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CD14 and Toll-like Receptor Gene Polymorphisms, Country Living, and Asthma in Adults

¹ INSERM, U780, Villejuif, France; ² Division of Environmental Epidemiology, Institute for Risk Assessment Sciences, Utrecht, The Netherlands; ³ INSERM, U823, Centre de Recherche Albert Bonniot, Epidémiologie des cancers et des affections graves, La Tronche, France; ⁴ Université Joseph Fourier, Grenoble, France; ⁵ INSERM, U794, Paris, France; ⁶ Université d'Evry, Evry, France; ⁷ Fondation Jean Dausset-Centre d'Etude du Polymorphisme Humain (CEPH), Paris, France; ⁸ Université Paris-Sud, IFR69, Villejuif, France; ⁹ Commissariat à l'Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry, France

Correspondence and requests for reprints should be addressed to Francine Kauffmann, M.D., INSERM U780, 16 Avenue Paul Vaillant Couturier, 94807 Villejuif Cedex, France. E-mail: francine.kauffmann{at}inserm.fr

Rationale: It has been shown that country living protects against asthma, which may be explained by microbial exposures.

Objectives: To study whether single nucleotide polymorphisms (SNPs) in CD14 and Toll-like receptor (TLR) 2, TLR4 and TLR9 genes are associated with asthma in adults, and whether these SNPs modify associations between country living and asthma.

Methods: Twenty-five SNPs in CD14, TLR2, TLR4, and TLR9 genes were genotyped in adult subjects from the French Epidemiological study on the Genetics and Environment of Asthma, Bronchial Hyperresponsiveness, and Atopy (EGEA). We conducted a case-control analysis on unrelated subjects (239 with asthma and 596 without asthma), and a family-based association test (FBAT) in 192 families ascertained through probands with asthma.

Measurements and Main Results: The TLR2/+596 C allele was associated with an increased risk for asthma in both case-control and family-based analyses (under a dominant model, odds ratio [OR] 1.91 and 95% confidence interval [CI] 1.34–2.72, P = 0.0003; Z statistics from FBAT = 2.48, P = 0.01). In skin prick test (SPT) positive subjects, the CD14/-260 C allele was negatively associated with asthma (additive model, OR 0.66; CI 0.48–0.91). Significant gene–environment interactions between variation in CD14 and TLR genes and country living during childhood were found for ten SNPs. In SPT positive subjects carrying CD14/-260 CC, country living protected against asthma (OR, 0.32; 95% CI, 0.12–0.85), whereas country living was not associated with asthma in subjects who were atopic and carrying CD14/-260 T (OR, 1.11; 95% CI, 0.65–1.90) (gene–environment interaction, P < 0.05).

Conclusions: TLR2 and CD14 SNPs were associated with asthma and atopic asthma respectively. In addition, CD14, TLR2, TLR4, and TLR9 SNPs modified associations between country living and asthma.

Key Words: asthma • atopy • epidemiology • gene–environment interaction • hygiene hypothesis

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Several studies have suggested that gene–environment interactions play an important role in the occurrence of asthma and allergy. Genes dependent on the innate immunity pathway are candidates for the understanding of the protective effects of exposure to microbial agents on allergy and asthma. What This Study Adds to the Field TLR2 and CD14 SNPs were associated with asthma and atopic asthma, respectively. Variation in CD14, TLR2, TLR4, and TLR9 genes modified associations between country living during childhood and asthma, particularly among subjects who were atopic.