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

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 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 (chi2 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.

• Authors: Akira Matsuda, Tomomitsu Hirota, Mitsuteru Akahoshi, Makiko Shimizu, Mayumi Tamari, Akihiko Miyatake, Atsushi Takahashi, Kazuko Nakashima, Naomi Takahashi, Kazuhiko Obara, Noriko Yuyama, Satoru Doi, Yumiko Kamogawa, Tadao Enomoto, Koichi Ohshima, Tatsuhiko Tsunoda, Shoichiro Miyatake, Kimie Fujita, Moriaki Kusakabe, Kenji Izuhara, Yusuke Nakamura, Julian Hopkin, Taro Shirakawa
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 14 Issue 19 Pg. 2779-86 (Oct 01 2005) ISSN: 0964-6906 [Print] England
• PMID: 16115819 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fibronectins
• Tenascin
• Isoleucine
• Leucine

Topics

• Adult
• Alternative Splicing
• Amino Acid Substitution
• Asthma (genetics)
• Case-Control Studies
• Computer Simulation
• Fibronectins (metabolism)
• Haplotypes
• Humans
• Isoleucine (genetics)
• Japan
• Leucine (genetics)
• Lung (immunology)
• Polymorphism, Single Nucleotide
• Protein Structure, Tertiary
• Tenascin (analysis, genetics, metabolism)