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Published ahead of print on November 10, 2006, doi:10.1165/rcmb.2006-0090OC

Am. J. Respir. Cell Mol. Biol., Volume 36, Number 4, April 2007, 491-496

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Submitted on February 28, 2006
Revised on November 6, 2006

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

Michishige Harada1, Kazuko Nakashima2, Tomomitsu Hirota3, Makiko Shimizu1, Satoru Doi4, Kimie Fujita5, Taro Shirakawa6, Tadao Enomoto7, Mamoru Yoshikawa8, Hiroshi Moriyama8, Kenji Matsumoto9, Hirohisa Saito9, Yoichi Suzuki10, Yusuke Nakamura11, and Mayumi Tamari1*

1 Laboratory for Genetics of Allergic Diseases, The Institute of Physical and Chemical Research (RIKEN), SNP Research Center, Kanagawa, Japan, 2 Laboratory for Genetics of Allergic Diseases, The Institute of Physical and Chemical Research (RIKEN), SNP Research Center, Kanagawa, Japan; Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Public Health, Kyoto, Japan, 3 Laboratory for Genetics of Allergic Diseases, The Institute of Physical and Chemical Research (RIKEN), SNP Research Center, Kanagawa, Japan; Department of Microbiology and Immunology, Kagoshima University Dental School, Kagoshima, Japan, 4 Department of Pediatric Allergy, Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Habikino Osaka, Japan, 5 School of Human Nursing, The University of Shiga Prefecture, Shiga, Japan, 6 Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Public Health, Kyoto, Japan, 7 Department of Otolaryngology, Japanese Red Cross Society, Wakayama Medical Center, Wakayama, Japan, 8 Department of Otorhinolaryngology, Jikei University School of Medicine, Minato-ku Tokyo, Japan, 9 Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo, Japan, 10 Department of Public Health, Chiba University, Graduate School of Medicine, Chiba, Japan, 11 Laboratory of Molecular Medicine, The University of Tokyo, The Institute of Medical Science, Tokyo, Japan

* To whom correspondence should be addressed. E-mail: tamari{at}src.riken.jp.

Suppressor of cytokine signaling (SOCS) 1 is an essential physiological regulator of the interferon (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 SOCS 1 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 controls. After screening for polymorphisms, we identified a total of thirteen 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 3-locus haplotype of SOCS1 using these 3 polymorphisms also showed a positive association with a haplotype T-C-del (-5388T, -3969C and -1478del; P = 0.0097). Furthermore, reporter gene analysis revealed that related promoter variant -1478del 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.




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