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.
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.
Haq
Imran
I
School of Molecular Medical Sciences, Institute of Genetics, Queen's Medical Centre, University of Nottingham, UK.
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
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
D020780:Matrix Metalloproteinase 9; D053508:Matrix Metalloproteinase 12; D020781:Matrix Metalloproteinase 1