Human Molecular Genetics Advance Access originally published online on August 23, 2005
Human Molecular Genetics 2005 14(19):2919-2927; doi:10.1093/hmg/ddi323
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Functional SNPs in the distal promoter of the ST2 gene are associated with atopic dermatitis
1Laboratory for Genetics of Allergic Diseases, SNP Research Center, RIKEN, Yokohama, Japan, 2Department of Dermatology, Yokohama City University School of Medicine, Yokohama, Japan, 3Department of Biochemistry, Jichi Medical School, Tochigi, Japan, 4Takao Hospital, Kyoto, Japan, 5Department of Dermatology, Shiga Medical School, Shiga, Japan, 6Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Public Health, Kyoto, Japan, 7Department of Otolaryngology, Japanese Red Cross Society, Wakayama Medical Center, Wakayama, Japan, 8Laboratory of Allergy Transcriptome, Research Center for Allergy and Immunology, RIKEN, Yokohama, Japan and 9Johns Hopkins Asthma and Allergy Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
* To whom correspondence should be addressed at: Laboratory for Genetics of Allergic Diseases, SNP Research Center, RIKEN, 1-7-22, Suehiro, Tsurumi-KU, Yokohama 230-0045, Japan. Tel: +81 455039616; Fax: +81 455039615; Email: akimatsu{at}src.riken.go.jp
Received June 15, 2005; Accepted August 18, 2005
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) (
2-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.
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