Association of Plasma Soluble CTLA-4 with Lung Function and GenePolymorphism in Chinese Asthmatic Children

Abstract

Background: Cytotoxic T lymphocyte antigen 4 (CTLA-4) is known to downregulate the T_H2 immune response. Recent studies have suggested an association of CTLA-4 polymorphisms with allergic diseases. We investigated the effects of single nucleotide polymorphisms (SNPs) of CTLA-4 on asthma traits and plasma sCTLA-4 in 298 Chinese asthmatic children and 175 controls. Methods: Plasma sCTLA-4, total and allergen-specific IgE concentrations were measured by enzyme immunoassay. Six SNPs, namely –1147CT, +49AG, CT60, JO31, JO30 and JO27_1, in CTLA-4 were genotyped by restriction fragment length polymorphism. Results: Plasma sCTLA-4 was negatively associated with FEV₁/FVC (r = –0.146, p = 0.036) among our asthmatic patients. Analysis of locus-locus interaction by generalized multifactor dimensionality reduction showed that –1147CT was the best model for plasma sCTLA-4 with a cross-validation consistency of 10 out of 10 and a prediction error of 40.9% (p < 0.001). Multivariate regression analysis confirmed the association between plasma sCTLA-4 concentration with –1147CT among the 6 SNPs tested (p = 0.002) after adjustment for gender and age. The plasma sCTLA-4 concentration was significantly lower in patients homozygous for the C allele than in T allele carriers (p = 0.001). There was also a significant association between the most common haplotypes with low sCTLA-4 in asthmatics. We could not find any significant association between plasma total IgE, atopy and lung function with the 6 SNPs after Bonferroni correction. Conclusions: Plasma sCTLA-4 is associated with lung function and –1147CT polymorphism in Chinese asthmatic children. This may help to identify CTLA-4 signaling as a potential therapeutic target in asthma.