title: Thymic stromal lymphopoietin gene promoter polymorphisms are associated with susceptibility to bronchial asthma.
abstract: Thymic stromal lymphopoietin (TSLP) triggers dendritic cell--mediated T helper (Th) 2 inflammatory responses. A single-nucleotide polymorphism (SNP), rs3806933, in the promoter region of the TSLP gene creates a binding site for the transcription factor activating protein (AP)-1. The variant enhances AP-1 binding to the regulatory element, and increases the promoter--reporter activity of TSLP in response to polyinosinic-polycytidylic acid (poly[I:C]) stimulation in normal human bronchial epithelium (NHBE). We investigated whether polymorphisms including the SNP rs3806933 could affect the susceptibility to and clinical phenotypes of bronchial asthma. We selected three representative (i.e., Tag) SNPs and conducted association studies of the TSLP gene, using two independent populations (639 patients with childhood atopic asthma and 838 control subjects, and 641 patients with adult asthma and 376 control subjects, respectively). We further examined the effects of corticosteroids and a long-acting β(2)-agonist (salmeterol) on the expression levels of the TSLP gene in response to poly(I:C) in NHBE. We found that the promoter polymorphisms rs3806933 and rs2289276 were significantly associated with disease susceptibility in both childhood atopic and adult asthma. The functional SNP rs3806933 was associated with asthma (meta-analysis, P = 0.000056; odds ratio, 1.29; 95% confidence interval, 1.14-1.47). A genotype of rs2289278 was correlated with pulmonary function. Moreover, the induction of TSLP mRNA and protein expression induced by poly(I:C) in NHBE was synergistically impaired by a corticosteroid and salmeterol. TSLP variants are significantly associated with bronchial asthma and pulmonary function. Thus, TSLP may serve as a therapeutic target molecule for combination therapy.
authors.affiliation: Laboratory for Respiratory Diseases, Center for Genomic Medicine, Institute of Physical and Chemical Research, Kanagawa, Japan.
authors.forename: Michishige
authors.initials: M
authors.lastname: Harada
authors.forename: Tomomitsu
authors.initials: T
authors.lastname: Hirota
authors.forename: Aya I
authors.initials: AI
authors.lastname: Jodo
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hitomi
authors.forename: Masafumi
authors.initials: M
authors.lastname: Sakashita
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tsunoda
authors.forename: Takehiko
authors.initials: T
authors.lastname: Miyagawa
authors.forename: Satoru
authors.initials: S
authors.lastname: Doi
authors.forename: Makoto
authors.initials: M
authors.lastname: Kameda
authors.forename: Kimie
authors.initials: K
authors.lastname: Fujita
authors.forename: Akihiko
authors.initials: A
authors.lastname: Miyatake
authors.forename: Tadao
authors.initials: T
authors.lastname: Enomoto
authors.forename: Emiko
authors.initials: E
authors.lastname: Noguchi
authors.forename: Hironori
authors.initials: H
authors.lastname: Masuko
authors.forename: Tohru
authors.initials: T
authors.lastname: Sakamoto
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Hizawa
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Shigemi
authors.initials: S
authors.lastname: Yoshihara
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Adachi
authors.forename: Motohiro
authors.initials: M
authors.lastname: Ebisawa
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Saito
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Nakajima
authors.forename: Rasika A
authors.initials: RA
authors.lastname: Mathias
authors.forename: Nicholas
authors.initials: N
authors.lastname: Rafaels
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Barnes
authors.forename: Blanca E
authors.initials: BE
authors.lastname: Himes
authors.forename: Qing Ling
authors.initials: QL
authors.lastname: Duan
authors.forename: Kelan G
authors.initials: KG
authors.lastname: Tantisira
authors.forename: Scott T
authors.initials: ST
authors.lastname: Weiss
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Steven F
authors.initials: SF
authors.lastname: Ziegler
authors.forename: Mayumi
authors.initials: M
authors.lastname: Tamari
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000420:Albuterol / Q000031:analogs & derivatives / Q000494:pharmacology; D001249:Asthma / Q000235:genetics*; D001665:Binding Sites; D001993:Bronchodilator Agents / Q000494:pharmacology; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000235:genetics* / Q000502:physiology; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D000068299:Salmeterol Xinafoate; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D001993:Bronchodilator Agents; D016207:Cytokines; D000068299:Salmeterol Xinafoate; D000420:Albuterol; D000094632:Thymic Stromal Lymphopoietin