Coding SNP in tenascin-C Fn-III-D domain associates with adult asthma.
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.
Matsuda
Akira
A
Laboratory for Genetics of Allergic Diseases, SNP Research Center, RIKEN, Yokohama, Japan. akimatsu@src.riken.go.jp
Hirota
Tomomitsu
T
Akahoshi
Mitsuteru
M
Shimizu
Makiko
M
Tamari
Mayumi
M
Miyatake
Akihiko
A
Takahashi
Atsushi
A
Nakashima
Kazuko
K
Takahashi
Naomi
N
Obara
Kazuhiko
K
Yuyama
Noriko
N
Doi
Satoru
S
Kamogawa
Yumiko
Y
Enomoto
Tadao
T
Ohshima
Koichi
K
Tsunoda
Tatsuhiko
T
Miyatake
Shoichiro
S
Fujita
Kimie
K
Kusakabe
Moriaki
M
Izuhara
Kenji
K
Nakamura
Yusuke
Y
Hopkin
Julian
J
Shirakawa
Taro
T
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*
D005353:Fibronectins; D019063:Tenascin; D007532:Isoleucine; D007930:Leucine