title: Association of genes of protease-antiprotease balance pathway to lung function and emphysema subtypes.
abstract: 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 (FEV₁), 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 FEV₁/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 rs2277698 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 rs2277698 variant allele (p = 0.011).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Finnish Institute of Occupational Health, Topeliuksenkatu 41 a A, FI-00250, Helsinki, Finland. mari.kukkonen@ttl.fi
authors.forename: Mari K
authors.initials: MK
authors.lastname: Kukkonen
authors.forename: Emmi
authors.initials: E
authors.lastname: Tiili
authors.forename: Tapio
authors.initials: T
authors.lastname: Vehmas
authors.forename: Panu
authors.initials: P
authors.lastname: Oksa
authors.forename: Päivi
authors.initials: P
authors.lastname: Piirilä
authors.forename: Ari
authors.initials: A
authors.lastname: Hirvonen
mesh_terms: D000368:Aged; D004646:Emphysema / Q000145:classification* / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008168:Lung / Q000503:physiopathology*; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics; D008875:Middle Aged; D010447:Peptide Hydrolases / Q000235:genetics* / Q000502:physiology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011480:Protease Inhibitors; D012129:Respiratory Function Tests; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D011480:Protease Inhibitors; C560823:TIMP2 protein, human; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D019716:Tissue Inhibitor of Metalloproteinase-2; D010447:Peptide Hydrolases; D020782:Matrix Metalloproteinases