Open Journal of Respiratory Diseases, 2013, 3, 52-62 Published Online May 2013 (
Genetic Implications in COPD. The Current Knowledge
Ioannis Sotiriou, Demosthenes Makris
Intensive Care Unit, University Hospital of Larisa, Larisa, Greece
Received December 28, 2012; revised January 30, 2013; accepted February 10, 2013
Copyright © 2013 Ioannis Sotiriou, Demosthenes Makris. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
Chronic Obstructive Pulmonary Disease (COPD) is a multifactorial disease in the pathogenesis of which contributes a
variety of causative factors including genetic and environmental ones. They may also be interactions of genetic suscep-
tibilities and environmental influences. Towards to that in the pathogenesis of the disease except smoking, it seems to
have a great impact the genetic predisposition of the individuals suffering from that serious progressive disease. Re-
garding to these observations and findings very interesting studies have been conducted in order to elucidate the impli-
cations of different genes, and their polymorphisms in disease aetiology. This is a review which elucidates the impact of
genetic susceptibility in COPD.
Keywords: Association Studies; Chronic Obstructive Pulmonary Disease; Genetics; Genes; Polymorphisms
1. Introduction
Chronic Obstructive Pulmonary Disease (COPD) is a
progressive disease which is characterized by alteration
in normal lung architecture and by a non-fully reversible
airflow limitation. The airflow limitation is usually pro-
gressive and associated with an inflammatory response of
the lungs to noxious particles or gases. Chronic inflam-
mation causes structural changes and narrowing of the
airways. Moreover, it causes obstruction of the small
airways (obstructive bronchiolitis) leading to the secon-
dary destruction of the lung parenchyma (emphysema)
[1]. Although cigarette smoking is the major environ-
mental risk factor for the development of chronic ob-
structive pulmonary disease (COPD), the fact that only
20% of the smokers develop the disease, suggests that
genetic factors influence COPD susceptibility. Firstly,
there is substantial variability in the development of
chronic airflow obstruction among cigarette smokers [2,
3]. Secondly, studies conducted among families, mem-
bers of which were free from lung diseases, have demon-
strated familial accumulation of spirometric measures,
suggesting that genetic factors influence to varying de-
grees the integrity of the pulmonary function [4,5]. Addi-
tionally familial studies with members suffering from
COPD, demonstrated serious disturbances of pulmonary
function tests (PFT’s), regarding the degree of airway
obstruction, in first-degree relatives of patients with
COPD compared with control subjects, suggesting the
impact of genetic influences in COPD [6,7]. Last but not
least, severe A1-antitrypsin deficiency is a proven ge-
netic factor which causes pulmonary emphysema in a
small group of patients with chronic obstructive pulmo-
nary disease.
2. Evolutionary Technologies
In the era of genetic analysis and conduction of studies,
in order to elucidate and simultaneously to confirm a
plausible association between genes and the disease
pathophysiology, arises the substantial need to develop
molecular methods in order to facilitate, at laboratory
scale the genetic aspect of the disease. With regard to
that the current applied methods and genome technolo-
gies include the polymerase chain reaction (PCR) and
2.1. Applicable Methods in Genetic Analyses
Polymerase Chain Reaction (PCR)
PCR presents an important development in DNA tech-
nology that has enormous implications for basic research
and genetic diagnostics. This method allows the multi-
plication of selected DNA sequences (with a relatively
simple enzyme reaction) to produce a large number of
copies for a limited time. This allows the analysis of a
specific piece of DNA without prior cloning, which sig-
nificantly increases the speed of analysis. It is necessary
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to synthesize chemically two small oligonucleotide prim-
ers (usually 15 - 30 nucleotides in length), based on the
known sequence of the region. Because of the fact that
the primers are presented in large excess, every launcher
will find a sequence complementary to the overall mix-
ture of DNA and will be hybridised in situ. Subsequently,
it is also added an enzyme that can withstand high tem-
peratures up to 95˚C, called Taq polymerase. This en-
zyme synthesizes a DNA chain by the end of the primer
using DNA as the original matrix. This whole process
can be done in an easy way round, with each cycle last-
ing only a few minutes. 30 - 40 cycles can be performed
without having to add new enzymes or primers. The re-
sult is an exponential increase of the amount of DNA in
the region between the two primers. The practical effect
is that it can begin the experimental phase in nanograms
amounts of DNA, PCR can take place, and then the sam-
ple is analyzed on agarose gel to produce a specific band,
which corresponds exactly to the distance between the
primers. The primers are added to double-stranded DNA,
which is then denaturated to monoclonal DNA through a
thermal procedure. As a technique the major advantages
are: quick (speed) and easy to perform, DNA cloning by
PCR can be performed in a few hours, using relatively
unsophisticated equipment, sensitive, PCR is capable to
amplify sequences from minute amounts of target DNA,
even the DNA from a single cell and robust, PCR permits
amplification of specific sequences from biological sub-
strates in which the DNA is badly degraded or embedded
in a medium from which conventional DNA isolation is
problematic. Major disadvantages are extremely liable to
contamination, high degree of operator skill required, not
easy to set up a quantitative assay, and finally a positive
result may be difficult to interpret.
2.2. DNA Microarreys
DNA microarrays can be used to detect diversities in the
levels of gene expression in different populations of cells
on a genome-wide level. DNA microarrays rely on the
hybridization properties of nucleic acids to monitor DNA
or RNA abundance on a genomic scale in different types
of cells. Since the initial application of this a very prom-
ising technology in the 90’s faced a wide scope of use in
almost all the biomedical fields. A DNA microarray is a
collection of microscopic DNA spots attached to a solid
surface. Microarrays could be applied as a method to
measure diversities in expression levels, to point single
nucleotide polymorphisms (SNPs) or to genotype or re-
sequence mutant genomes. It is well established the no-
tion that the pathophysiology of COPD extends beyond
the scope of the cigarette smoke as the cornerstone of the
inflammatory response unlocks in the lung cell substrates.
Thus, numerous studies focused on the application of the
microarreys technology to elucidate the complexity of
pathological pathways of this progressive disease. With
regard to this issue a study conducted and the results drew
out a quite wide scope of diversity which could be address
to the variability of the gene expression among the dif-
ferent individuals [8]. Despite its role as a useful tool in
genome analysis it is engaged with advantages and draw-
backs. Advantages of DNA microarray tests include high
throughput (lots of information with one test), and good
coverage of the genome with the chips that have larger
numbers of test spots. Disadvantages include the incom-
plete coverage, which can lead to false normal results, and
the ability to test only for unbalanced rearrangements
(duplications and deletions), and not balanced transloca-
tions or inversions. However being high throughput and
cost effective most of the elements for this technology, it
still suffers from lack of perfect processing methods and
acceptable sensitivity as much as real time PCR.
2.3. Microsatellites
Microsatellites also widely known as Simple Sequence
Repeats (SSRs) or short tandem repeats (STRs), are
repeating sequences of 2 - 6 base pairs of DNA [9].
They are classified in simple and composite ones. Sim-
ple microsatellites contain only one kind of repeat se-
quences and composite contains more than one type of
repeats. Microsatellites present advantages as markers.
They are abundant, high polymorphic and evenly dis-
tributed. They are used as molecular markers in genet-
ics and other studies. They can also be used to study
gene duplication or deletion. Microsatellites are also
predictors of SNP density as regions of thousands of
nucleotides flanking microsatellites. They have an in-
creased or decreased density of SNPs depending on the
microsatellite sequence [10]. As a molecular technol-
ogy they present a wide variability. Their variability is
due to a higher rate of mutation compared to other
neutral loci of DNA. These high amplitudes of muta-
tion can be explained more frequently by slipped strand
mispairing (slippage) during DNA replication on a sin-
gle DNA strand. Microsatellites are a proven molecular
method which present a high level of versatility as a
plausible marker in pathobiology of COPD, but are not
free of limitations. For their application previous ge-
netic information is necessary, a great amount of up-
front work demands, and last but not least drawbacks
could be revealed regarding the PCR of microsatellites.
With regard to the role of microsatellites as a marker
presenting a crucial impact in the clinical course of
COPD, there is evidence drawn out from studies. The
results enforced the notion that the microsatellite DNA
instability (MSI) is strongly associated with increased
exacerbation frequency in COPD patients, and reveals
that a somatic mutation may hold a key role in the
pathobiology of the disease [11,12].
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3. Data on the Genetic Basis of the COPD
The genetic basis of COPD has been investigated using
association studies and candidate gene polymorphisms,
which may have an important role in pathogenesis of that
multifactorial disease. Until now they have studied sev-
eral genes that may be associated with the development
of COPD. Genes include proteases, anti-proteases, anti-
oxidants, xenobiotic metabolizing enzymes, and also in-
flammatory metabolites. The core of the numerous inves-
tigations and researches is to shed more light upon the
diversities of the genetic susceptibility that occur among
different ethnic groups. It is crucial to reveal and to asso-
ciate the potentially clinically relevant observations for
development the optimal therapies of tomorrow today.
4. Genes Impact in COPD
The Human Genome Project, the technological advances
in single nucleotide polymorphism (SNP) genotyping,
and the DNA sequencing have enriched our research
arsenal of useful tools for highlighting potential candi-
date genes in the complex pathogenesis of the disease.
Considering the diversity of diseases such as chronic
obstructive pulmonary disease, which are influenced by
various genetic factors, environmental factors, as well as
interactions between genes and between genes and envi-
ronment, it is imperative to carry out more studies in or-
der to illuminate the pathophysiology of the disease. The
most commonly applied approach is to select a candidate
gene from known or suspected COPD pathophysiology,
and to test genetic variants within that gene for associa-
tion to COPD. Candidate genes selected from gene asso-
ciation studies. A large number of genetic association
studies conducted in order to evaluate the distribution of
variants within candidate genes selected based on COPD
pathophysiology (Table 1).
4.1. A-1-Antithrypsin in Genetics of COPD
The genetic factor that has been extensively studied is the
lack of an A1 antitrypsin glycoprotein belonging to the
group of protease inhibitors of serine (protease inhibitor,
PI or SEPRINA 1) encoding a1AT. It is synthesized in
the liver and then it moves into the systemic circulation.
Through the inhibition of neutrophil elastase it protects
the lung parenchyma from destruction. The normal M
allele is associated with normal levels a1AT. The S allele
is associated with mild lowering a1AT. The G allele is
associated with significant lowering a1AT and occurs
with a frequency >1% among Caucasians. This rare
autosomal recessive disorder occurs at a higher rate in
Northern European. People with two G alleles or one Z
and one non-viable allele are characterized as PiZ which
is the most common form of severe a1AT. Sandford et
al., in the Lung Health Study showed that the PiZ allele
a1AT gene in heterozygous state is the largest proven
genetic factor for the development of pulmonary emphy-
sema [13]. In order to identify a possible correlation of
descent affinity of the airflow and whether it correlates
with the presence of genetic predisposition affecting a
possible loci in chromosomes, the Framingham study
assessed 1578 members of 330 families (linkage studies),
showed that loci affecting peak values of FVC and FEV1
are located on chromosomes 21, 4 and 6 [14]. These evi-
dences enforce the hypothesis that genetic variability
might be involved in the clinical diverse presentation of
the disease among different individuals or populations.
4.2. Genes and Oxidative Stress
Pivotal role in pathophysiology of COPD has the oxida-
tive stress. Towards to this Connett et al. conducted a
study to highlight a possible genetic predisposition in
antioxidant gene polymorphisms and susceptibility to a
rapid decline in lung function among smokers. The in-
vestigated polymorphisms were polymorphisms of anti-
oxidant enzyme glutathione S-transferase (GST) and in
particular GSTM1, GSTT1 and GSTP1. The study re-
vealed that the combination of family history of COPD
with the presence of genotype GSTP1 105ILe/ILe is as-
sociated with the rapid decline in lung function [15]. The
protein that encodes the Microsomal epoxide hydrolase 1
(mEPHX1) gene plays an important antioxidant role in
the lungs. There is in vitro evidence that the polymor-
phism in the gene promoter region reduces the upregula-
tion of heme oxygenase-1 in response to reactive oxygen
species in cigarette smoke. Also, the combination of
family history of COPD and the presence in homozygous
state of the haplotype His113/His139 of the microsomal
epoxide hydrolase (mEPHX) gene is associated with ac-
celerated decline in lung function in smokers. At last but
not least, the HMOX 1 gene (GT) n alleles revealed no
association with rapidly decline lung function [15]. The
protective role of the EPHX1 Tyr113His polymorphism
in the pathogenetic pathways of COPD has been empha-
sized by the case-control study, conducted by Brogger J.
et al. [16]. Hu G. et al. in a study reviewing meta analy-
sis results concerning the association of antioxidant
genes in pathogenesis of COPD, concluded that EPHX1
113 and EPHX1 139 are both genetically relative factors
for susceptibility of COPD in Asian population, espe-
cially the fast activity phenotype EPHX1.This observa-
tion did not appeared in Caucasians who are more sus-
ceptible in the risk for developing COPD concerning the
slow activity phenotype of the EPHX 1 in contrast to the
Asians. These facts underline that the susceptibility in
COPD depends upon the diverse ethnic gene-environ-
ment interactions [17]. Analyses the same aspect of the
oxidative stress and the plausible role of the EPHX 1 as a
protective mechanism against it Lakhdar R. et al. in an
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Table 1. Candidate genes and their impact in COPD.
Investigated genes Type of study ReferencesPolymorphisms Associations revealed
PI gene, PI MZ
Sandford et al., in the
lung health study [13] PiZ allele a1AT gene Associated with pulmonary emphysema, in
heterozygous condition
CLCA1 gene [clustered
on the short arm of
chromosome 1
(1p 22-31)]
Hegab A.E. et al.
(association study) [19] SNP’s [clustered on the short arm
of chromosome 1(1p 22-31)]
Association with susceptibility in COPD in
Japanese but not in Egyptian population.
CYP2A6 gene Nakamura H. et al.
(association study) [34] CYP2A6del polymorphism
Protective factor versus development of pul-
monary emphysema
Independent from smoking habit
TGF-β1 gene
1) Van Diemen C. et al.
2) Yoon H.I. et al.
3) Wu L. et al.
Association study.
1) SNP’s in decorin.
2) SNP’s-10807G/A, 509T/C,
29T/C in exon of TGFB1 gene
3) SNP’s at exon1 position
29(T-C) of TGF-1 gene
1) Association with COPD but not in rapid
decline in general population
2) No association with COPD and TGFB1
3) Inhibition of MMP’s protective role in
Interleukine IL-4, IL-13
beta (2)-adrenoceptor
(ADRB2) genes
(location: chromosome
1) Hegab A.E. et al. (2004)
association study
different ethnic groups
2) Van der Pouw Kraan
T.C. et al.
3) Liu S.F. et al.
589C/T, 33C/T in IL-4,
111C/T and +2044G/A in IL-13
+79C/G in ADRB2
1055 IL-13 promoter
1) Possible association with COPD
2) Iincreased frequency of the -1055 T allele in
COPD patients
3) Association with severity of COPD
Microsomal epoxide
hydrolase gene
S-transferase M1
1) Connett J.E.
2) Hu G. et al.
3) Lakhdar R. et al.
(association study)
4) Brogger J. et al.
GST M1, T1, PI microsomal
epoxide hydrolase (mEPHX)
haplotype His113/His139
EMPX Tyr 113 His
1) Accelerate decline in smokers with
presence GST, M1, T1, PI Polymorphisms
2) Phenotypes of EPHX1 associated with
3) Weak relation of His113 no with His139
4) EMPX Tyr 113 His polymorphism
protective role
Gene TIMP-2 (tissue
inhibitors of
Hirano K. et al.
(association study) [23] +853 G/A and 418 G/C Associated with the onset of COPD.
MMP1 (interstitial
collagenase) and
MMP12 (macrophage
elastase) genes
Joos L. et al. [24]
MMP1 (G-1607GG)
MMP12 (Asn357Ser) Association with rapid decline in FEV1
Vitamin D binding
protein gene
Ito I. et al., Lu M. et al.,
Shen LH et al.
(association study)
[38-40] Alleles 1F nad 2F IF allele related to COPD the 2F Possible
protective role
GST gene Connett J.E. et al.
(GSTM1, GSTT1 and GSTP1)
GSTP1 105ILe/Ile
Rapid decline in lung function in presents
of family history
TNF-α gene
(TNF-α-308 1/2 alleles)
1) Μolfino A.
2) Chieracul N. et al.
(association study)
3) Hu G.P. et al.
4) Zhan P. et al.
1) Association in COPD smokers
2) No plausible association in subpopulation
3) No association in Caucasians
4) No association in Caucasians
Klotho gene Sotiriou I. Froudarakis M.
et al. [46] SNP-395G > A Association with the increased BMI in
COPD patients
association study concluded in weak association of the
EPHX 1 113His genotype and no association with the
EPHX 139His genotype in Tunisians, when adjusted on
the basis of phenotypical appearance of the disease [18].
Summarising the conclusions throughout the numerous
studies it arises the notion that the influences of the di-
verse gene-environment interactions present a strong race
based relation. The above observation points out the dif-
ficulty to draw out conclusions for the general COPD
4.3. Interleukins in COPD Genetics
Interleukins are a group of cytokines (secreted pro-
teins/signaling molecules) expressed by leucocytes. They
promote the development and differentiation of T, B, and
haematopoietic cells. IL-13 is a pleiotropic cytokine that
may be important in the regulation of the inflammatory
and immune responses. It inhibits inflammatory cytokine
production and synergises with IL-2 in regulating inter-
feron-gamma synthesis. The sequences of IL-4 and IL-13
are distantly related. Interleukin (IL)-4, IL-13 and beta-2-
adrenoceptor (ARDB2) are involved with the hyperre-
sponsiveness of the airways that by itself constitutes a
danger factor for COPD. A study that has been carried
out in this field included two different ethnic group
populations, has proven that the polymorphism ARDB2
+ 79 C/G is probably involved with the pathogenesis of
COPD [19]. Investigating the impact of the IL-13 in the
pathogenesis of COPD a case control study concluded
that the polymorphisms in promotor of the gene IL-13
may increase the risk of COPD [20]. The same conclu-
sion has been reached out from a case-control study
conducted in Taiwanese population [21]. The ADRB2
are specific receptors on the cell membrane and simulta-
neously therapeutic target in the treatment of COPD. To
elucidate the role of these receptors in different geno-
typic expression of the COPD patients a case control
study concluded that the Gly16 polymorphism of beta-2-
adrenoceptor may increase susceptibility to develop
COPD, and Gln27 beta2 adrenoceptor polymorphism
may be associated with the severity of COPD in Chinese
population [22]. Current evidence comes from Asian
populations only, and the necessity for further investiga-
tion is crucial in order to reach out conclusive results for
the COPD patients as a whole.
4.4. Protease/Antiprotease Imbalance.
Metalloproteinases in COPD
Another crucial factor in the pathophysiology and patho-
genesis of COPD is the metalloproteinases. The metallo-
proteinases are endopeptidases. Their catalytic center is
stabilized by zinc ions (Zn) and calcium (Ca). They have
the capacity to degrade all proteins and proteoglycans of
the extracellular matrix. Their action is inhibited by
natural tissue inhibitors of metalloproteinases (TIMP’s).
The imbalance between proteases-antiproteases represents
another important field in the pathogenesis of the COPD.
Polymorphisms of the gene TIMP-2 (tissue inhibitors of
metalloproteinases) +853 GIA and 418 G/C, in a study
conducted among 88 patients with COPD and 40 healthy,
was found to be associated with the onset of COPD [23].
On the other hand patients with a rapid decline in FEV1
have polymorphisms in the genes MMP1 (G-1607GG)
and MMP12 (Asn357Ser) [24]. The results are the
evidence of susceptibility of the lung parenchyma in
cigarette smoke among specific population. The in-
vestigated polymorphisms suggest high affinity to the
progress of the pulmonary functional decline. However,
further investigation must be conducted in order to
elucidate the susceptibility of this evidence per se or in
correlation with other factors which influence the natural
history of the disease.
It is generally accepted that COPD is associated with an
abnormal inflammatory response. This extends beyond
the lung to systemic manifestations. The inflammatory
process having a leading role in the pathophysiology of
COPD, lists a variety of inflammatory mediators. TNF-a
mediated inflammation is thought to play a key role in
both the respiratory and systemic features of COPD. The
TNF-308 polymorphism is a biallelic restriction fragment
length polymorphism (RFLP) originally described by
Wilson [25]. The alleles of TNF-a-308-1 and TNF-a-
308-2, in section 308 of the promotor of TNF-a gene are
related, in part, with extensive emphysema like lesions in
smokers, as they are demonstrated by a study in Japanese
patients. On the other hand, in the study of Chieracul N.
et al. no association was revealed among the Thai popu-
lation [26]. A similar result has been reached in the study
of Hu GP et al. who demonstrated that the TNF2 allele is
a risk factor for COPD among Asians but no association
of TNFa-308 polymorphism and COPD was revealed in
Caucasians [27]. The same results reached out in a
meta-analysis of Zhan P. et al. [28]. The studies that have
been conducted to this direction had ambiguous results.
A possible explanation for this is the genetic diversity of
the studied populations and the various interactions of
exogenous causative factors, and the environmental in-
fluences on gene expression.
4.5. The Cytokine TGF-β1
The TGF-β1 (transforming growth factor-beta1) is a cy-
tokine with diverse actions in cell proliferation, differen-
tiation and inflammation, simultaneously. Plus it is an-
other potential candidate gene which appears to have a
pivotal role in the pathogenesis of COPD. Wu L et al.
conducted an association study carried out in order to
derive a relationship between TGF-β1 gene and COPD.
They concluded that this gene could conceivably act to
prevent the degradation of elastin by inhibiting the ex-
pression of matrix metalloproteases. It is also possible
that TGF-β1 may acts to promote the synthesis of elastin
and, as a result, it can have a role in repairing the loss of
elastic fibres that occurs as a result of smoking. From this
perspective it may be associated with the pathogenesis of
COPD as a factor against the inflammation pathways in
the lung tissue [29]. In addition Van Diemen et al. have
revealed that SNP’s in decorin alone or in combination
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with the TGF β-1 does not disrupt the balance of those
genes expression. Also TGF-β1 is associated with COPD
but not with severe decline in FEV1 in general popula-
tion [30]. On the other hand Yoon HI et al. concluded
that there is no significant association between the SNP’s
10807G/A, 509T/C, 29T/C in exon of TGFB1 gene,
and the presence of COPD [31]. Despite this current evi-
dence from previous studies results are inconclusive.
These evidence based observations once more underline
the plausible impact of the genetic diversity in the ex-
pression for the pathogenesis of the disease combined
with the degree in gene-by-gene and gene-environment
4.6. CFTR and COPD
The role of the CFTR in the pathophysiology of COPD
still remains a future field to elucidate. In patients with
brochitic predominant phenotype, known as “blue bloat-
ers”, has not been clarified completely whether the muta-
tions of transmembrane regulator transfer of cystic fibro-
sis (CFTR), are associated with COPD. However a link
has been reported on chromosome 22. The study that
implicates the impact that CFTR-dependent ceramide
signalling may have in lung injury and emphysema has
been conducted by Bodas et al. [32]. Ceramides is a fam-
ily of lipid molecules. A ceramide is composed of sphin-
gosine and a fatty acid. Ceramides are found in high
concentrations within the cells membrane. They are one
of the component lipids that make up sphingomyelin, one
of the major lipids in the lipid bilayer. It is unclear how
membrane-CFTR may modulate ceramide signaling in
lung injury and emphysema. Cftr(+/+) and Cftr(/)
mice and cells were used to evaluate the CFTR-depend-
ent ceramide signaling in lung injury. The results indicate
that inhibition of de novo ceramide synthesis may be
effective in disease states with low CFTR expression like
emphysema and chronic lung injury, but not in complete
absence of lipid-raft CFTR as in ΔF508-cystic fibrosis.
The data demonstrate the critical role of membrane-lo-
calized CFTR in regulating ceramide accumulation and
inflammatory signaling in lung injury and emphysema
4.7. The CYP2A6 Genotypes and CYP2A6del
CYP2A6 is another molecular structure. It is member of
the enzyme system cytochrome P450, which metabolizes
nicotine to cotinine. It appears to have important role in
the pathogenesis of COPD. The polymorphism CYP2A6del
acts as a protective factor against the development of
pulmonary emphysema, regardless of smoking habit, as
was highlighted by the study of Nakamura H et al. [34].
Despite the current evidence, the results are confounding
and the avoidance of such factor depends strongly in the
well patients’ classification and the stratification of the
severity of the pulmonary tissue injuries.
4.8. Vitamin D Binding Protein (VDBP)
Scientific interest has in recent years the emergence of a
possible association of polymorphisms VDBP (vitamin
d-binding protein) in the pathophysiology of COPD and
particularly in pulmonary emphysema. Towards to this
direction association studies have been conducted to
achieve this goal. The VDBP, also known as Gc-globulin,
is a protein with molecular weight of 55 kda, which is
produced in the liver and connects the extracellular actin
to endotoxin with the addition of vitamin D. Is a precur-
sor of macrophage activating factor (maf) and enhances
the neutrophil chemotactic properties of c5 derived pep-
tides. This function is prevented by neutrophil elastase
inhibitors, suggesting a relationship between the prote-
ase-antiprotease pathway and inflammation [35-37].
Subsequently, Ito et al. performed a case control study,
in which they found that the prevalence of the Gc 1F
homozygotes was significantly greater in patients with
copd than among controls, yielding a significant associa-
tion of the studied polymorphism with the susceptibility
of the disease and with the severity as well [38]. In the
case-control study Lu M et al. concluded that allele 1F is
one of the risk factors for COPD associated with smok-
ing. 1F homozygote may increase the risk of copd. On
the other hand, allele 2 might have a protective effect on
pathogenesis of COPD [39]. Shen LH et al. revealed
similar results regarding to the role of F1 and F2 alleles,
found significantly higher proportion of VDBP-1F ho-
mozygosity in COPD patients, while the frequency of
VDBP-2 homozygosity was significantly lower in COPD
patients, which seemed to suggest that VDBP-2 homo-
zygocity provided a protective effect. The study con-
ducted in a limited genetic uniform chinese han popula-
tion, due to lower incidence of the 1F haplotype among
the caucasians [40]. These data are consistent with stud-
ies conducted in the same population regarding to the
different polymorphisms, a fact that underlines the high
affinity of gene-by gene and gene-by-environment inter-
actions in the pathobiological progress of the disease.
4.9. Klotho Gene
Kuro-o et al. cloned a mouse gene from a transgenic
mouse model with several age-related disorders. This
new gene named Klotho, is involved in the suppression
of different aging phenotypes [41]. The Klotho gene is or-
chestrated by 5 exons (those of the transcribed regions of
a gene present in the mature mRNA and usually contain
coding information) and lists more than 50 kb on chro-
mosome 13q12. Spans approximately 50 kb of genomic
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cDNA, encodes both membrane and secreted forms, en-
codes type I membrane protein not a helicase (Figure 1).
Defect in the expression of the Klotho gene in mice mod-
els, led to the appearance of a syndrome resembling to
the human pre-ageing, emphysema, reduction of life ex-
pectancy, subfertility, arteriosclerosis, skin atrophy and
osteoporosis. The (kl/) show short life expectancy be-
ginning of pulmonary emphysema that resembles hu-
man pulmonary emphysema both histologically and
functionally [42]. Studies conducted in humans have
shown already the correlation between gene polymor-
phisms and osteoporosis, and coronary heart disease
(CAD: Coronary Artery Disease), the blood pressure,
stroke episode and longevity. Mice that were deficient
(lack) of Klotho protein showed extensive and progres-
sive atherosclerosis in combination with medial calcifi-
cation of the aorta as well as thickening of the inner layer
of mid-range, arteries [43]. Study that analyzed the func-
tional KL-VS allele of the Klotho, gene concluded that it
affects the duration of life. The homozygous in this allele
subjects showed a decline in survival rate of 2.6% in the
age of 65 years. Also, smoking carriers of this allele
had increased risk of occult coronary artery disease,
which reinforces the strong interaction of gene-envi-
ronment. Finally, in this study the carriers of the allele
with normal blood pressure had higher risk of latent
coronary heart disease than the hypertensive patients not
carrying the allele [44]. Another study analyzed the SNPs
(single nucleotide polymorphisms) of the gene Klotho for
any correlation with bone density. The study included
population of 1187 white women and 215 postmeno-
pausal Japanese women. The result was that the popula-
tion of white women two polymorphisms, one in the
promotor of the G-395A and the other in exon 4,
C-1818T, and their haplotypes, as well, were signifi-
cantly associated with bone mineral density in elderly
postmenopausal females (65 years), but not in younger
premenopausal or postmenopausal female [45]. A recent
study based on the histological changes in animals, hy-
pothesised that genetic variations likely to regulate the
levels of expression of the Klotho gene might be involved
in the manifestation of COPD. Thus, the aim of this
study was to assess the detect and distribution of 395G
> A variant alleles between patients with COPD and their
possible relation with clinical parameters such as severity
of the disease, lung function, age, or BMI. The poly-
Figure 1. The Klotho gene.
morphism 395G > A of the Klotho gene was detected in
the COPD patients. No association was found, except
with the BMI, with the parameters studied such as lung
function, the GOLD stage, the age and the severity of
smoking. Considering that Klotho gene is a metabolic
gene, question is raised whether the mechanism of em-
physema induction of the Klotho deficient gene is
through a possible metabolic path in patients with COPD
5. Gene Therapies and Pharmacogenetics in
Considering the diversity of conclusion and final end-
points from numerous studies to date, with regard to ge-
netic susceptibility as a plausible factor in the develop-
ment and progression of COPD, a need for a comment in
gene therapy for the disease is raised. The subject de-
serves a de profundum mention, and the analysis of such
promising field of research needs a whole review per se.
for those reasons the review regarding this subject will be
brief in nature. Pharmacogenetics in COPD is a very
promising field of research waiting to be strongly eluci-
date. Several studies have been conducted towards to that
direction. They’ve launched from the mostly prescribed
therapy of COPD the short-acting β-agonists (SABA’s),
the long-acting β-agonist (LABA’s) and anticholinergic
agents. They focused on different genes with possible
association with COPD such as beta-2-adrenoceptor
(ardb2), genotyping single nucleotide polymorphisms
(SNP’s). Two of the most commonly coding variants
arg16gly and gln27glu, were examined. In Japanese
population with diverse severity stage of the disease was
found decreased bronchodilator effect in alleles [47]. But
in a study conducted in caucasians the results were in
contrary indicating no association of both alleles and
bronchodilator response [48]. Another trial included
asian population, investigated the results of the combina-
tion of different pharmaceutical agents concluded in no
association in bronchodilator effects or a significant
change functional parameters at the end of the treatment
period [49]. Another study concluded in increased pul-
monary functional parameters with regard to the arg16gly
haplotype, after treatment with tiotropium [50]. Despite
the current evidence of previous studies results are in-
conclusive, and the diversity of the studied population
regarding the race and the disease severity make really
difficult the effort to draw out firm conclusions. Gene
therapy is a fundamentally different treatment approach
based on intervention techniques in gene expression in
pathological tissues. The aim is to transfer nucleic acid
(DNA or RNA) with specific vectors within the cell to
terminate the pathogenetic process. The development of
this technology is being tested. The strategies are: a nor-
Copyright © 2013 SciRes. OJRD
mal gene into the genome randomly enters and replaces a
non-functional gene (replacement gt) or interferes with
the cell cycle of the cell. Intervention in a gene expres-
sion: induction or repression (knockout gt) by introduc-
ing dominant gene or antisence on or small interfering
RNA’s. The introduction of genes converts the prodrug
to the toxic metabolites (suicide gt). The specific immune
responses (immunomodulatory gt) stimulation could be
achieved by vaccination with genetically modified cells.
The main concern for this therapy strategy is the suffi-
ciency of the diverse vectors, adenovirus vectors, retro-
virus or lentivirus vectors and even aa vectors to reach
and activate the cellular flora of the lung tissue. Thus the
route of the application of those transfer molecules either
through airways or intravenously even the combination
of both may be of advance for targeting the pulmonary
parenchyma. However the strategy is yet in its infancy
regarding chronic obstructive lung disease.
6. Discussion
Chronic obstructive pulmonary disease (COPD) is, with-
out doubt, a disease which employs and will employ in
more extensive profile the global scientific community in
the coming years. As the harmful exogenous factors that
have a serious impact on the natural course of disease are
multiplied, the more urgent is the need for more de pro-
fundum research focusing on the causative factors of the
disease beyond the cornerstone agent, the cigarette
smoke. The fact that only a small fraction of smokers
develop the disease (about 15%), suggests that except
environmental factors, genetic susceptibility also have a
possible important role in the pathophysiology and
pathogenesis of COPD [51]. Numerous investigations
have been conducted which were aimed to highlight the
importance of genetic aspect of this dismal disease. The
last 15 - 20 years have been studied various genes and
polymorphisms with a common denominator to elucidate
their possible association with the disease. Towards this
direction the more extensively studied and proven ge-
netic factor is the a-1-antithrypcin deficiency [13,14].
The accumulating evidence of these data guided physi-
cians to develop more efficient diagnostic algorithms and
to provide optimal therapeutic procedures. But still the
treatment tools, available to date, are insufficient to per-
form panacea of the disease. Studies that have been im-
plicated the oxidative stress as a crucial impact factor in
lung inflammatory pathways and COPD concluded that
several antioxidant genes such as gst (gstm1, gstt1 and
gstp1), microsomal epoxide hydrolase 1 (mephx1) [15-18]
and Klotho gene [52] exert an important role regarding
the rapid decline in pulmonary function. However, some
inconclusive results drawn out from previous studies are
due to diversities in population that have been studied.
With regard to the role of inflammatory mediators and
cytokines, such as il-4, il-13, beta-2-adrenoceptor (ardb2),
the protease/antiprotease imbalance, the tgf-β1 factor, the
tnf-a factor despite the ambiguous results from the stud-
ies conducted towards plausible association between
genes encoded those factors and the onset or the progres-
sive severity of copd, the conclusion is that susceptibility
of the lung tissue depends not only on the exogenous
noxious substances but on the genetic based host de-
fending mechanisms as well.
Promising field in the research era towards genetics
and COPD is the further investigation of somatic muta-
tions of lung epithelial barrier cells (lebc’s) and the mi-
crosatellite instability (msi), on specific chromosomal
loci of the related to the disease genes, since cigarette
smoke may provoke the genesis of somatic mutation on
lebc’s due to oxidative stress. In particularly, the genes
that have presented high affinity to the pathobiological
mechanisms of the COPD (Klotho gene, antioxidant
genes) [11,12,53]. The future avenue in COPD pharma-
cogenetics is constellating by the emergence of fully and
carefully designed protocols assessing the specific pa-
tient phenotype, clinical evaluation and radiographic as-
sessment for the disease extension, plus the collection of
blood samples for DNA determination. When all the
above become the routine clinical practice then we will
can consider the pharmacogenetics as a crucial tool in the
physicians quiver for optimal and personalized therapy.
Towards the future of the novel and more efficient thera-
pies for this multifactorial disease the common notion is
to enforce the research interest to genetic susceptibility.
The necessity of further investigation with regard to gene
therapy is demanded. The scope of the research has to be
focused on the most efficient cell vehicles, in order to
develop more accurate and efficient biological therapy
strategies for COPD. Antioxidant genes, specific cells
lines which present in abundance in the lung epithelium,
such as neutrophils could be the core of the future thera-
peutic targets in maintenance or even the regression of
such a dismal disease.
7. Conclusion
COPD is a multifactorial disease with many complex and
multifaceted pathophysiology, associated with cigarette
smoking that generally manifests with increasing age.
Several studies have been conducted in order to under-
stand the mechanisms involved in disease. Although
some progress has been made in COPD genetics, there
are many areas that require more investigation. Regard-
ing the inflammation pathways and the extrapulmonary-
systemic manifestation of the disease, novel approaches
will likely also be essential in the identification of COPD
genetic determinants, including biomarkers of the patho-
physiologic processes involved in COPD. Interpretation
Copyright © 2013 SciRes. OJRD
of the results of the association studies is a demanding
procedure due to the heterogeneity of different pheno-
types in genetics. Genome-wide association studies may
contribute the best insights towards the identification of
the susceptibility genes in COPD. Finally, epigenetics
and gene therapies have a pivotal role as an impact factor
in the genetics of COPD and they need to be considered
in concert with genetic findings.
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