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Human Molecular Genetics Advance Access originally published online on August 22, 2005
Human Molecular Genetics 2005 14(19):2779-2786; doi:10.1093/hmg/ddi311
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Coding SNP in tenascin-C Fn-III-D domain associates with adult asthma

Akira Matsuda1,*, Tomomitsu Hirota1, Mitsuteru Akahoshi1, Makiko Shimizu1, Mayumi Tamari1, Akihiko Miyatake3, Atsushi Takahashi2, Kazuko Nakashima1,4, Naomi Takahashi1, Kazuhiko Obara1, Noriko Yuyama5, Satoru Doi6, Yumiko Kamogawa7, Tadao Enomoto9, Koichi Ohshima10, Tatsuhiko Tsunoda2, Shoichiro Miyatake7, Kimie Fujita11, Moriaki Kusakabe12, Kenji Izuhara13, Yusuke Nakamura8, Julian Hopkin14 and Taro Shirakawa1,4

1Laboratory for Genetics of Allergic Diseases and 2Laboratory for Medical Informatics, SNP Research Center, RIKEN, Yokohama, Japan, 3Miyatake Asthma Clinic, Osaka, Japan, 4Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Public Health, Kyoto, Japan, 5Genox Research Inc., Kawasaki, Japan, 6Osaka Prefectural Habikino Hospital, Osaka, Japan, 7Department of Molecular and Developmental Biology and 8Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan, 9Department of Otolaryngology, Japanese Red Cross Society, Wakayama Medical Center, Wakayama, Japan, 10Department of Pathology, School of Medicine, Fukuoka University, Fukuoka, Japan, 11College of Nursing, University of Shiga, Shiga, Japan, 12Experimental Animal Research Center, Institute for Animal Reproduction, Ibaraki, Japan, 13Department of Biomolecular Sciences, Saga Medical School, Saga, Japan and 14Experimental Medicine Unit, University of Wales Swansea, Swansea, UK

* To whom correspondence should be addressed at: Laboratory for Genetics of Allergic Diseases, SNP Research Center, RIKEN, Suehiro 1-7-22, Tsurumi-KU, Yokohama 230-0045, Japan. Tel: +81 455039616; Fax: +81 455039615; Email: akimatsu{at}src.riken.go.jp

Received June 20, 2005; Accepted August 9, 2005

The extracellular matrix glycoprotein tenascin-C (TNC) has been accepted as a valuable histopathological subepithelial marker for evaluating the severity of asthmatic disease and the therapeutic response to drugs. We found an association between an adult asthma and an SNP encoding TNC fibronectin type III-D (Fn-III-D) domain in a case–control study between a Japanese population including 446 adult asthmatic patients and 658 normal healthy controls. The SNP (44513A/T in exon 17) strongly associates with adult bronchial asthma ({chi}2 test, P=0.00019, Odds ratio=1.76, 95% confidence interval=1.31–2.36). This coding SNP induces an amino acid substitution (Leu1677Ile) within the Fn-III-D domain of the alternative splicing region. Computer-assisted protein structure modeling suggests that the substituted amino acid locates at the outer edge of the beta-sheet in Fn-III-D domain and causes instability of this beta-sheet. As the TNC fibronectin-III domain has molecular elasticity, the structural change may affect the integrity and stiffness of asthmatic airways. In addition, TNC expression in lung fibroblasts increases with Th2 immune cytokine stimulation. Thus, Leu1677Ile may be valuable marker for evaluating the risk for developing asthma and plays a role in its pathogenesis.


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