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      Association of Single Nucleotide Polymorphisms in Toll-like Receptor Genes With Asthma Risk: A Systematic Review and Meta-analysis

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          Abstract

          Purpose

          Asthma is a complex disease, with contributions from multiple genes, various genetic backgrounds, and environmental factors. Many human epidemiological studies have demonstrated that single nucleotide polymorphisms (SNPs) in Toll-like receptor (TLR) genes are inconsistently associated with asthma risk. Some have demonstrated differences concerning the study design and effect size, and conflicting results have been reported. A meta-analysis is necessary to determine the magnitude of this association.

          Methods

          Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, a systematic search and meta-analysis of the literature was conducted to estimate the association of SNPs in TLR genes with asthma risk. We screened the medical literature based on the following keyword searches in MEDLINE and EMBASE databases: 'TLR', 'polymorphism', 'asthma', and their combinations.

          Results

          Meta-analysis of eight studies on TLR4 Asp299Gly showed a marginal association of TLR4 with asthma risk (odds ratio [OR]=0.814 [95% confidence interval [CI], 0.652-1.016; P=0.069]) in the recessive model. TLR4 Thr399Ile was not associated with asthma risk under any genetic model. Meta-analysis of four studies on TLR2 Arg753Gln indicated that TLR2 might be significantly associated with asthma in the dominant and codominant models ( P=0.029, P=0.030, and P=0.009, respectively). TLR9 -1237 was marginally associated with asthma risk (OR=0.408 [95% CI, 0.163-1.021; P=0.065]) in the codominant model. Analysis using the allele contrast model showed that the major TLR9 -1237 T allele tended to be a significant protective factor with OR=0.689 (95% CI, 0.471-1.007; P=0.055).

          Conclusions

          The results showed that TLR4 Asp299Gly, TLR2 Arg753Gln, and TLR9-1237 might contribute significantly to asthma susceptibility. Future genetic association studies would consolidate these findings.

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          Most cited references79

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          Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA.

          Sandra S. Diebold, Tsuneyasu Kaisho, Hiroaki Hemmi … (2004)
          Interferons (IFNs) are critical for protection from viral infection, but the pathways linking virus recognition to IFN induction remain poorly understood. Plasmacytoid dendritic cells produce vast amounts of IFN-alpha in response to the wild-type influenza virus. Here, we show that this requires endosomal recognition of influenza genomic RNA and signaling by means of Toll-like receptor 7 (TLR7) and MyD88. Single-stranded RNA (ssRNA) molecules of nonviral origin also induce TLR7-dependent production of inflammatory cytokines. These results identify ssRNA as a ligand for TLR7 and suggest that cells of the innate immune system sense endosomal ssRNA to detect infection by RNA viruses.
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            The genetics of asthma and allergic disease: a 21st century perspective.

            Carole Ober, Tsung-Chieh Yao (2011)
            Asthma and allergy are common conditions with complex etiologies involving both genetic and environmental contributions. Recent genome-wide association studies (GWAS) and meta-analyses of GWAS have begun to shed light on both common and distinct pathways that contribute to asthma and allergic diseases. Associations with variation in genes encoding the epithelial cell-derived cytokines, interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP), and the IL1RL1 gene encoding the IL-33 receptor, ST2, highlight the central roles for innate immune response pathways that promote the activation and differentiation of T-helper 2 cells in the pathogenesis of both asthma and allergic diseases. In contrast, variation at the 17q21 asthma locus, encoding the ORMDL3 and GSDML genes, is specifically associated with risk for childhood onset asthma. These and other genetic findings are providing a list of well-validated asthma and allergy susceptibility genes that are expanding our understanding of the common and unique biological pathways that are dysregulated in these related conditions. Ongoing studies will continue to broaden our understanding of asthma and allergy and unravel the mechanisms for the development of these complex traits. © 2011 John Wiley & Sons A/S.
            Article 0 comments Cited 181 times – based on 0 reviews     Review now
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              Toll-like receptor 2 as a major gene for asthma in children of European farmers.

              Walt Klimecki, Charlotte Braun-Fahrländer, … (2004)
              The finding that the prevalence of asthma and allergies is less frequent in children raised on animal farms has led to the conjecture that exposure to microbial products modifies immune responses. The toll-like receptors (TLRs) represent an evolutionarily conserved family of innate immunity receptors with microbial molecules as ligands. We reasoned that polymorphisms in genes encoding TLRs might modulate the protective effects observed in farming populations. Farmers' and nonfarmers' children living in rural areas in Austria and Germany and who were enrolled in the cross-sectional ALEX study were genotyped for single nucleotide polymorphisms in the TLR2 and TLR4 genes. The frequencies of asthma, allergic rhinitis, and atopic sensitization were compared between the genotypes in relation to exposure to farming and endotoxin. Among farmers' children, those carrying a T allele in TLR2/-16934 compared with children with genotype AA were significantly less likely to have a diagnosis of asthma (3% vs 13%, P = .012), current asthma symptoms (3% vs 16%, P = .004), atopic sensitization (14% vs 27%, P = .023), and current hay fever symptoms (3% vs 14%, P = .01). The association between TLR2/-16934 and asthma among children of farmers was independent of atopy. No such association was found among children from the same rural communities but not living on farms. Our results suggest that genetic variation in TLR2 is a major determinant of the susceptibility to asthma and allergies in children of farmers.
              Article 0 comments Cited 71 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Allergy Asthma Immunol Res
                Journal ID (iso-abbrev): Allergy Asthma Immunol Res
                Journal ID (publisher-id): AAIR
                Title: Allergy, Asthma & Immunology Research
                Publisher: The Korean Academy of Asthma, Allergy and Clinical Immunology; The Korean Academy of Pediatric Allergy and Respiratory Disease
                ISSN (Print): 2092-7355
                ISSN (Electronic): 2092-7363
                Publication date (Print): March 2015
                Publication date (Electronic): 05 November 2014
                Volume: 7
                Issue: 2
                Pages: 130-140
                Affiliations
                [1 ]Division of Histology and Immunology, Department of Basic Sciences, Faculty of medicine Tunis, Tunis El Manar University, Tunis, Tunisia.
                [2 ]Division of Pulmonology, Unit research: 1 2 SP15"Homeostasis and Cell Immune Dysfunction", A. Mami Hospital, Ariana, Tunisia.
                Author notes
                Correspondence to: Kalthoum Tizaoui, PhD student, Division of Histology and Immunology, Department of Basic Sciences, Faculty of medicine Tunis, Tunis El Manar University, 15 Rue Djebel Lakdhar, 1007 Tunis, Tunisia. Tel: +216-24-616-454; Fax: +216-71-660-444; kalttizaoui@ 123456gmail.com
                Article
                DOI: 10.4168/aair.2015.7.2.130
                PMC ID: 4341334
                PubMed ID: 25729620
                SO-VID: 47e36d95-6d0d-4e3a-9644-7720a91072b5
                Copyright © Copyright © 2015 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 09 January 2014
                Date revision received : 13 April 2014
                Date accepted : 02 May 2014
                Funding
                Funded by: Ministry of Higher Education
                Categories
                Subject: Original Article

                ScienceOpen disciplines: Immunology
                Keywords: asthma,tlr genes,snps,association,meta-analysis
                Data availability:
                ScienceOpen disciplines: Immunology
                Keywords: asthma, tlr genes, snps, association, meta-analysis

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