title: 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.
authors.affiliation: School of Molecular Medical Sciences, Institute of Genetics, Queen's Medical Centre, University of Nottingham, UK.
authors.forename: Imran
authors.initials: I
authors.lastname: Haq
authors.forename: Sally
authors.initials: S
authors.lastname: Chappell
authors.forename: Simon R
authors.initials: SR
authors.lastname: Johnson
authors.forename: Juzer
authors.initials: J
authors.lastname: Lotya
authors.forename: Leslie
authors.initials: L
authors.lastname: Daly
authors.forename: Kevin
authors.initials: K
authors.lastname: Morgan
authors.forename: Tamar
authors.initials: T
authors.lastname: Guetta-Baranes
authors.forename: Josep
authors.initials: J
authors.lastname: Roca
authors.forename: Roberto
authors.initials: R
authors.lastname: Rabinovich
authors.forename: Ann B
authors.initials: AB
authors.lastname: Millar
authors.forename: Seamas C
authors.initials: SC
authors.lastname: Donnelly
authors.forename: Vera
authors.initials: V
authors.lastname: Keatings
authors.forename: William
authors.initials: W
authors.lastname: MacNee
authors.forename: Jan
authors.initials: J
authors.lastname: Stolk
authors.forename: Pieter S
authors.initials: PS
authors.lastname: Hiemstra
authors.forename: Massimo
authors.initials: M
authors.lastname: Miniati
authors.forename: Simonetta
authors.initials: S
authors.lastname: Monti
authors.forename: Clare M
authors.initials: CM
authors.lastname: O'Connor
authors.forename: Noor
authors.initials: N
authors.lastname: Kalsheker
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics*; D053508:Matrix Metalloproteinase 12 / Q000235:genetics*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics*; D012720:Severity of Illness Index
chemical_list: D020780:Matrix Metalloproteinase 9; D053508:Matrix Metalloproteinase 12; D020781:Matrix Metalloproteinase 1