Thymic Stromal Lymphopoietin Gene Promoter Polymorphisms Are Associated with Susceptibility to Bronchial Asthma

被引：184

作者：

Harada, Michishige

Hirota, Tomomitsu

Jodo, Aya I.

Hitomi, Yuki

Sakashita, Masafumi

Tsunoda, Tatsuhiko ^{[2
]}

Miyagawa, Takehiko ^{[3
]}

Doi, Satoru ^{[4
]}

Kameda, Makoto ^{[4
]}

Fujita, Kimie ^{[5
]}

Miyatake, Akihiko ^{[6
]}

Enomoto, Tadao ^{[7
]}

Noguchi, Emiko ^{[8
]}

Masuko, Hironori ^{[9
]}

Sakamoto, Tohru ^{[9
]}

Hizawa, Nobuyuki ^{[9
]}

Suzuki, Yoichi ^{[10
]}

Yoshihara, Shigemi ^{[11
]}

Adachi, Mitsuru ^{[12
]}

Ebisawa, Motohiro ^{[13
]}

Saito, Hirohisa ^{[14
]}

Matsumoto, Kenji ^{[14
]}

Nakajima, Toshiharu ^{[14
]}

Mathias, Rasika A. ^{[15
]}

Rafaels, Nicholas ^{[15
]}

Barnes, Kathleen C. ^{[15
]}

Himes, Blanca E. ^{[16
,17
]}

Duan, Qing Ling ^{[16
,17
]}

Tantisira, Kelan G. ^{[16
,17
]}

Weiss, Scott T. ^{[16
,17
]}

Nakamura, Yusuke ^{[18
]}

Ziegler, Steven F. ^{[19
]}

Tamari, Mayumi ^{[1
]}

机构：

[1] Inst Phys & Chem Res, Ctr Genom Med, Lab Resp Dis, Tsurumi Ku, Kanagawa 2300045, Japan

[2] Inst Phys & Chem Res, Ctr Genom Med, Lab Med Informat, Kanagawa 2300045, Japan

[3] Miyagawa Clin, Gifu, Japan

[4] Osaka Prefectural Med Ctr Resp & Allerg Dis, Dept Pediat Allergy, Osaka, Japan

[5] Univ Shiga Prefecture, Sch Human Nursing, Shiga, Japan

[6] Miyatake Asthma Clin, Osaka, Japan

[7] Non Profit Org Japan Hlth Promot Supporting Netwo, Wakayama, Japan

[8] Univ Tsukuba, Dept Med Genet, Grad Sch Comprehens Human Sci, Ibaraki, Japan

[9] Univ Tsukuba, Inst Clin Med, Div Resp Med, Ibaraki, Japan

[10] Chiba Univ, Dept Publ Hlth, Grad Sch Med, Chiba, Japan

[11] Dokkyo Univ, Sch Med, Dept Pediat, Utsunomiya, Tochigi, Japan

[12] Showa Univ, Sch Med, Div Resp & Allergy Med, Dept Internal Med, Tokyo 142, Japan

[13] Natl Sagamihara Hosp, Dept Pediat Allergy, Clin Res Ctr Allergy & Rheumatol, Kanagawa, Japan

[14] Natl Res Inst Child Hlth & Dev, Dept Allergy & Immunol, Tokyo, Japan

[15] Johns Hopkins Univ, Johns Hopkins Asthma & Allergy Ctr, Baltimore, MD USA

[16] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA

[17] Harvard Univ, Sch Med, Boston, MA USA

[18] Univ Tokyo, Inst Med Sci, Mol Med Lab, Tokyo, Japan

[19] Benaroya Res Inst, Program Immunol, Seattle, WA USA

来源：

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY | 2011年 / 44卷 / 06期

基金：

美国国家卫生研究院;

关键词：

asthma; TSLP; bronchial epithelial cells; combination therapy; genetic polymorphisms; AIRWAY EPITHELIAL-CELLS; CHILDHOOD ATOPIC ASTHMA; NF-KAPPA-B; ALLERGIC INFLAMMATION; COMBINATION THERAPY; EXACERBATIONS; RHINOVIRUS; EXPRESSION; CHEMOKINES; INFECTION;

D O I：

10.1165/rcmb.2009-0418OC

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 beta(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.

引用

页码：787 / 793

页数：7

共 36 条

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