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<p>Abstract</p> <p>Background</p> <p>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 <it>matrix metalloproteinase </it>(<it>MMP</it>) 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 <it>MMP</it>s 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.</p> <p>Methods</p> <p>To address these issues we genotyped 26 SNPs, providing comprehensive coverage of reported SNP variation, in <it>MMP</it>s- 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.</p> <p>Results</p> <p>Haplotypes of two SNPs in <it>MMP</it>-12 (rs652438 and rs2276109), showed an association with severe/very severe disease, corresponding to GOLD Stages III and IV.</p> <p>Conclusions</p> <p>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 <it>MMP-12 </it>as modifiers of disease severity.</p>