Atopic dermatitis (AD) is a common inflammatory skin disease associated with the local infiltration of T helper type 2 (Th2) cells. The ST2 gene encodes both membrane-bound ST2L and soluble ST2 (sST2) proteins by alternative splicing. The orphan receptor ST2L is functionally indispensable for Th2 cells. We found a significant genetic association between AD and the -26999G/A single nucleotide polymorphism (SNP) (chi2-test, raw P-value=0.000007, odds ratio 1.86) in the distal promoter region of the ST2 gene (chromosome 2q12) in a study of 452 AD patients and 636 healthy controls. The -26999A allele common among AD patients positively regulates the transcriptional activity of the ST2 gene. In addition, having at least one -26999A allele correlated with high sST2 concentrations and high total IgE levels in the sera from AD patients. Thus, the -26999A allele is correlated with an increased risk for AD. We also found that the -26999G/A SNP predominantly affected the transcriptional activity of hematopoietic cells. Immunohistochemical staining of a skin biopsy specimen from an AD patient in the acute stage showed ST2 staining in the keratinocytes as well as in the infiltrating cells in the dermal layer. Our data show that functional SNPs in the ST2 distal promoter region regulate ST2 expression which induces preferential activation of the Th2 response. Our findings will contribute to the evaluation of one of the genetic risk factors for AD.

Suppressor of cytokine signaling (SOCS) 1 is an essential physiologic regulator of the IFN-gamma signaling that is crucial to lead appropriate immune responses, and impaired IFN-gamma production is considered a hallmark of atopic diseases. Recent study has shown that SOCS1 is also crucial in attenuating type 1 IFN signaling and in limiting the host response to viral infection. Clinical and experimental evidence suggest an important role for respiratory viral infections in the development of asthma. To assess genetic functional variants of SOCS1 related to susceptibility and clinical phenotypes in adult asthma in a Japanese population, we conducted association and haplotype analyses of 462 subjects with adult asthma and 639 control subjects. After screening for polymorphisms, we identified a total of 13 variants and characterized the linkage disequilibrium (LD) mapping of the gene. Three variants were selected for genotyping with regard to the LD pattern, and we found a significant association between an SOCS1 promoter polymorphism -1478CA > del and adult asthma (P = 0.0063). The three-locus haplotype of SOCS1 using these three polymorphisms also showed a positive association with a haplotype T-C-del (-5388T, -3969C, and -1478 del; P = 0.0097). Furthermore, reporter gene analysis revealed that related promoter variant -1478 del enhanced the transcriptional level of SOCS1 in human lung epithelial cells, and induced higher levels of protein expression of SOCS1 and lower phosphorylation of STAT1 stimulated with IFN-beta. These findings suggest that the SOCS1 gene might be involved in the development of adult asthma through functional genetic polymorphism.

Asthma is a phenotypically heterogeneous disorder with many etiologic factors and clinical characteristics. T-bet, a Th1-specific transcription factor of T-box family, has been found to control interferon-gamma (IFN-gamma) expression in T cells. Mice lacking the T-bet gene (tbx21) demonstrate multiple physiological and inflammatory features reminiscent of human asthma. In order to examine whether polymorphisms in the candidate gene, TBX21, located on chromosome 17q21.32, are related to the risk of human asthma phenotypes, we have searched for genetic variations in the human TBX21 gene and identified 24 single nucleotide polymorphisms (SNPs), including five novel SNPs, by direct sequencing in Japanese subjects. Among asthma phenotypes, a promoter -1993T-->C SNP, which is in linkage disequilibrium with a synonymous coding 390A-->G SNP in exon 1, is significantly associated with a risk of aspirin-induced asthma (AIA; P = 0.004, P(c) = 0.016). This association has also been confirmed in additional independent samples of asthma with nasal polyposis (P = 0.008), regardless of aspirin hypersensitivity. Furthermore, our data indicate that the -1993T-->C substitution increases the affinity of a particular nuclear protein to the binding site of TBX21 covering the -1993 position, resulting in increased transcriptional activity of the TBX21 gene. Thus, in addition to the antigen-driven excess Th2 response, increased T-bet (and subsequent IFN-gamma) production in human airways of individuals with the -1993T-->C polymorphism could contribute to the development of certain asthma-related phenotypes, such as AIA.