title: 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.affiliation: Laboratory for Genetics of Allergic Diseases, SNP Research Center, RIKEN, Yokohama, Japan. akimatsu@src.riken.go.jp
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuda
authors.forename: Tomomitsu
authors.initials: T
authors.lastname: Hirota
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Akahoshi
authors.forename: Makiko
authors.initials: M
authors.lastname: Shimizu
authors.forename: Mayumi
authors.initials: M
authors.lastname: Tamari
authors.forename: Akihiko
authors.initials: A
authors.lastname: Miyatake
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.forename: Kazuko
authors.initials: K
authors.lastname: Nakashima
authors.forename: Naomi
authors.initials: N
authors.lastname: Takahashi
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Obara
authors.forename: Noriko
authors.initials: N
authors.lastname: Yuyama
authors.forename: Satoru
authors.initials: S
authors.lastname: Doi
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Kamogawa
authors.forename: Tadao
authors.initials: T
authors.lastname: Enomoto
authors.forename: Koichi
authors.initials: K
authors.lastname: Ohshima
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tsunoda
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Miyatake
authors.forename: Kimie
authors.initials: K
authors.lastname: Fujita
authors.forename: Moriaki
authors.initials: M
authors.lastname: Kusakabe
authors.forename: Kenji
authors.initials: K
authors.lastname: Izuhara
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Julian
authors.initials: J
authors.lastname: Hopkin
authors.forename: Taro
authors.initials: T
authors.lastname: Shirakawa
mesh_terms: D000328:Adult; D017398:Alternative Splicing; D019943:Amino Acid Substitution; D001249:Asthma / Q000235:genetics*; D016022:Case-Control Studies; D003198:Computer Simulation; D005353:Fibronectins / Q000378:metabolism; D006239:Haplotypes; D006801:Humans; D007532:Isoleucine / Q000235:genetics; D007564:Japan; D007930:Leucine / Q000235:genetics; D008168:Lung / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D019063:Tenascin / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*
chemical_list: D005353:Fibronectins; D019063:Tenascin; D007532:Isoleucine; D007930:Leucine