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Background  The imbalance between proteases and antiproteases has been proposed to participate to the pathogenesis of chronic obstructive pulmonary disease (COPD) and emphysema. Gene level variation in different metalloproteinases, metalloproteinase inhibitors, and cytokines affecting them may contribute to this imbalance and destruction of the lung parenchyma. We investigated whether polymorphisms in selected protease-antiprotease balance pathway genes predispose to different emphysema subtypes (centrilobular, paraseptal, panlobular, and bullae) and airflow limitation among Finnish construction workers.    Methods  Eleven single nucleotide polymorphisms (SNPs) from seven genes ( GC : rs7041 and rs4588;  MMP1 : rs1799750;  MMP9 : rs3918242;  MMP12 : rs652438;  TIMP2 : rs2277698;  TNF : rs1799724 and rs1800629;  TGFB1 : rs1800469, rs1800470, and rs2241718) were analyzed from 951 clinically and radiologically characterized construction workers. The genotype and haplotype data was compared to different emphysematous signs confirmed with high resolution computed tomography (HRCT), forced vital capacity (FVC), forced expiratory volume in one second (FEV 1 ), and maximal expiratory flow at 50% of FVC (MEF50) by using linear and logistic regression analyses, adjusted for potential confounders.    Results  The  TIMP2  rs2277698 SNP was associated with overall ( p  = 0.022) and paraseptal ( p  = 0.010) emphysema, as well as with FEV 1 /FVC ratio ( p  = 0.035) and MEF50 ( p  = 0.008). The  TGFB1  rs2241718 and  MMP9  rs3918242 SNPs were associated with centrilobular emphysema ( p  = 0.022 and  p  = 0.008), and the  TNF  rs1800629 SNP with paraseptal emphysema ( p  = 0.017). In stratified analysis, individuals with at least one  TIMP2  rs227769 8  or  TNF  rs1800629 variant allele were found to be at around two-fold risk for pathological paraseptal changes (OR 1.94, 95% CI 1.14-3.30; OR 2.10, 95% CI 1.24-3.56). On the contrary, the risk for pathological centrilobular changes was halved for individuals with at least one  MMP9  rs3918242 (OR 0.51, 95% CI 0.30-0.86) or  TGFB1  rs2241718 (OR 0.53, 95% CI 0.30-0.90) variant allele, or  TGFB1  rs1800469-rs1800470 AT-haplotype (OR 0.55, 95% CI 0.33-0.93). MEF50, in turn, was significantly reduced among individuals with at least one  TIMP2  rs227769 8  variant allele ( p  = 0.011).    Conclusion  Our findings strengthen the hypothesis of the importance of protease-antiprotease balance in pathogenesis of emphysema and shed light on the aetiology of different emphysema subtypes by associating  MMP9  and  TGFB1  to centrilobular emphysema, and  TIMP2  and  TNF  to paraseptal emphysema and/or airflow obstruction.

Association of genes of protease-antiprotease balance pathway to lung function and emphysema subtypes