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Human Molecular Genetics Advance Access published online on August 23, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi323
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received June 15, 2005
Revised August 18, 2005
Accepted August 18, 2005

Article

Functional SNPs in the distal promoter of the ST2 gene are associated with atopic dermatitis

Makiko Shimizu 1, Akira Matsuda 2*, Ken Yanagisawa 3, Tomomitsu Hirota 4, Mitsuteru Akahoshi 4, Naoko Inomata 5, Kouji Ebe 6, Keiko Tanaka 7, Hisashi Sugiura 7, Kazuko Nakashima 8, Mayumi Tamari 4, Naomi Takahashi 4, Kazuhiko Obara 4, Tadao Enomoto 9, Yoshimichi Okayama 10, Pei-Song Gao 11, Shau-Ku Huang 11, Shin-ichi Tominaga 3, Zenro Ikezawa 5, and Taro Shirakawa 8

1 Laboratory for Genetics of Allergic Diseases, SNP Research Center, RIKEN, Yokohama, Japan; Department of Dermatology, Yokohama City University School of Medicine, Yokohama, Japan
2 Laboratory for Genetics of Allergic Diseases, SNP Research Center, RIKEN. 1-7-22, Suehiro, Tsurumi-KU, Yokohama, 230-0045, Japan
3 Department of Biochemistry, Jichi Medical School, Tochigi, Japan
4 Laboratory for Genetics of Allergic Diseases, SNP Research Center, RIKEN, Yokohama, Japan
5 Department of Dermatology, Yokohama City University School of Medicine, Yokohama, Japan
6 Takao Hospital, Kyoto, Japan
7 Department of Dermatology, Shiga Medical School, Shiga, Japan
8 Laboratory for Genetics of Allergic Diseases, SNP Research Center, RIKEN, Yokohama, Japan; Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Public Health, Kyoto, Japan
9 Department of Otolaryngology, Japanese Red Cross Society, Wakayama Medical Center, Wakayama, Japan
10 Laboratory of Allergy Transcriptome, Research Center for Allergy and Immunology, RIKEN, Yokohama, Japan
11 Johns Hopkins Asthma and Allergy Center, Johns Hopkins University School of Medicine

* To whom correspondence should be addressed.
Akira Matsuda, E-mail: akimatsu{at}src.riken.go.jp


  Abstract

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 (sST2) protein 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 SNP ({chi}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 evaluation of one of the genetic risk factors for AD.


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