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Open Access Highly Accessed Research article

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

Imran Haq12*, Sally Chappell1, Simon R Johnson2, Juzer Lotya3, Leslie Daly3, Kevin Morgan1, Tamar Guetta-Baranes1, Josep Roca4, Roberto Rabinovich48, Ann B Millar5, Seamas C Donnelly6, Vera Keatings7, William MacNee8, Jan Stolk9, Pieter S Hiemstra9, Massimo Miniati10, Simonetta Monti11, Clare M O'Connor6 and Noor Kalsheker1

Author Affiliations

1 School of Molecular Medical Sciences, Institute of Genetics, Queen's Medical Centre, University of Nottingham, UK

2 Therapeutics and Molecular Medicine, Queen's Medical Centre, University of Nottingham, UK

3 UCD School of Public Health and Population Science, University College Dublin, Belfield, Dublin, Ireland

4 Pulmonary Dept, CIBERES, Hospital Clinic, Hospital Clínico y Provincial de Barcelona, Villarroel, Barcelona, Spain

5 Lung Research Group, Dept of Clinical Science at North Bristol, Southmead Hospital, University of Bristol, Westbury on Trym, Bristol, UK

6 UCD School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Ireland

7 Letterkenny General Hospital, Letterkenny, Donegal, Ireland

8 Respiratory Medicine, ELEGI Colt Laboratories, Wilkie Building, University of Edinburgh, Edinburgh, UK

9 Dept of Pulmonology (C3-P), Leiden University Medical Center, Leiden, The Netherlands

10 Department of Medical and Surgical Critical Care, University of Florence, Italy

11 CNR Institute of Clinical Physiology, Pisa, Italy

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BMC Medical Genetics 2010, 11:7  doi:10.1186/1471-2350-11-7

Published: 15 January 2010



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.


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.


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.


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.