Chest
Impact of Basic Research on Tomorrow's MedicineGenetics of COPD
Section snippets
Genetic Studies in COPD
The genetic bases of COPD have been investigated using association studies of candidate genes that can play a role in the pathogenesis of COPD. The limitations of this approach are that only known genes can be examined, patients and control subjects are difficult to match, and studies have small sample sizes or include patients of various ethnicities, which result in a lack of reproducibility across studies.
Some linkage or positional cloning studies also have been reported. In these studies,
Healthy Subjects at Risk and Relatives of COPD Patients
Healthy subjects have been studied to pinpoint the genetic determinants of airway function as well as the predisposing factors that may confer susceptibility to COPD. These studies have found that COPD, like asthma,1718 seems to be a multigenic disease (Table 1).
The genetic determinants of FEV1, FVC, and the FEV1/FVC ratio have been studied by linkage analysis in both healthy subjects and COPD patients. In healthy young adults, a 10-centimorgan (cM) genome-wide scan of 1,578 members in 330
Smokers Who Develop COPD
Only a fraction of smokers acquire COPD.2829 It appears that smokers who acquire COPD may have a different genotype than those lifelong smokers in whom lung function declines at a slower pace or not at all. This predisposition of some smokers to acquire COPD has been investigated by genetic epidemiology and candidate gene association studies (Table 2). In this regard, the prevalence of the PiZ alleles of the α1AT gene in heavy smokers with COPD and in nonobstructed smokers appears to be
COPD With Predominant Emphysema Phenotype
Emphysema has been defined as a lung condition that is characterized by abnormal permanent enlargement of the distal airways accompanied by alveolar wall destruction with or without fibrosis. It has now become apparent that apoptosis of epithelial, endothelial, and other cells in the lung, together with excessive proteolysis and oxidative stress, contribute to the destruction of the lung.42434445 As such, it is not surprising that many genes, other than α1AT seem to be implicated in the
COPD With Predominant Bronchitic Phenotype
Chronic bronchitis is characterized by chronic cough and sputum production. There are few genetic studies that have addressed this particular phenotype (Table 4).
An autosomal 10-cM genome-wide scan of STR polymorphic markers was analyzed for linkage to COPD-related phenotypes in 585 members of 72 pedigrees ascertained through severe, early-onset COPD probands without severe α1AT deficiency.58 Multipoint nonparametric linkage analysis was performed for qualitative phenotypes, including moderate
COPD Phenotype With Response to Bronchodilators
Approximately half of COPD patients have a variable response to β2-agonists or ipratropium from visit to visit, and this variability is unrelated to their smoking status, atopy, withdrawal of therapy with inhaled corticosteroids, or disease progression.4 The genotype of responders vs nonresponders may be different. However, both candidate gene association studies and linkage analysis studies in this phenotype are scarce (Table 5).
To identify the susceptibility loci for bronchodilator response
Conclusions
It is often stated that further knowledge of the genetics of COPD may lead to new treatments or to an increased ability to identify risk genotypes. However, current knowledge of the genetics of COPD is limited. Different and extreme COPD phenotypes are likely due to different gene mutations or polymorphisms, and these data are now emerging from candidate gene and linkage analysis studies. As we await more evidence, and bearing in mind that inconsistent results may be due to the phenotype
Glossary of Terms
Allele: one of the variant forms of a gene at a particular locus, or location, on a chromosome.
Apoptosis: programmed cell death, the body's normal method of disposing of damaged, unwanted, or unneeded cells.
Candidate gene: a gene, located in a chromosome region suspected of being involved in a disease, the protein product of which suggests that it could be the disease gene in question.
Centimorgan: a measure of genetic distance that tells how far apart two genes are. Generally, 1 cM equals about
ACKNOWLEDGMENT
I would like to thank June Baldwin for help with the preparation of this manuscript.
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Genotype is associated with smoking and other key health behaviors among individuals with alpha-1 antitrypsin deficiency-associated lung disease
2018, Respiratory MedicineCitation Excerpt :Alpha-1 antitrypsin deficiency (AATD) is a genetic condition that increases the risk of developing lung disease [1]. The emphysema subtype of chronic obstructive pulmonary disease (COPD) is the most common health problem caused by AATD [2,3]. Various environmental exposures influence the risk of developing lung disease, but the primary factors that influence this risk are cigarette smoking and the severity of AATD [4–6].
Genomic mechanisms of transformation from chronic obstructive pulmonary disease to lung cancer
2017, Seminars in Cancer BiologyCitation Excerpt :It was estimated that COPD incidence is increasing at the rate of is about 1–2 percentage and the population of COPD may be about 85 million in 2030, of which approximately 1% develop lung cancer every year [4]. COPD and lung cancer are major respiratory diseases with a large amount of genetic variations and a high sensitivity to environmental risk factors [7–11]. The association between COPD and lung cancer was proposed by the finding that a considerable proportion of lung cancer patients have a history of COPD [12] and that COPD patients had four to six fold higher risk of developing lung cancer, as compared to smokers alone [13].
Association between glutathione S-transferase P1 Ile (105) Val gene polymorphism and chronic obstructive pulmonary disease: A meta-analysis based on seventeen case-control studies
2015, Meta GeneCitation Excerpt :However, only 10–15% of smokers develop clinically significant COPD (Mannino et al., 2002; Salvi, 2014). Many COPD patients have a family history and several studies have showed that the individual's risk differences to tobacco smoke injury may be related to genetic factors and the genetic factors may also play an important role in the pathogenesis of COPD (Hoidal, 2001; Molfino, 2004). Therefore, it is widely believed that COPD results from an interaction between genetic factors and environmental exposures.
Association of Egr-1 and autophagy-related gene polymorphism in men with chronic obstructive pulmonary disease
2015, Journal of the Formosan Medical AssociationCitation Excerpt :Inconsistent results for the genetic predisposition of smokers to acquired COPD and genetics bases of COPD severity with rapid decline of FEV1 was also found in the matrix metalloproteinase; matrix metalloproteinase 9 polymorphisms are associated with the development of smoking-induced pulmonary emphysema, but not associated with a rapid decline of lung function. This result may be due to COPD susceptibility and progressive airflow limitations are different clinical phenotypes associated with different genes.2 Another possible reason was that spirometry is not a suitable severity assessment tool in the present study.