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Published ahead of print on November 10, 2006, doi:10.1165/rcmb.2006-0090OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 36, pp. 491-496, 2007
© 2007 American Thoracic Society
DOI: 10.1165/rcmb.2006-0090OC

Functional Polymorphism in the Suppressor of Cytokine Signaling 1 Gene Associated with Adult Asthma

Michishige Harada*, Kazuko Nakashima*, Tomomitsu Hirota, Makiko Shimizu, Satoru Doi, Kimie Fujita, Taro Shirakawa, Tadao Enomoto, Mamoru Yoshikawa, Hiroshi Moriyama, Kenji Matsumoto, Hirohisa Saito, Yoichi Suzuki, Yusuke Nakamura and Mayumi Tamari

Laboratory for Genetics of Allergic Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Kanagawa; Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Public Health, Kyoto; Department of Microbiology and Immunology, Kagoshima University Dental School, Kagoshima; Department of Pediatric Allergy, Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Habikino, Osaka; School of Human Nursing, The University of Shiga Prefecture, Shiga; Department of Otolaryngology, Japanese Red Cross Society, Wakayama Medical Center, Wakayama; Department of Public Health, Graduate School of Medicine, Chiba University, Chiba; Department of Otorhinolaryngology, Jikei University School of Medicine; Department of Allergy and Immunology, National Research Institute for Child Health & Development; and Laboratory of Molecular Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

Correspondence and requests for reprints should be addressed to Mayumi Tamari, M.D., Ph.D., Laboratory for Genetics of Allergic Diseases, SNP Research Center, Institute of Physical and Chemical Research (RIKEN), 1-7-22 Suehiro, Tsurumi-ku, Yokohama, Kanagawa 230–0045, Japan. E-mail: tamari{at}src.riken.jp

Suppressor of cytokine signaling (SOCS) 1 is an essential physiologic regulator of the IFN-{gamma} signaling that is crucial to lead appropriate immune responses, and impaired IFN-{gamma} production is considered a hallmark of atopic diseases. Recent study has shown that SOCS1 is also crucial in attenuating type 1 IFN signaling and in limiting the host response to viral infection. Clinical and experimental evidence suggest an important role for respiratory viral infections in the development of asthma. To assess genetic functional variants of SOCS1 related to susceptibility and clinical phenotypes in adult asthma in a Japanese population, we conducted association and haplotype analyses of 462 subjects with adult asthma and 639 control subjects. After screening for polymorphisms, we identified a total of 13 variants and characterized the linkage disequilibrium (LD) mapping of the gene. Three variants were selected for genotyping with regard to the LD pattern, and we found a significant association between an SOCS1 promoter polymorphism –1478CA > del and adult asthma (P = 0.0063). The three-locus haplotype of SOCS1 using these three polymorphisms also showed a positive association with a haplotype T-C-del (–5388T, –3969C, and –1478 del; P = 0.0097). Furthermore, reporter gene analysis revealed that related promoter variant –1478 del enhanced the transcriptional level of SOCS1 in human lung epithelial cells, and induced higher levels of protein expression of SOCS1 and lower phosphorylation of STAT1 stimulated with IFN-beta. These findings suggest that the SOCS1 gene might be involved in the development of adult asthma through functional genetic polymorphism.

Key Words: SOCS1 • bronchial asthma • polymorphisms • haplotype • association study


CLINICAL RELEVANCE

Viral infections influence both the development and the severity of asthma. Our data suggest that the susceptible variant might affect the increased sensitivity to viral infection through higher SOCS1 production and contribute to asthma etiology.

 



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