IL-17F sequence variant (His161Arg) is associated with protection against asthma and antagonizes wild-type IL-17F activity

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 χ ² 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.