Download Mandev Guram – COPD

Mandev Guram
Dr. Ely
Genetics
13 November 2008
The Genetics of Chronic Obstructive Pulmonary Disease
Currently the fourth highest cause of death in the United States, chronic obstructive
pulmonary disease (COPD) is a major killer with no effective therapy8. Today, COPD affects
more than 16 million Americans and is the only disease among the top ten causes of death with a
rising mortality rate in the U.S. 8. It has been predicted to be the third largest cause of death by
the year 20208. COPD is a serious disease that causes the airways of the lungs to narrow, airflow
decreases and the air sacs of the lungs become damaged making it difficult to breathe. The
disease is poorly reversible and although treatment may help alleviate symptoms, there is no
cure.
There is no doubt that cigarette smoking is the main risk factor for COPD8. Smoking is
responsible for 90% of COPD in the United States1. Cigarette smoke damages the lungs by
irritating the lungs, promoting inflation, and releasing an enzyme (elastase) that breaks down
fibers in lung tissue1. Smoking also causes oxidative stress which can mutate DNA and lead to
chronic lung injury1. Another major risk factor for the disease is pollution. Although it is
unclear whether or not outdoor air pollution contributes to the development of COPD, indoor air
pollution is considered a common cause of the disease1.
More recently, researchers have investigated what other factors may contribute to the
development of COPD. For example, Beck et al., (1981) showed that although there is clearly a
relationship between smoking and decline in lung function, smoking habits (such as pack years
and duration of smoking) were estimated to account for only 15% of the variation in expiratory
volume of the lungs1. Therefore, other factors must contribute to the development of COPD.
While environmental risk factors such as childhood viral respiratory infections and air
pollution were identified, genetic risk factors also may be involved. Investigators have shown
that COPD prevalence is increased in the relatives of cases compared with the relatives of
controls8. It has also been shown that the prevalence of COPD and similarity in lung function
decreased with increased genetic distance7. It was found that there was a higher correlation of
lung function between parents and children or between siblings than between spouses7. These
results are consistent with the idea that there is a genetic component to COPD, but because a
Mendelian pattern of inheritance has not been observed, it is unlikely that there is a single major
susceptibility gene7.
Two genes that may influence the development or severity of COPD are α1 –Antitrypsin
and Glutathione S-Transferase genes7. α1 -Antitrypsin (α1 -AT) can inhibit a large range of
proteases, including neutrophil elastase, an important enzyme in the pathogenesis of COPD that
breaks down lung tissue7. Laurell and Eriksson (1963) showed that individuals with low levels
of α1 –AT have an increased prevalence of emphysema3. It was also shown that α1 -AT
deficiency follows a simple Mendelian pattern of inheritance and is usually associated with the Z
isoform of α1 –AT7. The ZZ genotype (severe α1 –AT deficiency) is undoubtedly a risk factor for
COPD, and most case-control studies and some population studies have indicated that
intermediate α1 –AT deficiency is probably a modest risk factor. 7
Glutathione S-Transferases (GSTs) are a family of enzymes that play an important role in
detoxifying various aromatic hydrocarbons found in cigarette smoke7. Basically, GSTs play a
major role in cellular defense by detoxifying various substrates in tobacco smoke and a
deficiency of certain GSTs has been associated with emphysema2.
Ishii et al. investigated whether a polymorphism in the GSTP1 gene is associated with the
development of COPD2. Polymorphisms of the GSTP1 gene have been detected and have been
shown to have considerable effects2. The activity of GSTP1 is affected by substitution at
position 105 which is located in the hydrophobic substrate binding site, so depending on what
amino acid occurs at this position, there can be significant consequences2. For example, a study
by Ryberg et al.6 showed that individuals with a certain polymorphism (the 105Val allele rather
than the 105Ile allele) have a higher risk of developing lung cancer. Therefore, Ishii et al.
sought to determine whether the polymorphism of the GSTP1 gene would have an association
with COPD.
The study was performed in Tokyo with blood samples taken from 53 patients with
COPD and 50 control patients from various hospitals2. GSTP1 is known to have genetic
polymorphisms in exon 5 and exon 62. A guanine to adenine transition in exon 5 changes Ile 105
to Val, and a cytosine to thymidine transition in exon 6 changes Ala 114 to Val2. The study
found that the proportion of GSTP1/Ile105 homozygotes was significantly higher in the patients
with COPD than in the control subjects (79% vs 52%, odds ratio 3.5, 95% confidence interval
2.7 to 4.6 for COPD)2. This study indicates that the GSTP1/Ile105 genotype may be less
protective against toxins in tobacco smoke, showing that there is in fact a genetic side to COPD2.
A second study examined the relationship between the nuclear factor erythroid-derived-2related factor 2 gene (NRF2) and COPD4. NRF2 functions as a “master gene” by turning on
numerous antioxidant and pollutant-detoxifying genes to protect the lungs from environmental
pollutants. A previous study by Rangasamy et al. showed that when NRF2 was inactivated in
mice, the mice went on to contract emphysema5. Therefore, Malhotra et al. 4 assessed the
expression of NRF2, NRF2-dependent antioxidants, regulators of NRF2 activity, and oxidative
damage in non-COPD (in both smokers and former smokers) and smoker COPD lungs (mild and
advanced) 4. Cigarette smoke–exposed human lung epithelial cells and mice were used to
understand the mechanisms. Compared with non-COPD lungs, COPD lungs showed a marked
decline in NRF2-dependent antioxidant levels, had increased oxidative stress markers, and had
significantly decreased DJ-1 levels (a protein that stabilizes NRF2 proteins) 4. Furthermore,
expression of NRF2 was significantly decreased in smokers with advanced COPD compared to
smokers without COPD4. These findings were extremely significant since not only was this the
first time a correlation was made between a decline in the antioxidant system and progression of
COPD in humans, but also it showed that NRF2 may be important therapeutic target for
intervention in the pathogenesis of COPD4. The authors stated that, “therapy directed toward
enhancing NRF2-regulated antioxidants may be a novel strategy for attenuating the effects of
oxidative stress in the pathogenesis of COPD.”
Whereas in the past it was believed that cigarette smoke and other environmental factors
were the only causes of the disease, these three studies have shown that there are genetic risk
factors for chronic obstructive pulmonary disease. Hopefully, researchers will be able to build on
these studies to find a cure to this horrible disease.
Works Cited
1. Barnes, P.J.. "Chronic Obstructive Pulmonary Disease." New England Journal of Medicine
343(2000): 269-280.
2. Ishii, et al. "Glutathione S-transferase P1 (GSTP1) polymorphism in patients with chronic
obstructive pulmonary disease." Thorax 54(1999): 693-696.
3. Laurell CC, Eriksson S: The electrophorectic α1 -globulin pattern of serum in α1 -antitrypsin
deficiency. Scand J Clin Lab Invest 15:132, 1963.
4. Malhotra, et al. "Decline in NRF2-regulated Antioxidants in Chronic Obstructive Pulmonary
Disease Lungs Due to Loss of Its Positive Regulator, DJ-1." American Journal of
Respiratory and Critical Care Medicine 178(2008): 592-604.
5. Rangasamy T, Cho CY, Thimmulappa RK, Zhen L, Srisuma SS, Kensler TW, Yamamoto M,
Petrache I, Tuder RM, Biswal S. Genetic ablation of Nrf2 enhances susceptibility to
cigarette smoke-induced emphysema in mice. J Clin Invest 2004;114:1248–1259.
6. Ryberg D, Skaug V,Hewer A, et al.Genotypes of glutathione transferase M1 and P1 and their
significance for lung DNA adduct levels and cancer risk. Carcinogenesis 1997;18:1285–
9.
7. Sandford, et al. "Genetic risk factors for Chronic Obstructive Pulmonary Disease." European
Respiratory Journal 10(1997).
8. Schiffman, George. "Chronic Obstructive Pulmonary Disease." MedicineNet.com 20 Oct
2008.
<http://www.medicinenet.com/chronic_obstructive_pulmonary_disease_copd/article.htm
>.