system is prone to alterations caused by the exposome. The timing of exposure seems critical for the developing immune system, and certain exposures may have detrimental effects in the earliest life, but no or even beneficial effects later. The human microbiome and infections are candidates as intermediary in the interaction between the host and the environment. The evidence seems inconsistent as infections as well as particular colonization patterns in neonates drive both short‐term and long‐term asthma symptoms, while, on the other hand, the composition of the microbiome in early life may protect against asthma and allergy in later life. This apparent contradiction may be explained by a deeper disease heterogeneity than we are currently able to discriminate, and in particular, the indiscriminate lumping together of different diseases into one atopic disease category. Also, the microbiome needs a differentiated understanding, considering balance between microbial groups, diversity and microbial genetic capability. Furthermore, the effects of the microbial exposure may only affect individuals with certain susceptibility genes. Few of the observations have been replicated, and publication bias is likely. Therefore, we are still far from understanding, or having proved, causal effects of the human microbiome. Still, the microbiome–gene interaction is a fascinating paradigm that fosters exiting research and promises a breakthrough in the understanding of the mechanisms driving asthma, allergy and eczema, and potentially also other immune‐mediated non‐communicable diseases.     

Interaction between CD14−159C>T polymorphism and Helicobacter pylori is associated with serum total immunoglobulin E

Background Total serum IgE is regulated by both environmental and genetic factors. Association and linkage studies have suggested a role of CD14?159C>T polymorphism in the regulation of serum total IgE, but the results have been contradictory. It seems that gene–environment interactions are involved in this regulation. Objective The aim of this study was to examine the possible gene–environment interactions among Toxoplasma gondii, Helicobacter pylori, CD14?159C>T and Toll‐like receptor (TLR) 4+896A>G polymorphism on serum total IgE. For this study, we expanded the scope of our earlier comparison of allergic sensitization and microbial load between Finland and Russian Karelia by studying the CD14?159C>T and TLR4+896A>G polymorphism in a cohort of Russian Karelian children. Methods For this study, CD14?159C>T and TLR4+896A>G polymorphisms were analysed in 264 healthy Russian Karelian children. Serum total IgE levels and H. pylori and T. gondii antibodies were also measured. Results We constructed a multiway anova model to analyse the gene–environment interactions among T. gondii seropositivity, H. pylori seropositivity, CD14?159C>T and TLR4+896A>G polymorphisms on serum total IgE. The model showed that there was an interaction between the CD14?159 allele T carrier status and H. pylori antibodies on serum total IgE (P=0.004). No other interactions were found. Conclusion Our results further emphasize the role of gene–environment interaction in the regulation of serum total IgE.     

Atopy and new-onset asthma in young Danish farmers and CD14, TLR2, and TLR4 genetic polymorphisms: a nested case-control study

BACKGROUND: Evidence exists that exposure to high levels of microbial agents such as endotoxin in the farm environment decreases the risk of atopic sensitization. Genetic variation in innate immunity genes may modulate the response to microbial agents and thus influence susceptibility to asthma and atopy. OBJECTIVE: To study potential associations between single nucleotide polymorphisms (SNPs) in CD14, Toll-like receptor 2 (TLR2), and TLR4 genes, and atopy and new-onset asthma in young farmers. METHODS: A nested case-control study was conducted within a cohort of 1901 young Danish farmers. We genotyped 100 new-onset asthma cases and 88 control subjects for three CD14 SNPs, three TLR2 SNPs, and two TLR4 SNPs. Atopy at baseline (defined as a positive skin prick test to one or more common inhalant allergens) was found in 17 asthma cases (17.0%) and in 17 controls (19.3%). RESULTS: The CD14/-260T allele was significantly associated with less atopy [odds ratio (OR) 0.39; 95% confidence interval (CI) 0.21-0.72, additive genetic model], whereas the CD14/-651T allele was positively associated with atopy (OR 2.53; 95% CI 1.33-4.80). Similar results were obtained by haplotype analysis. Stratified analysis by farm childhood showed stronger effects of both CD14 SNPs on atopy among farmers who were born and raised on a farm, although no significant interaction was found. No associations between CD14, TLR2, or TLR4 genotypes and new-onset asthma were found. CONCLUSION: The CD14/-260 and CD14/-651 promoter polymorphisms are associated with atopy prevalence among young adults exposed to farm environments.     

The role of lipopolysaccharide in the development of atopy in humans

Atopy is a highly prevalent condition and remains the single biggest risk factor for asthma. Although atopy has a heritable component, the time frame of the increase in the prevalence indicates that it is not due to genetic factors alone. The relationship between allergen exposure and sensitization is complex. Lipopolysaccharide (LPS) and its bioactive moiety endotoxin are common to all gram‐negative bacteria, and have been used as a surrogate of microbial load. Endotoxin can be readily measured in dust collected from homes. Some studies have demonstrated a clear inverse dose–response relationship between exposure to endotoxin and the risk of atopy but this finding has not been reproduced in all studies. Our innate immune system recognizes LPS readily via the LPS signal transduction pathway, which has the trimolecular complex of CD14/TLR4/MD2 at the core. A common single‐nucleotide polymorphism in the promoter region of CD14 rs2569190 C to T (CD14/?260 or CD14/?159) has been associated with elevated sCD14. Although early studies suggested that this variant was associated with more severe atopy, this finding was not uniformly replicated. It has now been demonstrated in four independent populations that high exposure to endotoxin in the domestic environment is protective against the development of atopy, but only among carriers of the C allele, that is, the environmental exposure is only relevant when taken in the context of the genotype. Furthermore, this interaction is biologically plausible. We propose that neither the environmental exposure nor the genotype in isolation is sufficient to cause complex diseases like asthma and atopy, but disease results from the one acting in the context of the other, of which CD14 and endotoxin is one example contributing to the risk for atopy. Cite this as: A. Simpson and F. D. Martinez, Clinical & Experimental Allergy, 2010 (40) 209–223.     

Gene-Environment Interactions in Asthma: Genetic and Epigenetic Effects

Over the past three decades, a large number of genetic studies have been aimed at finding genetic variants associated with the risk of asthma, applying various genetic and genomic approaches including linkage analysis, candidate gene polymorphism studies, and genome-wide association studies (GWAS). However, contrary to general expectation, even single nucleotide polymorphisms (SNPs) discovered by GWAS failed to fully explain the heritability of asthma. Thus, application of rare allele polymorphisms in well defined phenotypes and clarification of environmental factors have been suggested to overcome the problem of ''missing'' heritability. Such factors include allergens, cigarette smoke, air pollutants, and infectious agents during pre- and post-natal periods. The first and simplest interaction between a gene and the environment is a candidate interaction of both a well known gene and environmental factor in a direct physical or chemical interaction such as between CD14 and endotoxin or between HLA and allergens. Several GWAS have found environmental interactions with occupational asthma, aspirin exacerbated respiratory disease, tobacco smoke-related airway dysfunction, and farm-related atopic diseases. As one of the mechanisms behind gene-environment interaction is epigenetics, a few studies on DNA CpG methylation have been reported on subphenotypes of asthma, pitching the exciting idea that it may be possible to intervene at the junction between the genome and the environment. Epigenetic studies are starting to include data from clinical samples, which will make them another powerful tool for research on gene-environment interactions in asthma.     

Polymorphisms in the novel gene acyloxyacyl hydroxylase (AOAH) are associated with asthma and associated phenotypes

BACKGROUND: The gene encoding acyloxyacyl hydroxylase (AOAH), an enzyme that hydrolyzes secondary fatty acyl chains of LPS, is localized on chromosome 7p14-p12, where evidence for linkage to total IgE (tIgE) concentrations and asthma has been previously reported. OBJECTIVE: We hypothesized that variants in AOAH are associated with asthma and related phenotypes. Because both AOAH and soluble CD14 respond to LPS, we tested for gene-gene interaction. METHODS: We investigated the association between 28 single nucleotide polymorphisms throughout the AOAH gene and asthma, concentrations of tIgE, the ratio of IL-13/IFN-gamma, and soluble CD14 levels among 125 African Caribbean, multiplex asthmatic pedigrees (n = 834). Real-time PCR was used to assess whether AOAH cDNA expression differed with AOAH genotype. RESULTS: Significant effects were observed for all 4 phenotypes and AOAH markers in 3 distinct regions (promoter, introns 1-6, and the intron 12/exon 13 boundary/intron 13 region) by means of single-marker and haplotype analyses, with the strongest evidence for a 2-single-nucleotide-polymorphism haplotype and log[tIgE] (P = .006). There was no difference in AOAH expression levels by AOAH genotype for any of the markers. Comparing genotypic distributions at both the AOAH marker rs2727831 and CD14(-260)C >T raises the possibility of gene-gene interaction (P = .006-.036). CONCLUSION: Our results indicate that polymorphisms in markers within the AOAH gene are associated with risk of asthma and associated quantitative traits (IgE and cytokine levels) among asthmatic subjects and their families in Barbados, and there is an interactive effect on tIgE and asthma concentrations between an AOAH marker and the functional CD14(-260)C >T polymorphism. CLINICAL IMPLICATIONS: AOAH is a novel innate immunity candidate gene associated with asthma and related phenotypes in an African ancestry population.     

Respiratory allergy in agricultural workers: recent developments

PURPOSE OF REVIEW: To review recent evidence on the relationship between occupational exposure to allergens and asthmagens, and risk for developing allergy and asthma and the role of modifying factors in farmers and farm workers. RECENT FINDINGS: Recent studies identified agents that have not been associated with allergy or asthma in farming populations before. The most intriguing findings, however, are those that suggest that the development of atopy and asthma might be influenced by exposure to pathogen associated molecular patterns (PAMPs), including endotoxin. SUMMARY: The adverse and potentially protective effects of microbial exposures in the farm environment are discussed. Recent findings indicate that it is very likely that the protective effect of exposure to PAMPs such as endotoxin is not limited to childhood age. The protective effects that probably developed during childhood can still be observed at adult age. Furthermore, it even seems likely that exposures at adult age (in occupational environments), which stimulate the innate immune system, have an effect on allergy, independently of childhood exposure. It is hypothesized that reversal of atopy might occur as a result of high exposure to endotoxins and other PAMPs.     

Gene-environmental interaction in asthma

PURPOSE OF REVIEW: Asthma is likely to result from the effects of environmental stimuli in genetically susceptible individuals. This review summarizes recent studies of gene-environmental interaction in the pathogenesis of asthma, focusing on study designs. RECENT FINDINGS: Studies using genetic epidemiology, in-vitro and ex-vivo models and in-vivo model organisms demonstrate that gene-environmental interaction in involved in the development of asthma. Genetic association studies show a reduced risk of asthma and atopy with early life exposure to farming environments and house dust endotoxin, and increased risk with environmental tobacco smoke. These associations are modified by CD14 genotype. In people with a specific genotype, high environmental exposure may have the opposite effect of low exposure, possibly explaining some of the inconsistencies in previous studies. In-vitro and ex-vivo cell culture experiments show gene-environmental interactions with Toll-like receptor agonists, viruses and tobacco smoke. Interactions between innate immunity genes and exposure to endotoxin and air pollution have been observed in in-vivo mouse models. SUMMARY: The expanding evidence for gene-environmental interaction in asthma indicates the importance of measuring environmental factors in genetic studies of asthma. Understanding gene-environmental interaction would facilitate risk prognostication, improve preventive strategies and develop targeted interventions in people with asthma.     

Evaluation of the CD14/-260 polymorphism and house dust endotoxin exposure in the Barbados Asthma Genetics Study

BACKGROUND: Both a functional promoter polymorphism in the gene encoding CD14 (C-260T) and exposure to endotoxin are believed to play key roles in modulating the immune response and expression of atopic disease. OBJECTIVE: We aimed to evaluate the role of the CD14 C-260T polymorphism in a population of African descent and to test for interaction between this genotype and house dust endotoxin (HDE) exposure on atopic phenotypes. METHODS: Asthmatic probands and their families were recruited as part of the Barbados Asthma Genetics Study. The C-260T polymorphism and two additional CD14 promoter markers (G-1461T, C-1721T) were genotyped. Endotoxin was measured in house dust samples. RESULTS: Using a Family-Based Association Test, the C-260T allele appeared to be protective against asthma ( z = -2.444; P = .015) and asthma severity ( z = -2.615; P = .009) under a recessive model. No significant associations were observed for the G-1461T and C-1721T markers both individually and in haplotypes. In a case-control analysis, the CD14 TT genotype was found to reduce risk of asthma compared with the CD14 CC/CT genotypes (odds ratio [OR], 0.26; 95% CI, 0.14-0.49) and was associated with lower asthma severity scores ( P < .002). The TT genotype might protect against asthma for individuals with low HDE (OR, 0.09; 95% CI, 0.03-0.24), but may be a risk factor for individuals with high HDE (OR, 11.66; 95% CI, 1.03-131.7), suggesting a gene-environment interaction. CONCLUSION: These data suggest that the CD14-260 polymorphism may play a role in controlling risk to atopic disease and underscore the importance of incorporating key environmental exposures into studies of genetic risk factors.     

Impact of genetic variants of CD14 and TLR4 on subgingival periodontopathogens

CD14 and toll‐like receptor 4 (TLR4) are involved in host's immune response to bacterial pathogens including periodontal bacteria. Functional important gene polymorphisms are described for both genes. The aim of this study was to evaluate links between genetic polymorphisms of CD14 and TLR4 and risk markers of periodontitis in a multivariate model. One hundred and thirty‐three periodontitis patients (chronic: n = 60, aggressive: n = 73) and 80 healthy controls without periodontitis were included in the study. Polymorphisms in CD14 c.–159C>T and in TLR4 Asp299Gly, Thr399Ile were determined by restriction fragment length polymorphism analyses. The clinical investigation included smoking status, plaque and bleeding indexes, pocket depth and attachment loss. Subgingival bacterial colonization was analysed molecularbiologically using the micro‐Ident®test. Prevotella intermedia occurred less frequently in individuals positive for the TT genotype of CD14 in bivariate analysis (odds ratio = 0.36%, confidence interval: 0.14–0.91, P = 0.045). In binary logistic regression analyses, the occurrence of this bacterium was significantly decreased in TT carriers (odds ratio = 0.31%, confidence interval: 0.81–0.12, P = 0.017) considering age, smoking and maximum clinical attachment loss at microbial test site as confounding factors. However, no significant association with chronic and or aggressive periodontitis and polymorphisms in CD14 and TLR4 could be proven. Although the CD14 c.–159C>T polymorphism could be shown to be associated with subgingival colonization with P. intermedia, there is no evidence that CD14 and TLR4 polymorphisms investigated are independent risk factors for chronic or aggressive periodontitis in German periodontitis patients.     

Polymorphisms of the CD14 gene and atopic phenotypes in Czech patients with IgE-mediated allergy

IgE-mediated allergy is a common chronic disorder resulting from interactions between genetic and environmental factors. The gene encoding CD14 is a positional candidate gene for allergic diseases as it is localised on chromosome 5q31.1, a region linked to asthma and bronchial hyperresponsiveness. We investigated the relationship among atopic phenotypes and six polymorphisms in the CD14 gene. Polymerase chain reaction with RFLP analyses was used to determine the CD14 genotypes in subjects with IgE-mediated allergic diseases (n=282) and random controls (n=187). No significant differences in allele or genotype frequencies for individual polymorphisms between patients and controls were found. However, when atopic patients were subdivided into subjects with positive and with negative skin prick tests for separate antigens, T allele of the 1341G/T polymorphism was significantly associated with positive reactivity to mites (P=0.007) and moulds (P=0.041). Similarly, the C allele frequency of the −159C/T variant was increased in patients with positive skin prick tests for mites (P=0.046) and moulds (P=0.056). In haplotype analysis, the common −1619A/−1359G/−550C/−159C/+1188G/+1341T haplotype was associated with positive reaction to these antigens (P values: 0.0008–0.0035). Our study supports the idea that CD14 plays a role in IgE-mediated allergic diseases, and its gene polymorphisms can be important for manifestation of these disorders.     

Multiple microbial exposures in the home may protect against asthma or allergy in childhood

Background Experimental animal data on the gram‐negative bacterial (GNB) biomarker endotoxin suggest that persistence, dose, and timing of exposure are likely to influence its effects on allergy and wheeze. In epidemiologic studies, endotoxin may be a sentinel marker for a microbial milieu, including gram‐positive bacteria (GPB) as well as GNB, that may influence allergy and asthma through components (pathogen‐associated molecular patterns) that signal through innate Toll‐like receptor pathways. Objective To determine the influence of current GNB and GPB exposures on asthma and allergic sensitization in school‐aged children. Methods We examined the relationship between bacterial biomarkers and current asthma and allergic sensitization in 377 school‐aged children in a birth cohort study. We then evaluated the effects of school‐aged endotoxin, after controlling for exposure in early life. Results Exposure to GNB was inversely associated with asthma and allergic sensitization at school age [for >median endotoxin: prevalence odds ratio (POR)=0.34, 95% CI=0.2–0.7, for current asthma and prevalence ratio=0.77, 95% CI=0.6–0.97, for allergic sensitization]. In contrast, elevated GPB in the bed was inversely associated with current asthma (POR=0.41, 95% CI=0.2–0.9) but not with allergic sensitization (POR=1.07, 95% CI=0.8–1.4). School‐aged endotoxin exposure remained protective in models for allergic disease adjusted for early‐life endotoxin. Conclusion Both GNB and GPB exposures are associated with decreased asthma symptoms, but may act through different mechanisms to confer protection. Endotoxin exposure in later childhood is not simply a surrogate of early‐life exposure; it has independent protective effects on allergic disease.     

Toll-like receptors and CD14 genes polymorphisms and susceptibility to asthma in Tunisian children

Many studies have shown the implication of CD14 and toll-like receptors (TLRs) 2, 4 and 9 in the pathogenesis of asthma or atopy. To evaluate the association of CD14 and TLRs gene polymorphisms with asthma or atopy, 210 asthmatic children, 224 controls and 80 families were enrolled in this study. Six single nucleotide polymorphisms TLR2 (+2408 G-->A), TLR4 (+1196 C-->T), TLR4 (+896 A-->G), TLR9 (-1237 T-->C), TLR9 (-1486 T-->C) and CD14 (-159 C-->T) were genotyped using polymerase chain reaction followed by restriction fragment length polymorphism in the case-control and family study. The -1237C allele in TLR9 gene polymorphisms was associated with increased risk of asthma [odds ratio 1.53, 95% confidence interval (1.03-2.27)], although no statistically significant differences in allele or genotype frequencies of four other TLRs polymorphisms were evident between the asthmatic and control groups. The CD14 -159 C allele was found to be significantly higher in the asthmatic group when compared with controls (P=0.0006<0.05). Transmission disequilibrium test of 80 asthmatic families showed significant transmission of the -159 C allele in the CD14 gene to asthma-affected offspring. It was concluded that TLR9 and CD14 gene polymorphisms may contribute to an inherited predisposition to asthma in Tunisian children.     

17q12-21 and asthma: interactions with early-life environmental exposures

Background17q12-21 polymorphisms are associated with asthma presence and severity across different populations.ObjectiveTo extensively investigate the genes in this region among Croatian schoolchildren in a case-control study, taking account of early-life environmental exposures.MethodsWe included 423 children with asthma and 414 controls aged 5 to 18 years. Fifty-one haplotype tagging single-nucleotide polymorphisms (SNPs) were genotyped (GSDMA, GSDMB, ORMDL3, IKZF3, ZPBP2, and TOP2). Data on exposure to smoking and furry pet ownership were collected using a validated questionnaire. Information on severe asthma exacerbations with hospital admission were retrieved from hospital notes. All patients underwent spirometry.ResultsWe found 2 SNPs (1 novel rs9635726 in IKZF3) to be associated with asthma. Among children with asthma, 4 SNPs (in ZPBP2, GSDMB, and GSDMA) were associated with hospital admissions and 8 SNPs with lung function. One SNP (rs9635726) remained significantly associated with a predicted forced expiratory volume in 1 second after false discovery rate correction. Nine markers across 5 genes showed interaction with early-life environmental tobacco smoke (ETS) exposure in relation to asthma and 2 with furry pet ownership. Among children with asthma, we observed significant interactions between early-life ETS exposure and 3 SNPs for lung function and among early-life ETS exposure, 3 SNPs (in ORMDL3 and GSDMA), and hospital admission with asthma exacerbation. Three SNPs (in ORMDL3) interacted with current furry pet ownership in relation to hospital admissions for asthma exacerbation.ConclusionOur results indicate that several genes in the 17q12-21 region may be associated with asthma. This study confirms that environmental exposures may need to be included into the genetic association studies.     

Promoter polymorphisms of the CD14 gene are not associated with bronchial asthma in Caucasian children

Several studies have investigated the association of a promoter polymorphism in CD14 with atopic phenotypes. We screened this and another polymorphism in 182 asthmatic children and found no association with asthma. Furthermore, there was substantial linkage disequilibrium of the polymorphisms. Thus CD14 does not play a major role in the development of asthma in our population of Caucasian children.     

GSTP1 is a hub gene for gene–air pollution interactions on childhood asthma

There is growing evidence that multiple genes and air pollutants are associated with asthma. By identifying the effect of air pollution on the general population, the effects of air pollution on childhood asthma can be better understood. We conducted the Taiwan Children Health Study (TCHS) to investigate the influence of gene–air pollution interactions on childhood asthma. Complete monitoring data for the ambient air pollutants were collected from Taiwan Environmental Protection Agency air monitoring stations. Our results show a significant two‐way gene–air pollution interaction between glutathione S‐transferase P (GSTP1) and PM₁₀ on the risk of childhood asthma. Interactions between GSTP1 and different types of air pollutants have a higher information gain than other gene–air pollutant combinations. Our study suggests that interaction between GSTP1 and PM₁₀ is the most influential gene–air pollution interaction model on childhood asthma. The different types of air pollution combined with the GSTP1 gene may alter the susceptibility to childhood asthma. It implies that GSTP1 is an important hub gene in the anti‐oxidative pathway that buffers the harmful effects of air pollution.     

Polymorphisms in Toll‐like receptor 3 are associated with asthma‐related phenotypes in the Chinese Han patients

Toll‐like receptor (TLR) 3 mediates antivirus immunity and is involved in asthma exacerbation and development. However, the genetic association between TLR3 and asthma remains unclear. This study aimed to evaluate the effects of polymorphisms within TLR3 on asthma risk and asthma‐related phenotypes in the Chinese Han population. A total number of 462 unrelated adult patients with asthma and 398 healthy volunteers were enrolled in this study. The genotypes of tagging single nucleotide polymorphisms (SNPs) in TLR3 gene were determined using multiplex SNaPshot SNP genotyping assays. Case–control and case‐only studies were used to assess any links with asthma and asthma‐related phenotypes. The results showed that the genetic variants in TLR3 were associated with asthma‐related phenotypes, including eosinophil counts, serum immunoglobulin E levels and lung function. However, there was no obvious association between the TLR3 SNPs and asthma susceptibility or asthma severity. TLR3 polymorphisms may play a considerable role in the pathogenesis of asthma. It will help in better understanding the pathogenesis of asthma and development of more effective strategies for the prevention, prediction and treatment of asthma.     

Interleukin 3 (IL3) polymorphisms associated with decreased risk of asthma and atopy

Cytokines, having central functions in immunological and inflammatory process, are always expected to play important roles in the pathogenesis of various diseases, such as asthma. Genetic polymorphisms of those cytokine and cytokine receptor genes are the focus of genetic association studies. In an effort to identify gene(s) whose variant(s) are involved in the development of asthma, we examined the genetic effects of 19 single nucleotide polymorphisms in eight cytokine and cytokine receptor genes, including IL1A, IL1B, IL2, IL3, IL4, IL8, IL10, and IL5RA, on asthma and atopy. Nineteen single nucleotide polymorphisms in eight cytokine and cytokine receptor genes were genotyped using the single-base extension method in a Korean asthma cohort (n=723). Logistic regression and multiple regressions were used for statistical analyses controlling for smoking, age, and gender as covariables. Genetic association analysis of polymorphisms revealed that one exonic (exon 1), IL3+79T>C (Ser27Pro), showed significant association with the risk of asthma and atopy. The Pro allele had shown dominant and protective effects on development of asthma in nonatopic subjects (P=0.002) and also showed significant association with the risk of atopy in normal control subjects (P=0.007). This information about the genetic association of important genes with asthma might provide valuable insights into strategies for the pathogenesis of asthma and atopy.