Thymic stromal lymphopoietin gene promoter polymorphisms are associated with susceptibility to bronchial asthma.
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.
Harada
Michishige
M
Laboratory for Respiratory Diseases, Center for Genomic Medicine, Institute of Physical and Chemical Research, Kanagawa, Japan.
Hirota
Tomomitsu
T
Jodo
Aya I
AI
Hitomi
Yuki
Y
Sakashita
Masafumi
M
Tsunoda
Tatsuhiko
T
Miyagawa
Takehiko
T
Doi
Satoru
S
Kameda
Makoto
M
Fujita
Kimie
K
Miyatake
Akihiko
A
Enomoto
Tadao
T
Noguchi
Emiko
E
Masuko
Hironori
H
Sakamoto
Tohru
T
Hizawa
Nobuyuki
N
Suzuki
Yoichi
Y
Yoshihara
Shigemi
S
Adachi
Mitsuru
M
Ebisawa
Motohiro
M
Saito
Hirohisa
H
Matsumoto
Kenji
K
Nakajima
Toshiharu
T
Mathias
Rasika A
RA
Rafaels
Nicholas
N
Barnes
Kathleen C
KC
Himes
Blanca E
BE
Duan
Qing Ling
QL
Tantisira
Kelan G
KG
Weiss
Scott T
ST
Nakamura
Yusuke
Y
Ziegler
Steven F
SF
Tamari
Mayumi
M
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
D001993:Bronchodilator Agents; D016207:Cytokines; D000068299:Salmeterol Xinafoate; D000420:Albuterol; D000094632:Thymic Stromal Lymphopoietin