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Association of MMP-2 polymorphisms with severe and very severe COPD: a case control study of MMPs-1, 9 and 12 in a European population.

ABSTRACT: BACKGROUND: Genetic factors play a role in chronic obstructive pulmonary disease (COPD) but are poorly understood. A number of candidate genes have been proposed on the basis of the pathogenesis of COPD. These include the matrix metalloproteinase (MMP) genes which play a role in tissue remodelling and fit in with the protease--antiprotease imbalance theory for the cause of COPD. Previous genetic studies of MMPs in COPD have had inadequate coverage of the genes, and have reported conflicting associations of both single nucleotide polymorphisms (SNPs) and SNP haplotypes, plausibly due to under-powered studies. METHODS: To address these issues we genotyped 26 SNPs, providing comprehensive coverage of reported SNP variation, in MMPs- 1, 9 and 12 from 977 COPD patients and 876 non-diseased smokers of European descent and evaluated their association with disease singly and in haplotype combinations. We used logistic regression to adjust for age, gender, centre and smoking history. RESULTS: Haplotypes of two SNPs in MMP-12 (rs652438 and rs2276109), showed an association with severe/very severe disease, corresponding to GOLD Stages III and IV. CONCLUSIONS: Those with the common A-A haplotype for these two SNPs were at greater risk of developing severe/very severe disease (p = 0.0039) while possession of the minor G variants at either SNP locus had a protective effect (adjusted odds ratio of 0.76; 95% CI 0.61 - 0.94). The A-A haplotype was also associated with significantly lower predicted FEV1 (42.62% versus 44.79%; p = 0.0129). This implicates haplotypes of MMP-12 as modifiers of disease severity.

SUBMITTER: Haq I

PROVIDER: S-EPMC2820470 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Association of MMP-2 polymorphisms with severe and very severe COPD: a case control study of MMPs-1, 9 and 12 in a European population.

Haq Imran I Chappell Sally S Johnson Simon R SR Lotya Juzer J Daly Leslie L Morgan Kevin K Guetta-Baranes Tamar T Roca Josep J Rabinovich Roberto R Millar Ann B AB Donnelly Seamas C SC Keatings Vera V MacNee William W Stolk Jan J Hiemstra Pieter S PS Miniati Massimo M Monti Simonetta S O'Connor Clare M CM Kalsheker Noor N

BMC medical genetics 20100115

<h4>Background</h4>Genetic factors play a role in chronic obstructive pulmonary disease (COPD) but are poorly understood. A number of candidate genes have been proposed on the basis of the pathogenesis of COPD. These include the matrix metalloproteinase (MMP) genes which play a role in tissue remodelling and fit in with the protease--antiprotease imbalance theory for the cause of COPD. Previous genetic studies of MMPs in COPD have had inadequate coverage of the genes, and have reported conflicti ...[more]

PMID: 20078883

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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:BackgroundSevere acute pancreatitis (SAP) is a severe form of inflammatory disease with a high mortality rate. Ulinastatin, as a urinary trypsin inhibitor (UTI), is a glycoprotein playing a critical role in SAP. Consequently, we identified the hypothesis that both matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) gene polymorphisms might promote the efficacy of ulinastatin in SAP.MethodsA total of 235 patients with SAP were treated by intravenous drip of ulinastatin for the duration of 10 days. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed for testing the distribution of genotypes and alleles frequency of MMP-2 and MMP-9 gene polymorphisms, and analyzing association of MMP-2 rs243865, MMP-2 rs2285053, MMP-9 rs3918242, or MMP-9 rs17576 with efficacy of ulinastatin in patients with SAP. Shesis software was adopted for analyzing single genotypes of MMP-2 and MMP-9 gene polymorphisms site A Generalized Multifactor Dimensionality Reduction (GMDR) model and a logistic regression analysis were used for analyzing effect of MMP-2 and MMP-9 gene polymorphisms on the efficacy of ulinastatin in treating patients with SAP.ResultsCC genotype of MMP-2 gene rs243865 C>T was observed to have a better positive effect in promoting the efficacy of ulinastatin in comparison with CT and TT genotypes. Haplotype CCTG, CCTA, CTTG, and CTTA were combined by MMP-2 and MMP-9 gene polymorphisms which have the ability to increase the efficacy of ulinastatin in treating patients with SAP. MMP-2 gene rs243865 C>T site polymorphism was served as a favorable factor while the MMP-9 gene rs3918242 C>T site polymorphism was noticed as an unfavorable factor for the efficacy of ulinastatin in treating patients with SAP.ConclusionThe key findings clearly demonstrated that both the MMP-2 rs243865 and MMP-9 rs3918242 gene polymorphisms served as biological indicators for the efficacy of ulinastatin in treating patients with SAP.

Dataset Information

Association of MMP-2 polymorphisms with severe and very severe COPD: a case control study of MMPs-1, 9 and 12 in a European population.

Publications

Association of MMP-2 polymorphisms with severe and very severe COPD: a case control study of MMPs-1, 9 and 12 in a European population.

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