Association study of matrix metalloproteinase-12 gene polymorphisms and asthma in a Japanese population.
BACKGROUND
Matrix metalloproteinase 12 gene (MMP12) has been shown to be associated with asthma in a Caucasian population. In this study, we investigate whether single-nucleotide polymorphisms (SNPs) of MMP12 are associated with a risk for asthma in a Japanese population.


METHODS
We tested for an association between SNPs in MMP12 and asthma, including its severity, in a Japanese population (630 pediatric and 417 adult patients with atopic asthma and 336 children and 632 adults as controls). The rs652438 A and G variants (N357S) were generated by site-directed mutagenesis and an assay with artificial peptide substrates was used to compare two types of MMP12 activity. The effect of MMP12 inhibition with MMP12-specific small interfering RNA (siRNA) on chemokine secretion from airway epithelial cells was also tested in vitro.


RESULTS
N357S showed a p value <0.05 for childhood and combined (adult plus childhood) asthma in the dominant model [odds ratio (OR) 1.60, 95% confidence interval (CI) 1.00-2.56, p = 0.047; OR 1.40, 95% CI 1.04-1.89, p = 0.028, respectively]. This risk variant is associated with asthma severity in adult patients. In the functional assay, the minor-allele enzyme showed significantly lower activity than the major-allele enzyme. MMP12-specific siRNA suppressed IP-10 secretion from airway epithelial cells upon stimulation with IFN-β.


CONCLUSIONS
Our results suggest that MMP12 confers susceptibility to asthma and is associated with asthma severity in a Japanese population. MMP12 may be associated with asthma through inappropriate attraction of leukocytes to the inflamed tissue.
Department of Public Health, Graduate School of Medicine, Chiba University, Chiba, Japan.
Fumiya
F
Yamaide
Siizkhuu
S
Undarmaa
Yoichi
Y
Mashimo
Naoki
N
Shimojo
Takayasu
T
Arima
Yoshinori
Y
Morita
Tomomitsu
T
Hirota
Kimie
K
Fujita
Akihiko
A
Miyatake
Satoru
S
Doi
Kazuki
K
Sato
Shuichi
S
Suzuki
Toshiyuki
T
Nishimuta
Hiroko
H
Watanabe
Akira
A
Hoshioka
Minako
M
Tomiita
Akiko
A
Yamaide
Misa
M
Watanabe
Yoshitaka
Y
Okamoto
Yoichi
Y
Kohno
Mayumi
M
Tamari
Akira
A
Hata
Yoichi
Y
Suzuki
D000293:Adolescent; D000328:Adult; D000368:Aged; D001249:Asthma / Q000235:genetics* / Q000276:immunology; D054357:Chemokine CXCL10 / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D018450:Disease Progression; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D016899:Interferon-beta / Q000276:immunology; D007564:Japan; D053508:Matrix Metalloproteinase 12 / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D034741:RNA, Small Interfering / Q000235:genetics; D020545:Respiratory Mucosa / Q000276:immunology*; D012306:Risk; D055815:Young Adult
D054357:Chemokine CXCL10; D034741:RNA, Small Interfering; D016899:Interferon-beta; D053508:Matrix Metalloproteinase 12