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

Autor: Tapio Vehmas, Emmi Tiili, Panu Oksa, Päivi Piirilä, Ari Hirvonen, Mari K Kukkonen
Přispěvatelé: Clinicum, Department of Diagnostics and Therapeutics
Jazyk: angličtina
Rok vydání: 2013
Předmět:
ASBESTOS-EXPOSED WORKERS
Male
Vital capacity
GENOTYPE DATA
Protease-antiprotease balance
Pathogenesis
0302 clinical medicine
SMOKE-INDUCED EMPHYSEMA
Medicine
VITAMIN-D
Lung
0303 health sciences
COPD
medicine.diagnostic_test
respiratory system
Middle Aged
3. Good health
Respiratory Function Tests
medicine.anatomical_structure
Female
Research Article
Signal Transduction
Pulmonary and Respiratory Medicine
High-resolution computed tomography
Genotype
education
Single-nucleotide polymorphism
FUNCTION TESTS
OBSTRUCTIVE PULMONARY-DISEASE
Polymorphism
Single Nucleotide
Transforming Growth Factor beta1
03 medical and health sciences
FEV1/FVC ratio
TISSUE INHIBITOR
SEVERE COPD
Genetics
Humans
Genetic Predisposition to Disease
Protease Inhibitors
Pathological
030304 developmental biology
Aged
Emphysema
Tissue Inhibitor of Metalloproteinase-2
business.industry
Tumor Necrosis Factor-alpha
RESOLUTION COMPUTED-TOMOGRAPHY
medicine.disease
Lung function
Matrix Metalloproteinases
respiratory tract diseases
030228 respiratory system
Haplotypes
3121 General medicine
internal medicine and other clinical medicine
Immunology
SERPINE2 GENE
business
Peptide Hydrolases
Zdroj: BMC Pulmonary Medicine
ISSN: 1471-2466
Popis: 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.
Databáze: OpenAIRE
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