A single nucleotide polymorphism on the promoter of eotaxin1 associates with its mRNA expression and asthma phenotypes

Abstract

Eotaxin1 plays a pivotal role in eosinophil-associated inflammation. Previously, we demonstrated 14 single-nucleotide polymorphisms (SNPs) in the human eotaxin 1 gene and the association between the EOT+67G>A allele and the level of IgE,. In this study. we investigated the association between the SNPs and plasma eotaxin 1 levels. peripheral blood eosinophil counts, and PC20 methacholine values in normal and asthmatic subjects, and the effects of SNI's on the process of eotaxin 1 production. The EOT-576C>T and EOT-384A>G polymorphisms and haplotypes (ht1 and ht4) were si--nificantly associated with pin a eotaxin 1 levels in the asthmatics (p < 0.001-0.040). The log [plasma eotaxin1] values correlated with the log (serum total 1g] values in the asthmatics and the normal controls (p = 0.012 and p = 0.004, respectively), and with the log [PC20 methacholine] values in the asthmatics (p = 0.014). A DNA-protein complex was formed with EOT-384A > G. but not with the other SNTs or the promoter. The interaction was stronger with the minor allele than with the common allele. and was reduced upon TNT-alpha exposurte. TNF-alpha-stimulated PBMCs front the asthmatics with the minor allele homozygote expressed sigificantly lower levels of eotaxin 1 mRNA than those front individuals with the common allele. The EOT+67G>A polymorphism. which substitutes alanine with threonine, did not affect eotaxin1 production or activity. Our data suggest that the EOT-384.A>G SNP participates in the regulation of eotaxinl expression by providing a potential binding site for a repressor. and that the ANOVA of EOT-3844 > G may predict asthma phenotypes.