IL-17F sequence variant (His161Arg) is associated with protection against asthma and antagonizes wild-type IL-17F activity - 17/08/11
, Daisuke Takahashi, MD b, , Nobuyuki Hizawa, MD b, ⁎ 
, Shintaro Suzuki, MD a, Satoshi Matsukura, MD a, Fumio Kokubu, MD a, Yukiko Maeda, MD b, Yoshinobu Fukui, MD b, Satoshi Konno, MD b, Shau-Ku Huang, PhD c, Masaharu Nishimura, MD b, Mitsuru Adachi, MD aReprint requests: Nobuyuki Hizawa, MD, First Department of Medicine, Hokkaido University Graduate School of Medicine, Kita-Ku N-15 W-7, Sapporo 060-8638, Japan.Tokyo and Sapporo, Japan, and Baltimore, Md
Abstract |
Background |
IL-17F is a recently discovered cytokine that plays a role in tissue inflammation by inducing release of proinflammatory and neutrophil-mobilizing cytokines. Upregulated IL17F gene expression has been observed at sites of allergen challenge in the airways of patients with asthma, suggesting that IL-17F is involved in the pathophysiology of asthma.
Objective |
To investigate the role of IL-17F in asthma pathogenesis, we conducted genetic analyses of association of asthma with the common variants of IL17F, using 867 unrelated Japanese subjects.
Methods |
Five polymorphisms were studied, including the coding-region sequence variant single nucleotide polymorphism rs763780 (7488T/C), which causes a His-to-Arg substitution at amino acid 161 (H161R). Functional consequences of the H161R substitution were examined by using recombinant wild-type and mutant IL-17F proteins.
Results |
Homozygosity of the H161R variant was inversely associated with asthma; the odds ratio (95% CI) for asthma was 0.06 (0.01-0.43) for the H161R homozygote compared with the wild-type homozygote (P = .0039). This result remains significant (P = .0079) after adjustment for the presence of atopy using the Mantel-Haenszel χ2 test. In addition, in vitro functional experiments demonstrated that the H161R variant of IL-17F lacks the ability to activate the mitogen-activated protein kinase pathway, cytokine production, and chemokine production in bronchial epithelial cells, unlike wild-type IL-17F. Furthermore, the H161R variant blocked induction of IL-8 expression by wild-type IL-17F.
Conclusion |
The current findings indicate that the IL-17F H161R variant influences the risk of asthma and is a natural IL-17F antagonist, suggesting a potential role for IL-17F in the etiology of asthma.
Le texte complet de cet article est disponible en PDF.Key words : Asthma, candidate gene, case-control association analysis, IL-17F, single nucleotide polymorphism
Abbreviations used : ENA, ERK, GRO⍺, MEK, muIL-17F, OR, SNP, wtIL-17F
Plan
| Supported in part by the Ministry of Health, Labor and Welfare of Japan (15590788), and by a National Institutes of Health grant (AI-52468). Disclosure of potential conflict of interest: The authors have declared they have no conflict of interest. |
Vol 117 - N° 4
P. 795-801 - avril 2006 Retour au numéro
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