title: Functional SNPs in the distal promoter of the ST2 gene are associated with atopic dermatitis.
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 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.
authors.affiliation: Laboratory for Genetics of Allergic Diseases, SNP Research Center, RIKEN, Yokohama, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Shimizu
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuda
authors.forename: Ken
authors.initials: K
authors.lastname: Yanagisawa
authors.forename: Tomomitsu
authors.initials: T
authors.lastname: Hirota
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Akahoshi
authors.forename: Naoko
authors.initials: N
authors.lastname: Inomata
authors.forename: Kouji
authors.initials: K
authors.lastname: Ebe
authors.forename: Keiko
authors.initials: K
authors.lastname: Tanaka
authors.forename: Hisashi
authors.initials: H
authors.lastname: Sugiura
authors.forename: Kazuko
authors.initials: K
authors.lastname: Nakashima
authors.forename: Mayumi
authors.initials: M
authors.lastname: Tamari
authors.forename: Naomi
authors.initials: N
authors.lastname: Takahashi
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Obara
authors.forename: Tadao
authors.initials: T
authors.lastname: Enomoto
authors.forename: Yoshimichi
authors.initials: Y
authors.lastname: Okayama
authors.forename: Pei-Song
authors.initials: PS
authors.lastname: Gao
authors.forename: Shau-Ku
authors.initials: SK
authors.lastname: Huang
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Tominaga
authors.forename: Zenro
authors.initials: Z
authors.lastname: Ikezawa
authors.forename: Taro
authors.initials: T
authors.lastname: Shirakawa
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D003876:Dermatitis, Atopic / Q000235:genetics / Q000276:immunology*; D005347:Fibroblasts / Q000737:chemistry / Q000378:metabolism; D017930:Genes, Reporter; D006239:Haplotypes; D006412:Hematopoietic Stem Cells / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein; D015603:Keratinocytes / Q000737:chemistry / Q000378:metabolism; D008407:Mast Cells / Q000737:chemistry / Q000378:metabolism; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011956:Receptors, Cell Surface; D018418:Th2 Cells / Q000276:immunology; D014158:Transcription, Genetic
chemical_list: C079241:IL1RL1 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; D008565:Membrane Proteins; D011956:Receptors, Cell Surface