CTLA-4 polymorphisms in allergy and asthma and the TH1/TH2 paradigm

Background: Several genomic regions are reported to be associated with the development of asthma and allergy, including chromosome 2q33. This region harbors the candidate gene cytotoxic T-lymphocyte antigen 4 (CTLA-4), an important regulator of T-cell activation and differentiation. Objective: We sought to explore possible associations between CTLA-4 polymorphisms and allergy and asthma. Methods: Seven single nucleotide polymorphisms (SNPs; MH30, -1147CT, +49AG, CT60, JO31, JO30, JO27_1) in CTLA-4 were analyzed for associations with total serum IgE, allergic sensitization (positive skin prick test to common allergens), bronchial hyperresponsiveness (BHR) to methacholine, asthma, and lung function (FEV1% of predicted) in 364 asthmatic families from 3 European countries. Results: Transmission disequilibrium test analysis showed that several SNPs were significantly associated with serum IgE levels, allergy, asthma, and FEV1% predicted below 80%, but not with BHR, and CTLA-4 polymorphisms of potentially direct pathogenic significance in atopic disorders were identified. Conclusion: We identified associations between 4 newly discovered SNPs in the CTLA-4 gene and serum IgE levels, allergy, asthma, and reduced lung function, but not BHR, suggesting an important role for CTLA-4 in atopy and reduced lung function in asthmatic subjects rather than asthma per se. The particular SNP alleles found positively associated with our phenotypes were recently shown to be associated negatively with autoimmune disorders. Although a skewing toward a T(H)1 reactivity pattern is believed to characterize autoimmune diseases, atopic diseases are considered T(H)2-mediated. Hence, our data suggest a role for CTLA-4 polymorphisms in determining the T(H)1/T(H)2 balance and identify CTLA-4 signaling as a potential therapeutic target in atopic disease.