Association Study of Matrix Metalloproteinase-12 Gene Polymorphisms and Asthma in a Japanese Population

作者：Yamaide Fumiya; Undarmaa Siizkhuu; Mashimo Yoichi; Shimojo Naoki; Arima Takayasu; Morita Yoshinori; Hirota Tomomitsu; Fujita Kimie; Miyatake Akihiko; Doi Satoru; Sato Kazuki; Suzuki Shuichi; Nishimuta Toshiyuki; Watanabe Hiroko; Hoshioka Akira; Tomiita Minako; Yamaide Akiko; Watanabe Misa; Okamoto Yoshitaka; Kohno Yoichi; Tamari Mayumi; Hata Akira; Suzuki Yoichi^*

来源：International Archives of Allergy and Immunology, 2013, 160(3): 287-296.

DOI：10.1159/000341672

• Matrix metalloproteinase 12
• Asthma
• Single-nucleotide polymorphism
• Association study
• Chemokine

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 %26lt;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-beta. 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.

• 出版日期2013