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Published on: July 26, 2017
Rare TLR2 mutations reduce TLR2 receptor function and can increase atopy risk
M S D Kormann1, R Ferstl, M Depner
1University Children's Hospital, Ludwig Maximilians University Munich, Germany.
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-kappaB-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.
Insights
Rare toll-like receptor 2 (TLR2) mutations can impact atopic diseases. The R753Q mutation in TLR2 increases atopic sensitization risk and elevates IgE levels in the general population.
Area of Science:
- Immunology
- Genetics
Background:
- Toll-like receptor 2 (TLR2) variations are linked to atopic diseases.
- The role of rare TLR2 mutations in atopic diseases is largely unknown.
Purpose of the Study:
- Investigate functional properties of rare TLR2 mutations.
- Assess the impact of these mutations on atopic sensitization and disease.
Main Methods:
- Identified rare TLR2 mutations from databases.
- Analyzed functional effects using in vitro assays (NF-kappaB luciferase reporter, IL-8 ELISA).
- Determined mutation frequency in the general population and association with atopic diseases in a German cohort.
Main Results:
- Three of six TLR2 mutations altered receptor activity in vitro.
- The R753Q mutation (3% minor allele frequency) significantly increased atopy risk by 50%.
- R753Q carriers showed elevated total and allergen-specific IgE levels.
Conclusions:
- The rare R753Q mutation in TLR2 is functionally relevant.
- This mutation may significantly influence atopic sensitization in the general population.
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