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Association of matrix metalloproteinase 8 genetic polymorphisms with bronchial asthma in a Japanese population.

ABSTRACT: Asthma has a strong genetic component. The final disease phenotype results from complex interactions between environment and multiple genes of small-to-modest effects. We investigated whether the polymorphism in genes encoding inflammatory mediators and cytokines is important for solving the onset and progression of asthma. We investigated whether 31 single nucleotide polymorphisms (SNPs) in genes encoding cytokines or monokines (interleukin [IL]-5R, matrix metalloproteinase [MMP] 8, beta2 adrenergic receptor, cytotoxic T-lymphocyte-associated antigen 4, IL-3, C-reactive protein, cytochrome P450 (CYP) 2C9, CYP3A4, a disintegrin and metalloproteinase [ADAM] 33, cysteinyl leukotriene receptor [CysLTR] 1, CysLTR2, eosinophilic cationic protein, glucocorticoid receptor, and leukotriene A 4 hydrolase) are related to asthma development in 206 Japanese bronchial asthma patients and 127 healthy controls. Using multifactor dimensionality reduction (MDR), we identified rs17099451 in MMP8, using a single locus model, with a mean cross-validation of 87.0%. Using a two-locus model, combinations of MMP8 and rs44707 in ADAM33, and MMP8 and rs40401 in IL-3, were identified, with mean cross-validation consistencies reaching 45.0%. Of the SNPs selected by the MDR method, rs17099451 in MMP8 and rs40401 in IL-3 were regarded as the most significant results in a 2 × 2 dominant model analysis. The finding that an MMP8 allele was most strongly related to asthma development indicates that metalloproteinase function is crucial to the airflow limitation process involved in this disease.

SUBMITTER: Shimoda T

PROVIDER: S-EPMC3911802 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Association of matrix metalloproteinase 8 genetic polymorphisms with bronchial asthma in a Japanese population.

Shimoda Terufumi T Obase Yasushi Y Kishikawa Reiko R Iwanaga Tomoaki T

Allergy & rhinology (Providence, R.I.) 20130101 3

Asthma has a strong genetic component. The final disease phenotype results from complex interactions between environment and multiple genes of small-to-modest effects. We investigated whether the polymorphism in genes encoding inflammatory mediators and cytokines is important for solving the onset and progression of asthma. We investigated whether 31 single nucleotide polymorphisms (SNPs) in genes encoding cytokines or monokines (interleukin [IL]-5R, matrix metalloproteinase [MMP] 8, beta2 adren ...[more]

PMID: 24498518

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Project description:Background Genetic variants influencing lung function or immune system may be involved in the development of asthma and/or its symptoms. Matrix metalloproteinases (MMPs) contribute to both normal and pathological tissue remodeling and also act as regulatory molecules by processing cytokines or adhesion molecules. In animal models, growing evidences suggest that MMPs play important roles in asthma phenotypes. Some MMP genes (e.g. MMP-9 and MMP-12) have recently been shown to be associated with asthma in Caucasian populations. We investigated whether single nucleotide polymorphisms (SNPs) in MMP-7 and MMP-12 could affect the susceptibility to and clinical phenotypes of asthma in the Japanese population. Methods We conducted a case-control study between SNPs in MMP-7 and MMP-12 genes and asthma-related phenotypes using childhood and adult Japanese populations (653 childhood asthma patients and 423 controls, and 428 adult asthma patients and 646 controls, respectively). To investigate the effects of amino acid substitutions by SNPs on MMPs' enzymatic activity, MMP activity assays were performed using commercially available kits based on fluorescence resonance energy transfer (FRET) peptide. We also evaluated the effect of 3’UTR SNP in MMP-7 on its mRNA stability and the effect of SNP in MMP-12 on its antimicrobial activity. Results We found that, in the Japanese population, SNPs of MMP-7 (rs10502001, G/A, Arg77His; rs14983, C/T, 3’UTR) (P = 0.006; odds ratio (OR), 1.46; 95% confidential interval (CI), 1.126-1.903) and MMP-12 (rs652438, A/G, Asn357Ser) (P = 0.015; OR, 1.60; 95% CI, 1.002-2.556) showed significant association with adult and childhood asthma, respectively. We also found that the SNP (rs652438) in MMP-12 was associated with severity in adult asthma (P = 0.010). Using supernatant from cultured HEK293 cells stably transfected with the pcDNA3.1(+)-MMP-7 or MMP-12 as MMP proteins, we evaluated activation kinetics, rate of proteolytic cleavage of FRET peptide, Michaelis constant, and substrate specificity of the enzyme. In this system, we couldn't detect the functional effects of amino acid substitutions by SNPs on the enzymatic activity. Conclusions Our association study suggested that genetic variants of MMP7 and MMP12 conferred risk for development of asthma in the Japanese population.

Project description:Published data on the association between MMP-9 polymorphisms (-1562 C > T, rs3918242; Gln279Arg, rs17576 Arg668Gln, rs17577) and asthma susceptibility are inconclusive. To derive a more precise estimation of this association, a meta-analysis was performed. A literature search was conducted in PubMed, Web of Science, EMBASE, Wanfang, and China National Knowledge Infrastructure (CNKI) databases to identify eligible studies. The pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were used to calculate the strength of association. Sensitivity analysis was performed to evaluate the influence of individual studies on the overall effect estimates, and funnel plots and Egger's test were inspected for indication of publication bias. Seven studies with 1592 asthma patients and 1987 controls were finally identified. Overall, we found no significant association between -1562 C > T, rs3918242 polymorphism, and asthma susceptibility in any of the genetic model comparisons. After categorizing studies into different subgroups on the basis of ethnicity and age, there is still no significant association. For the Gln279Arg, rs17576 polymorphism, there seems to be a significant association in the allelic genetic model in regard to the P value (OR = 1.11, 95% CI = 1.00-1.22, I 2 = 0%, P (Z)=0.044); however, the value of lower 95% CI is 1.0. For the Arg668Gln, rs17577 polymorphism, a high significant association was observed in the dominant model comparison (OR = 1.65, 95% CI = 1.28-2.11, I 2 = 22.50%, P (Z)=0), recessive model comparison (OR = 2.40, 95% CI = 1.23-4.72, I 2 = 0%, P (Z)=0.011), homozygote genotype comparison (OR = 2.69, 95% CI = 1.36-5.33, I 2 = 0%, P (Z)=0.004), and allelic genetic model (OR = 1.59, 95% CI = 1.29-1.97, I 2 = 36.9%, P (Z)=0). Sensitivity analysis demonstrated the stability of our results, and publication bias was not evident. The present meta-analysis suggests that MMP-9 Arg668Gln, rs17577 polymorphism may be the risk factor for asthma susceptibility.

Dataset Information

Association of matrix metalloproteinase 8 genetic polymorphisms with bronchial asthma in a Japanese population.

Publications

Association of matrix metalloproteinase 8 genetic polymorphisms with bronchial asthma in a Japanese population.

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