Rare TLR2 mutations reduce TLR2 receptor function and can increase atopy risk
Open accessAbstract
Background: Common genetic variations in toll‐like receptor 2 (TLR2), an innate pathogen recognition receptor, may influence the development of atopic diseases. So far, very little is known about the role of rare TLR2 mutations in these diseases. Objective: We investigated the functional properties of six rare amino acid changes in TLR2 (and one amino acid change in a TLR2 pseudogene) and studied their effect on atopic sensitization and disease. Methods: We identified rare TLR2 mutations leading to amino acid changes from databases. Functional effects of TLR2 variants were analyzed by NF‐κB‐dependent luciferase reporter assay and interleukin‐8 enzyme linked immunosorbent assay in vitro. The frequency of these mutations was determined in a random sample of the general population (n = 368). Association with atopic diseases were studied in a cross sectional German study population (n = 3099). Results: Three out of six mutations in the TLR2 gene altered receptor activity in vitro. Out of these, only the minor allele of R753Q occurred reasonably frequent in the German population (minor allele frequency 3%). The risk to develop atopy increased by 50% in carriers of the 753Q allele (P = 0.021) and total (P = 0.040) as well as allergen specific serum IgE levels (P = 0.011) were significantly elevated. Conclusion: The rare but functionally relevant mutation R753Q in TLR2 may significantly affect common conditions such as atopic sensitization in the general population.
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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 [500]
The Results report that the TLR2 R753Q variant was associated with increased atopic sensitization in German children, supporting the TLR2 portion of the claim. But Table 2 (shown in the indexed Discussion, page unavailable) shows no significant association with hay fever (P = 0.239), so this paper does not establish TLR2 as an allergic-rhinitis susceptibility variant. The other genes in the citing sentence are not attributed specifically to this source. (LLM, conf=0.90)
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International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis
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- Authors
- Kormann, M. S. D., Ferstl, R., Depner, M., Klopp, N., Spiller, S., Illig, T., Vogelberg, C., Von Mutius, E., Kirschning, C. J., & Kabesch, M.
- Affiliations
- Ludwig-Maximilians-Universität München (DE)
- Technical University of Munich (DE)
- Helmholtz Munich (DE)
- Corresponding author
- Kabesch, M.
- Venue
- Allergy
- Publisher
- Wiley
- Published
- 2009-03-12
- Volume
- 64
- Issue
- 4
- Pages
- 636-642
- ISSN
- 0105-4538 (ISSN-L)
- 1398-9995
- OpenAlex
- W1993385850
- Cited by
- 39
- References
- 20
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 2 · 2021: 1 · 2019: 1 · 2018: 2 · 2017: 5 · 2016: 1 · 2015: 2 · 2014: 3 · 2013: 7 · 2012: 3
- FWCI
- 1.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Allergy (publishedVersion)
- PubMed (publishedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Site cant be reached (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Dermatology › Dermatology and Skin Diseases
- Health Sciences › Medicine › Physiology › Asthma and respiratory diseases
- Keywords
- TLR2, rare mutations, atopy, atopic sensitization, serum IgE, NF-κB signaling, interleukin-8, innate immunity, genetic susceptibility
- MeSH terms
- Child, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Genotype, Humans, Hypersensitivity, Immediate, Mutation, Risk Factors, Immunoblotting, Polymerase Chain Reaction, Genes, Reporter, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Genetic Predisposition to Disease, Toll-Like Receptor 2
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