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The role of gene polymorphisms in the pathogenesis of chronic obstructive pulmonary disease

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Abstract

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. Irreversible airflow limitation, both progressive and associated with an inflammatory response of the lungs to noxious particles or gases, is a hallmark of the disease. Cigarette smoking is the most important environmental risk factor for COPD, nevertheless, only approximately 20–30% of smokers develop symptomatic disease. Epidemiological studies, case-control studies in relatives of patients with COPD, and twin studies suggest that COPD is a genetically complex disease with environmental factors and many involved genes interacting together. Two major strategies have been employed to identify the genes and the polymorphisms that likely contribute to the development of complex diseases: association studies and linkage analyses. Biologically plausible pathogenetic mechanisms are prerequisites to focus the search for genes of known function in association studies. Protease-antiprotease imbalance, generation of oxidative stress, and chronic inflammation are recognized as the principal mechanisms leading to irreversible airflow obstruction and parenchymal destruction in the lung. Therefore, genes which have been implicated in the pathogenesis of COPD are involved in antiproteolysis, antioxidant barrier and metabolism of xenobiotic substances, inflammatory response to cigarette smoke, airway hyperresponsiveness, and pulmonary vascular remodelling. Significant associations with COPD-related phenotypes have been reported for polymorphisms in genes coding for matrix metalloproteinases, microsomal epoxide hydrolase, glutathione-S-transferases, heme oxygenase, tumor necrosis factor, interleukines 1, 8, and 13, vitamin D-binding protein and β-2-adrenergic receptor (ADRB2), whereas adequately powered replication studies failed to confirm most of the previously observed associations. Genome-wide linkage analyses provide us with a novel tool to identify the general locations of COPD susceptibility genes, and should be followed by association analyses of positional candidate genes from COPD pathophysiology, positional candidate genes selected from gene expression studies, or dense single nucleotide polymorphism panels across regions of linkage. Haplotype analyses of genes with multiple polymorphic sites in linkage disequilibrium, such as the ADRB2 gene, provide another promising field that has yet to be explored in patients with COPD. In the present article we review the current knowledge about gene polymorphisms that have been recently linked to the risk of developing COPD and/or may account for variations in the disease course.

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Abbreviations

ACE:

angiotensin-converting enzyme

ADRB2:

β-2-adrenergic receptor

COPD:

chronic obstructive pulmonary disease

CYP1A1:

cytochrome P450 1A1

FEV1 :

forced exspiratory volume in the first second

GST:

glutathione S-transferase

HMOX-1:

heme oxygenase-1

5HTTLPR:

serotonin transporter gene-linked polymorphic region

IL:

inter-leukin

IL8R:

CXCR, IL-8 receptor

IL1RN:

IL-1 receptor antagonist

mEPHX:

microsomal epoxide hydrolase

MMP:

matrix metalloproteinase

SERT:

serotonin transporter

SFTB:

surfactant protein B

SNP:

single nucleotide polymorphism

TGFβ1:

transforming growth factor-β1

TIMP:

tissue inhibitor of metalloproteinases

TNF:

tumor necrosis factor

TNFR:

tumor necrosis factor receptor

VDBP:

vitamin D-binding protein

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  1. Institute of Medical Biology, Faculty of Medicine, P.J. Šafárik University, Trieda SNP 1, SK-04066, Košice, Slovakia

    Eva Slabá & Ján Šalagovič

  2. Department for Respiratory Diseases and Tuberculosis, Faculty of Medicine, P.J. Šafárik University, L. Pasteur Teaching Hospital, Rastislavova 43, SK-04190, Košice, Slovakia

    Pavol Joppa & Ružena Tkáčová

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  1. Eva Slabá
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Slabá, E., Joppa, P., Šalagovič, J. et al. The role of gene polymorphisms in the pathogenesis of chronic obstructive pulmonary disease. Biologia 63, 20–33 (2008). https://doi.org/10.2478/s11756-008-0020-4

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