Genetic variation in <it>TIMP1 </it>but not <it>MMPs </it>predict excess FEV₁decline in two general population-based cohorts

• Main Authors: Blokstra A, Siedlinski M, Postma DS, van Diemen CC, Smit HA, Boezen HM
• Format: Article
• Language: English
• Published: BMC 2011-04-01
• Series: Respiratory Research
• Online Access: http://respiratory-research.com/content/12/1/57

<p>Abstract</p> <p>Background</p> <p>An imbalance in Matrix MetalloProteases (MMPs) and Tissue Inhibitors of MMPs (TIMPs) contributes to Chronic Obstructive Pulmonary Disease (COPD) development. Longitudinal studies investigating Single Nucleotide Polymorphisms (SNPs) in <it>MMPs </it>and <it>TIMPs </it>with respect to COPD development and lung function decline in the general population are lacking.</p> <p>Methods</p> <p>We genotyped SNPs in <it>MMP1 </it>(G-1607GG), <it>MMP2 </it>(-1306 C/T), <it>MMP9 </it>(3 tagging SNPs), <it>MMP12 </it>(A-82G and Asn357Ser) and <it>TIMP1 </it>(Phe124Phe and Ile158Ile) in 1390 Caucasians with multiple FEV₁measurements from a prospective cohort study in the general population. FEV₁decline was analyzed using linear mixed effect models adjusted for confounders. Analyses of the X-chromosomal <it>TIMP1 </it>gene were stratified according to sex. All significant associations were repeated in an independent general population cohort (n = 1152).</p> <p>Results</p> <p><it>MMP2 </it>-1306 TT genotype carriers had excess FEV₁decline (-4.0 ml/yr, p = 0.03) compared to wild type carriers. <it>TIMP1 </it>Ile158Ile predicted significant excess FEV₁decline in both males and females. <it>TIMP1 </it>Phe124Phe predicted significant excess FEV₁decline in males only, which was replicated (p = 0.10) in the second cohort. The <it>MMP2 </it>and <it>TIMP1 </it>Ile158Ile associations were not replicated. Although power was limited, we did not find associations with COPD development.</p> <p>Conclusions</p> <p>We for the first time show that <it>TIMP1 </it>Phe124Phe contributes to excess FEV₁decline in two independent prospective cohorts, albeit not quite reaching conventional statistical significance in the replication cohort. SNPs in <it>MMPs </it>evidently do not contribute to FEV₁decline in the general population.</p>