Mechanisms of Allergy
Toll-like receptor 2 as a major gene for asthma in children of European farmers

https://doi.org/10.1016/j.jaci.2003.12.374Get rights and content

Abstract

Background

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.

Objectives

We reasoned that polymorphisms in genes encoding TLRs might modulate the protective effects observed in farming populations.

Methods

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.

Results

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.

Conclusion

Our results suggest that genetic variation in TLR2 is a major determinant of the susceptibility to asthma and allergies in children of farmers.

Section snippets

Population, phenotypes, and exposure to farming and endotoxin

Our study population included 609 children in school grades 1 to 6 from rural areas in Austria and Bavaria (Germany) who took part in the cross-sectional ALEX study, as previously described.8 In brief, a self-administered questionnaire on respiratory and allergic diseases was filled out by the parents of children living on a farm and the parents of children living in the same rural area but not raised on a farm. Participating children and their parents were asked for consent to venipuncture and

Results

Our study population included 229 farmers' children and 380 children from the same rural area but not living on a farm. The mean age was 9.4 years (SD, 1.5) in farmers' children and 9.3 years (SD, 1.5) in nonfarmers' children. There were slightly more boys among the farmers' children (56%) than among the nonfarmers' children (51%).

The median of the endotoxin concentrations from the mattress samples was 27.4 EU/mg dust (interquartile range, 24.0 EU/mg) and, as previously reported,13 was

Discussion

In this study we found that a polymorphism in the TLR2 gene is strongly associated with the frequency of asthma and allergies in children of European farmers and that a polymorphism in the TLR4 gene has an influence on atopy in children heavily exposed to endotoxin. These results point to a gene-by-environment interaction because both TLR2 and TLR4 are genes encoding ancient pattern-recognition receptors for different microbial molecules.

The potential role of TLRs as regulators of immune

Acknowledgements

We thank Cathy Holberg for statistical support and the collaborators of the ALEX Team: Soyoun Maisch, Rudi Schierl, David Carr (Munich, Germany), Marco Waser (Basel, Switzerland), Roger Lauener, Felix Sennhauser (Zurich, Switzerland), Mynda Schreuer, Gerd Oberfeld (Salzburg, Austria), Harald Renz, Udo Herz (Marburg Germany), Albrecht Bufe (Bochum, Germany), and Otto Holst (Borstel, Germany).

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    Supported by the National Heart, Lung, and Blood Institute (PGA-HL66800 and a Specialized Center of Research grant: HL67672), by the Bavarian Ministry for the Environment, by an Austrian grant from the Health Department of the Government of Salzburg, by the Zürich Lung Association, and by the United Bank of Switzerland.

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    Reprint requests: Fernando D. Martinez, MD, Arizona Respiratory Center, University of Arizona, 1501 N Campbell Ave, PO Box 245030, Tucson, AZ 85724.

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