Association analysis identifies TLR7 and TLR8 as novel risk genes in asthma and related disorders
Open accessAbstract
BACKGROUND: Toll-like receptors (TLRs) are structurally and functionally related and play important roles in the innate and adaptive immune system. By genome scanning, evidence of linkage between chromosome Xp22 and asthma and related atopic disorders has previously been obtained. Xp22 harbours the TLR7 and TLR8 genes. METHODS: The involvement of TLR7 and TLR8 in the aetiology of asthma and related disorders was investigated by a family based association analysis of two independently ascertained family samples comprising 540 and 424 individuals from 135 and 100 families, respectively. Ten affected individuals from families showing evidence of linkage to Xp22 were screened for sequence variations in TLR7 and 8, and nine single nucleotide polymorphisms (SNPs) identified were tested for association. RESULTS: In both samples, significant associations were observed for single SNPs and haplotypes of both TLR7 and 8 in all four phenotypes investigated: asthma, rhinitis, atopic dermatitis and increased specific IgE. The most significant association was seen for rs2407992 (TLR8) in asthma (p = 0.00023, sample A and B combined, recessive model). In TLR7, rs179008 showed the strongest association. Both rs179008 and rs2407992 are of putative functional significance, potentially affecting TLR7 processing and TLR8 splicing, respectively. Haplotypes comprising the major alleles of these two SNPs were overtransmitted to the affected offspring (eg, p = 0.00012 in asthma, combined sample, additive model). CONCLUSION: The results provide strong evidence that TLR7 and 8 may confer susceptibility to asthma and related atopic disorders and highlight these receptors as interesting targets for individualised, causally directed treatment.
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Candidate gene studies have found SNPs in genes involved in antigen presentation (HLA-DQA1), pathogen recognition (TLR2, TLR7, TLR8), and IL signaling and proinflammation (IL13, IL18, TSLP) to be important susceptibility variants for allergic rhinitis.
“Notably, SNPs in genes involved in antigen presentation (for example HLA-DQA1), pathogen recognition (TLR2, TLR7, TLR8), IL signaling and proinflammation (IL13, IL18, and TSLP) are considered important susceptibility variants for AR.496-502”
From International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis (2018) · cites this paper as [501]
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- Authors
- Moller-Larsen, S., Nyegaard, M., Haagerup, A., Vestbo, J., Kruse, T. A., & Borglum, A. D.
- Affiliations
- Aarhus University (DK)
- Hvidovre Hospital (DK)
- University of Southern Denmark (DK)
- Venue
- Thorax
- Publisher
- BMJ
- Published
- 2008-05-20
- Volume
- 63
- Issue
- 12
- Pages
- 1064-1069
- ISSN
- 0040-6376 (ISSN-L)
- OpenAlex
- W2144505818
- Cited by
- 154
- References
- 48
- Citations by year
- 2025: 4 · 2024: 8 · 2023: 6 · 2022: 6 · 2021: 2 · 2020: 5 · 2019: 4 · 2018: 3 · 2017: 12 · 2016: 11 · 2015: 15 · 2014: 8 · 2013: 18 · 2012: 12
- FWCI
- 9.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Thorax (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion)
- Funders
- Aarhus Universitet
- Danmarks Lungeforening
- Sundhed og Sygdom, Det Frie Forskningsråd
- Hørslev-Fonden
- Aarhus Universitets Forskningsfond
- Lundbeckfonden
- Augustinus Fonden
- H. Lundbeck A/S
- Medical Research Council
- Topics
- Health Sciences › Medicine › Physiology › Asthma and respiratory diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- TLR7, TLR8, asthma, atopic diseases, atopic rhinitis, atopic dermatitis, specific IgE, single nucleotide polymorphisms, haplotypes, genetic susceptibility, family-based association, Toll-like receptors
- MeSH terms
- Adolescent, Adult, Asthma, Dermatitis, Atopic, Female, Humans, Male, Middle Aged, Rhinitis, Risk Factors, Linkage Disequilibrium, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Toll-Like Receptor 7, Toll-Like Receptor 8
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