Association of Genes of Protease-antiprotease Balance Pathway to Lung Function and Emphysema Subtypes

Overview

Journal BMC Pulm Med

Publisher Biomed Central

Specialty Pulmonary Medicine

Date 2013 Jun 6

PMID 23734748

Citations 18

Authors

Mari K Kukkonen

Emmi Tiili

Tapio Vehmas

Panu Oksa

Paivi Piirila

Ari Hirvonen

Affiliations

Soon will be listed here.

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).

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.

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References

Janssens W, Lehouck A, Carremans C, Bouillon R, Mathieu C, Decramer M . Vitamin D beyond bones in chronic obstructive pulmonary disease: time to act. Am J Respir Crit Care Med. 2009; 179(8):630-6. DOI: 10.1164/rccm.200810-1576PP. View

Vierikko T, Jarvenpaa R, Autti T, Oksa P, Huuskonen M, Kaleva S . Chest CT screening of asbestos-exposed workers: lung lesions and incidental findings. Eur Respir J. 2006; 29(1):78-84. DOI: 10.1183/09031936.00073606. View

Finkelstein R, Ma H, Ghezzo H, Whittaker K, Fraser R, Cosio M . Morphometry of small airways in smokers and its relationship to emphysema type and hyperresponsiveness. Am J Respir Crit Care Med. 1995; 152(1):267-76. DOI: 10.1164/ajrccm.152.1.7599834. View

Tomashefski Jr J, Crystal R, Wiedemann H, Mascha E, Stoller J . The bronchopulmonary pathology of alpha-1 antitrypsin (AAT) deficiency: findings of the Death Review Committee of the national registry for individuals with Severe Deficiency of Alpha-1 Antitrypsin. Hum Pathol. 2004; 35(12):1452-61. DOI: 10.1016/j.humpath.2004.08.013. View

Pellegrino R, Viegi G, Brusasco V, Crapo R, Burgos F, Casaburi R . Interpretative strategies for lung function tests. Eur Respir J. 2005; 26(5):948-68. DOI: 10.1183/09031936.05.00035205. View

Hirano K, Sakamoto T, Uchida Y, Morishima Y, Masuyama K, Ishii Y . Tissue inhibitor of metalloproteinases-2 gene polymorphisms in chronic obstructive pulmonary disease. Eur Respir J. 2002; 18(5):748-52. DOI: 10.1183/09031936.01.00102101. View

DeMeo D, Mariani T, Lange C, Lake S, Litonjua A, Celedon J . The SERPINE2 gene is associated with chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2006; 3(6):502. DOI: 10.1513/pats.200603-070MS. View

Zhang S, Wang C, Xi B, Li X . Association between the tumour necrosis factor-α-308G/A polymorphism and chronic obstructive pulmonary disease: an update. Respirology. 2010; 16(1):107-15. DOI: 10.1111/j.1440-1843.2010.01879.x. View

Ozen S, Alikasifoglu M, Bakkaloglu A, Duzova A, Jarosova K, Nemcova D . Tumour necrosis factor alpha G-->A -238 and G-->A -308 polymorphisms in juvenile idiopathic arthritis. Rheumatology (Oxford). 2002; 41(2):223-7. DOI: 10.1093/rheumatology/41.2.223. View

10.

Hegab A, Sakamoto T, Uchida Y, Nomura A, Ishii Y, Morishima Y . Association analysis of tissue inhibitor of metalloproteinase2 gene polymorphisms with COPD in Egyptians. Respir Med. 2005; 99(1):107-10. DOI: 10.1016/j.rmed.2004.05.017. View

11.

Fujimoto K, Ikeda S, Arai T, Tanaka N, Kumasaka T, Ishii T . Polymorphism of SERPINE2 gene is associated with pulmonary emphysema in consecutive autopsy cases. BMC Med Genet. 2010; 11:159. PMC: 2994839. DOI: 10.1186/1471-2350-11-159. View

12.

Rothman K . No adjustments are needed for multiple comparisons. Epidemiology. 1990; 1(1):43-6. View

13.

Hautamaki R, Kobayashi D, Senior R, Shapiro S . Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science. 1997; 277(5334):2002-4. DOI: 10.1126/science.277.5334.2002. View

14.

Satoh K, Kobayashi T, Misao T, Hitani Y, Yamamoto Y, Nishiyama Y . CT assessment of subtypes of pulmonary emphysema in smokers. Chest. 2001; 120(3):725-9. DOI: 10.1378/chest.120.3.725. View

15.

Barnes P, Shapiro S, Pauwels R . Chronic obstructive pulmonary disease: molecular and cellular mechanisms. Eur Respir J. 2003; 22(4):672-88. DOI: 10.1183/09031936.03.00040703. View

16.

DArmiento J, Dalal S, Okada Y, Berg R, Chada K . Collagenase expression in the lungs of transgenic mice causes pulmonary emphysema. Cell. 1992; 71(6):955-61. DOI: 10.1016/0092-8674(92)90391-o. View

17.

Castaldi P, Cho M, Cohn M, Langerman F, Moran S, Tarragona N . The COPD genetic association compendium: a comprehensive online database of COPD genetic associations. Hum Mol Genet. 2009; 19(3):526-34. PMC: 2798725. DOI: 10.1093/hmg/ddp519. View

18.

Churg A, Wang R, Tai H, Wang X, Xie C, Dai J . Macrophage metalloelastase mediates acute cigarette smoke-induced inflammation via tumor necrosis factor-alpha release. Am J Respir Crit Care Med. 2003; 167(8):1083-9. DOI: 10.1164/rccm.200212-1396OC. View

19.

Gingo M, Silveira L, Miller Y, Friedlander A, Cosgrove G, Chan E . Tumour necrosis factor gene polymorphisms are associated with COPD. Eur Respir J. 2008; 31(5):1005-12. DOI: 10.1183/09031936.00100307. View

20.

Zhu G, Warren L, Aponte J, Gulsvik A, Bakke P, Anderson W . The SERPINE2 gene is associated with chronic obstructive pulmonary disease in two large populations. Am J Respir Crit Care Med. 2007; 176(2):167-73. DOI: 10.1164/rccm.200611-1723OC. View