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Human Molecular Genetics Advance Access published online on August 22, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi311
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received June 20, 2005
Revised August 9, 2005
Accepted August 9, 2005

Article

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

Akira Matsuda 1*, Tomomitsu Hirota 2, Mitsuteru Akahoshi 2, Makiko Shimizu 2, Mayumi Tamari 2, Akihiko Miyatake 3, Atsushi Takahashi 4, Kazuko Nakashima 5, Naomi Takahashi 2, Kazuhiko Obara 2, Noriko Yuyama 6, Satoru Doi 7, Yumiko Kamogawa 8, Tadao Enomoto 9, Koichi Ohshima 10, Tatsuhiko Tsunoda 4, Shoichiro Miyatake 8, Kimie Fujita 11, Moriaki Kusakabe 12, Kenji Izuhara 13, Yusuke Nakamura 14, Julian Hopkin 15, and Taro Shirakawa 5

1 Laboratory for Genetics of Allergic Diseases, SNP Research Center, RIKEN, Suehiro 1-7-22, Tsurumi-KU, Yokohama, 230-0045, Japan
2 Laboratory for Genetics of Allergic Diseases, SNP Research Center, RIKEN, Yokohama, Japan
3 Miyatake Asthma Clinic, Osaka, Japan
4 Laboratory for Medical Informatics, SNP Research Center, RIKEN, Yokohama, Japan
5 Laboratory for Genetics of Allergic Diseases, SNP Research Center, RIKEN, Yokohama, Japan; Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Public Health, Kyoto, Japan
6 Genox Research Inc, Kawasaki, Japan
7 Osaka Prefectural Habikino Hospital, Osaka, Japan
8 Department of Molecular and Developmental Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
9 Department of Otolaryngology, Japanese Red Cross Society, Wakayama Medical Center, Wakayama, Japan
10 Department of Pathology, School of Medicine, Fukuoka University, Fukuoka, Japan,
11 College of Nursing, University of Shiga, Shiga, Japan
12 Experimental Animal Research Center, Institute for Animal Reproduction, Ibaraki, Japan
13 Department of Biomolecular Sciences, Saga Medical School, Saga, Japan
14 Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
15 Experimental Medicine Unit, University of Wales Swansea, United Kingdom

* To whom correspondence should be addressed.
Akira Matsuda, E-mail: akimatsu{at}src.riken.go.jp


  Abstract

The extracellular matrix glycoprotein tenascin-C (TNC) has been accepted as a valuable histopathological subepithelial marker for evaluating the severity of asthmatic disease and therapeutic response to drugs. We found an association between adult asthma and an SNP encoding TNC fibronectin type III-D domain (Fn-III-D) in a case-control study between a Japanese population including 446 adult asthmatic patients and 658 normal healthy controls. The SNP (44513 A/T in exon 17) strongly associates with adult bronchial asthma ({chi}2 test, p = 0.00019, odds ratio = 1.76, 95% CI = 1.31-2.36). This coding SNP induces an amino acid substitution (Leu 1677 Ile) 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, and causes instability of this beta sheet. Since the TNC Fn-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 Leu 1677 Ile may be valuable marker in evaluating the risk for developing asthma, and play a role in its pathogenesis.


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