Pulmonary Perspective
Asthma and Chronic Obstructive Pulmonary Disease
Common Genes, Common Environments?
Dirkje S. Postma1,2, Marjan Kerkhof2,3, H. Marike Boezen2,3, and Gerard H. Koppelman2,4
Departments of 1Pulmonology, 3Epidemiology, 4Pediatric Pulmonology and Pediatric Allergology, University Medical Center Groningen, University
of Groningen, Groningen, The Netherlands; and 2Groningen Research Institute for Asthma and COPD, The Netherlands
Asthma and chronic obstructive pulmonary disease (COPD) show
similarities and substantial differences. The Dutch hypothesis stipu-
lated that asthma and COPD have common genetic and environ-
mental risk factors (allergens, infections, smoking), which ultimately
lead to clinical disease depending on the timing and type of en-
vironmental exposures (Postma and Boezen, Chest 2004;126:
96S2104S). Thus, a particular group of shared genetic factors may
lead to asthma when combined with specific environmental factors
that are met at a certain stage in life, whereas combination with
other environmental factors, or similar environmental factors at
a different stage in life, will lead toward COPD. Multiple genes have
been found for asthma and COPD. In addition to genes unique to
these diseases, some shared genetic risk factors exist. Moreover,
there are both common host risk factors and environmental risk
factors for asthma and COPD. Here we put forward, based on the
data available, that genes that affect lung development in utero and
lung growth in early childhood in interaction with environmental
detrimental stimuli, such as smoking and air pollution, are contrib-
uting to asthma in childhood and the ultimate development of
COPD. Additional genes and environmental factors then drive
specific immunological mechanisms underlying asthma, and others
may contribute to the ultimate development of specific subtypes of
COPD (i.e., airway disease with mucous hypersecretion, small airway
disease, and emphysema). The genetic predisposition to the de-
railment of certain pathways may further help to define subgroups
of asthma and COPD. In the end this may lead to stratification
of patients by their genetic make-up and open new therapeutic
prospects.
Keywords: asthma; COPD; genetics; risk factors
Genetic factors contribute to the development of lung diseases
such as cystic fibrosis, sarcoidosis, interstitial fibrosis, lung
cancer, asthma, and chronic obstructive pulmonary disease
(COPD). Cystic fibrosis is a monogenic disease, most frequently
caused by a deletion of three nucleotides from the CFTR gene.
In contrast, asthma and COPD are complex diseases wherein
multiple genes and their interaction with environmental factors
contribute to disease development. Thus, there is not a one-to-
one relationship between a gene and a disease.
Notwithstanding this complexity, genetic studies have dis-
covered genes and pathways contributing to disease develop-
ment, and some of them are targets for therapy (1).
(Received in original form November 6, 2010; accepted in final form February 3, 2011)
Correspondence and requests for reprints should be addressed to Dirkje S.
Postma, M.D., Ph.D., Department of Pulmonology, University Medical Center
Groningen, Hanzeplein 1, PO Box 30001, 9700 RB Groningen, The Netherlands.
E-mail: d.s.postma@long.umcg.nl
This article has an online supplement, which is accessible from this issue’s table of
contents at www.atsjournals.org
Am J Respir Crit Care Med Vol 183. pp 1588–1594, 2011
Originally Published in Press as DOI: 10.1164/rccm.201011-1796PP on February 4, 2011
Internet address: www.atsjournals.org
The field of genetics has evolved over the past decennia due
to completion of the HapMap project, applications to perform
genomic studies with high-throughput techniques, and develop-
ments of statistical analyses to test for association of a million
single nucleotide polymorphisms (SNPs) at the same time and
to assess gene–gene and gene–environment interaction. The
current challenge is to unravel the relation between variants
in newly identified genes and their function to better design
treatments of respiratory diseases.
Genetic studies initially addressed single genes that are
candidates for disease development and/or performed linkage
analyses followed by positional cloning in families of an affected
proband. Recently, genome-wide association studies (GWAS)
have identified novel genes, mostly without known function as-
sociated with diseases. However, these findings do not easily
lead to a genetic test for a specific disease, because the positive
predictive value of a single-gene test is limited and multiple
genes and environmental factors have to be incorporated (2).
This requires methods to model all these risk factors at the same
time, and large cohort sizes with all data available for validation
of the test. This review gives a bird’s-eye view of the past and
present of genetics in asthma and COPD in the context of their
common and differential origins.
DUTCH HYPOTHESIS
In 1961, Orie and colleagues postulated the Dutch hypothesis,
which stipulates that asthma and COPD have genetic and
environmental risk factors such as allergens, infections, and
smoking in common, which then ultimately lead to clinical
disease depending on the timing and type of environmental
exposure (3). This has led to a wide variety of research in-
vestigating similarities and differences between asthma and
COPD in cross-sectional studies. However, this type of study
will never give the answer to whether this hypothesis has a valid
basis. Only when investigating genes, environmental exposures,
and the timing of these environmental stimuli will we un-
derstand whether asthma and COPD have similar, different,
or both similar and different underlying genetic and environ-
mental factors. At this time we can make a (small) step forward,
because we have increased our knowledge on both genetic and
environmental factors for asthma and COPD development.
ENVIRONMENTAL RISK FACTORS FOR ASTHMA
AND COPD
In the search for risk factors for asthma and COPD, a distinction
can be made between host factors (genetic predisposition, sex)
and environmental factors (smoking, air pollution). Many
studies have tried to assess risk factors of asthma and found
evidence that, for example, atopy (4), hyperresponsiveness (5),
(passive) smoking (6, 7), air pollution (8), and respiratory tract
Pulmonary Perspective
infections (9) could be considered as single risk factors. There
are additional protective factors, such as breastfeeding (10),
maternal diet (11), and farming conditions (12). Smoking is the
predominant risk factor for development of COPD. However,
recent studies have shown that there are a considerable number
of people who develop COPD without having smoked ciga-
rettes (13). This signifies that indoor and outdoor air pollution
(14) and other environmental triggers, such as maternal smok-
ing (15, 16), may be important as well. As for asthma, airway
hyperresponsiveness (AHR) and low lung function are impor-
tant determinants of COPD development (17). Table 1 shows
an overview of common and different environmental risk
factors of asthma and COPD. Of interest, host factors such as
hyperresponsiveness, family history of asthma, and low lung
function are common risk factors for asthma and COPD, as are
environmental stimuli such as environmental tobacco smoke
and air pollution. It is difficult in this respect to dissect whether
maternal smoking during pregnancy, and parental smoking
during early childhood confer separate risks. Hence, many
studies report on environmental tobacco smoke (ETS) exposure
in general (Figure 1).
SINGLE CANDIDATE GENE ASSOCIATION STUDIES
Candidate genes are generally selected for their known bi-
ological function, differential expression in tissues or cells
involved in the pathogenesis of a disease, and/or based on
findings in relevant animal models. Association studies aim to
show that affected individuals in a population are more likely to
have a particular variant of a gene than healthy controls in the
same population. Association between the gene variant(s) and
disease may imply causality. However, association can also
occur if the allele is in linkage disequilibrium with another
polymorphism in the same or a nearby gene that is the real
causative polymorphism, or in the case of population admixture.
Even discrepant findings may not exclude a gene to be
important in disease development. In atopy, for instance, one
allele in the CD14 gene has been reported as a risk for disease
in one study and as protective in another study. Although this
initially was interpreted as nonreplication of a gene, it later
became apparent that other environmental levels of exposure
may underlie the discrepancy (18).
Asthma
There are at least 1,000 papers published examining SNPs in
genes that are candidates for asthma and allergy. Although
1589
many of these genes have not been replicated, which is needed
to reflect whether finding of this gene is a true observation,
there is a group that is replicated many times: ADAM33,
ADRB2, CD14, FCER1B, HLA-DRB1, HLA-DQB1, IL4,
IL13, IL4RA, and TNF (19). Meta-analyses do not always find
these genes as being significantly associated with asthma, but
when comparing different meta-analyses and large replication
studies, ADAM33, IL13, IL4RA, TNF, and TBXA2R appear as
consistent genes and may represent common major asthma
genes (19). Because multiple interactions between genes may
occur in disease development, it is important to perform
statistical interaction analyses between genes in biologically
plausible pathways of asthma development. Nevertheless, the
number of studies actually investigating gene–gene interactions
in pathways so far is limited. The Toll-like receptor–related
pathway is such a pathway (including CD14) and was investi-
gated in more than 3,000 children (20). Several genes in this
pathway were associated with atopy and/or asthma as a single
gene, such as IL1RL1 (also found with GWAS), BPI, NOD1,
NOD2, and MAP3K7IP1 (20). Of interest, multifactor dimen-
sionality reduction analysis showed novel, significant gene–gene
interactions in association with atopy and asthma. IL1RL1 and
TLR4 significantly interacted for their effect on specific IgE to
indoor allergens and IRAK1, NOD1, and MAP3K7IP1 with
asthma (20). An important finding was that an SNP in a gene
located in this pathway may not be associated with asthma on its
own, but the SNP does so in interaction with other SNPs in
genes in this pathway.
COPD
Candidate genes involved in established pathogenetic pathways
have been investigated for their association with COPD (i.e.,
oxidative stress, protease–antiprotease imbalance, chemokines,
cytokines, and extracellular matrix breakdown and repair).
COPD results from accelerated lung function decline; thus it
is plausible to investigate genes in association with accelerated
lung function decline in general populations. Some candidate
genes have been identified in this way, such as ADRB2,
CHRNA5, CSF3, EPHX1, IL1RN/IL1B, IL4R, IL6, IL8, IL10,
INFg, ADAM33, MMP1, GSTP1, GSTT1, GSTM1, HMOX1,
and SERPINA1 (21–26).
An additional list of genes has been associated with COPD
in case-control studies, wherein a COPD diagnosis was based on
FEV1/FVC less than 70% and FEV1 less than 80% predicted, or
less than 75% predicted. These genes involve, among others,
EPHX1, GSTM1, GSTO2, HMOX1, MMP12, SERPINA1,
Figure 1. Graph representing lung development, lung
growth, and decline in interaction with genetic and
environmental factors. Green line represents normal lung
development, growth, and decline; orange line represents
abnormal prenatal lung development and growth; red line
represents abnormal lung decline due to (environmental)
tobacco smoke (E)TS exposure. COPD 5 chronic obstruc-
tive pulmonary disease.
1590 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 183 2011

TABLE 1. RISK FACTORS FOR ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Asthma COPD

Host factors Male sex childhood, Family history of COPD

female sex in adulthood (68)
(Family) history of asthma (71) Family history asthma/atopy (71)
Genetic constitution Genetic constitution
Airway hyperresponsiveness (5) Airway hyperresponsiveness (17, 71)
Atopy (4) Low lung function (17)
Low lung function (69)
Overweight (70)
Perinatal factors Maternal smoking (72) Maternal smoking (72)
Maternal diet (11)
Mode of delivery (73)
Environmental exposures in childhood No breastfeeding (10) Lower respiratory tract infections (13, 71)
Viral respiratory infections (9)
Microbial deprivation (12) Maternal smoking (16)
Environmental tobacco smoke exposure (6) Indoor air pollution (13)
Air pollution (74)
Environmental exposures in adulthood Occupational exposures (75) Occupational exposures (13)
Cigarette smoking (7) Cigarette smoking (71)
Outdoor air pollution (8) Outdoor air pollution (8)
Indoor air pollution (13)

Definition of abbreviation: COPD 5 chronic obstructive pulmonary disease.

SERPINE2, SFTPB, SMOC2, TGFB1, and TNF (27). How- GWAS encompassing patients with all different subphenotypes
ever, recent meta-analyses on published candidate gene studies may dissect the overlapping genes, just as is aimed for with
on COPD using strict and well-defined criteria to include asthma and COPD.
studies showed that there are only a few genes reaching Table 2 shows the current data available with respect to
statistical significance for their association with COPD, namely: candidate genes associated with accelerated lung function de-
GSTM1, TGFB1, TNF, SOD3, IL1RN, VNTR, TNFA, GSTP1, cline in the general population and COPD defined by lung func-
and EPHX1 (27, 28) (http://caes.webfactional.com/copddb/ tion criteria, emphysema on CT, and airway wall changes on
copd). It is of interest to note that these genes are positioned CT. We have also included information on the association with
in biologically plausible pathways of oxidative stress response asthma of these candidate genes.
and defense against oxidative stress, like GSTM1, TGFB1,
TNF, SOD3, TNFA, GSTP1, and EPHX1. These studies have Asthma and COPD
provided insight into genetic susceptibility to COPD. Common genes identified for both asthma and COPD using
So far the only environmental factor studied substantially in single candidate association studies are ADRB2, GSTM1,
relation to COPD is smoking, and lately the role of gene-by- GSTP1, IL13, TGFB1, and TNF. This so far limited list of
smoking interaction has received attention. More recently, candidate genes underlying both asthma and COPD might be
gene–environmental interaction was expanded to nutritional extended in the near future, because some genes identified in
factors. Higher vitamin C intake has been reported to be asso- COPD have not been studied yet in asthma (e.g., SERPINA2)
ciated with better lung function. It was shown that for every or too few studies have been performed up to now trying to
level of vitamin C intake, lung function was worse if smokers replicate genes associated with asthma in COPD, and the other
had an SNP in the GCL gene, a detoxifying gene associated way around.
with COPD in two cohorts (29). Individuals with the variant in
the GCL gene and the lowest vitamin C intake had the lowest
lung function in the general population.
COPD encompasses small airway disease, emphysema, and TABLE 2. GENES ASSOCIATED WITH DIFFERENT PHENOTYPES
OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND
airway obstruction with chronic bronchitis. It is therefore not
WITH ASTHMA
surprising that different GWAS on COPD merely defined by
the severity of airway obstruction (e.g., FEV1 % predicted , FEV1 COPD: COPD: CT: Airway
70%) usually do not find identical genetic variants. This is Gene Decline Lung Function CT Emphysema Wall Thickening Asthma
probably because genes associated with small airway fibrosis are ADRB2 1 — — 1 1
likely different from genes determining emphysema. Moreover, CHRNA3 NT 1* 1 NT NT
some patients with COPD show evidence for both emphysema EPHX1 1* 1* 1† 1 —
and small airway obstruction. It is now widely acknowledged GSTP1 1 1 1 — 1
that COPD is a heterogeneous disease (30). Some patients with HMOX1 1* 1 1 NT —
SERPINE2 NT 1* 1 1 NT
COPD may have predominantly cough and phlegm, and others TGFB1 — 1* # 1 1
may have dyspnea (on exertion); some patients express pre- TNFa — 1* # NT 1
dominantly emphysema, others express airway disease or any
combination. It can be envisaged that these disease phenotypes Definition of abbreviations: COPD 5 chronic obstructive pulmonary disease;
are different in their genetic origins and constitute unique CT 5 computed tomography; NT 5 not tested.
Data from References 59–61, 70, 71.
diseases. Thus, genetic GWAS only analyzing lung function as
* Replicated genetic finding.
a COPD phenotype will not dissect the full spectrum, and many †
Loose replication because different Reference SNP (rs) numbers were
genes will go undetected that are relevant for emphysema, associated.
#
chronic mucous hypersecretion, or small airway disease. Also, Marginally associated, likely due to small sample sizes.
Pulmonary Perspective
LINKAGE ANALYSIS AND POSITIONAL CLONING
In diseases wherein the underlying biochemical or physiological
disorder is unknown, linkage analysis is one of the methods used
to identify novel genes. Linkage analysis is performed in
families, preferably in families with many members. A set of
polymorphic markers is spread out over the entire genome and
their linkage (i.e., coinheritance) with a trait is tested. For
example, it is tested whether a certain marker allele located on
chromosome 5q that is present in a proband with asthma is also
present in offspring with asthma and not in offspring without
asthma.
Asthma
In 1996 the first genome-wide search for asthma susceptibility
genes was presented and showed six potential linkages (31).
Twenty-two different linkage studies for asthma or its related
phenotypes have been performed in populations across the
world (32). Although the results are difficult to compare due to
the use of different phenotypes, markers, and P values, they
show consistent results in some regions (i.e., chromosome 5q,
6p, 11q, 12q, 13q, and 21q) (33). By this method several genes
have been identified, for example ADAM33, DPP10, GPRA,
HLA-G, PHF11, PTGDR, PLAUR, and PCDH1 (31, 33–37).
Despite these successes, linkage studies are performed less fre-
quently, because they are time consuming and expensive and
their power is limited. Of importance, meta-analyses of linkage
studies have replicated loci associated with AHR, but not with
asthma, suggesting this is due to heterogeneity of asthma as
a disease (32).
COPD
One genome scan linkage study has been published in COPD,
performed in the Boston Early-Onset COPD Study, showing
that chromosomes 2q, 12p, and 19q are likely locations of
COPD susceptibility genes (38).
Asthma and COPD
Because only one linkage study has been published in COPD,
looking for overlap in chromosomal regions that are linked to
both asthma and COPD is of limited value, and available
studies showed no overlap whatsoever.
GWAS
GWAS are applied to identify novel genetic variants that are
associated with disease. Contrary to candidate gene approaches,
GWAS are hypothesis-free, because the markers that are set
throughout the genome are merely used to identify loci associ-
ated with the disease and are not selected based on their assumed
biological function (39). On the basis of phase I HapMap data,
it was shown that approximately 500,000 of these markers are
required to capture all common SNPs in human populations (40).
Current technologies can evaluate more than 1,000,000 SNPs
simultaneously, interrogating the entire genome in one assay.
Asthma
To date, several GWAS have been performed on asthma. The
first GWAS on asthma identified a region on 17q12-12 including
the genes ORMDL3 and GSDMB (41). Several genes were
identified in this linkage block, and still it has not been fully
elucidated which SNP in this region is the culprit of the
association with asthma. ORMDL3 was suggested to be impor-
tant because gene expression studies in Epstein-Barr Virus-
transformed lymphoblastoid B-cell–derived cell lines showed
transcript levels from ORMDL3 to be associated with disease-
1591
associated markers on the genome (41). Subsequent studies
have replicated the association between rs7216389 and child-
hood asthma in ethnically diverse populations (42). Functional
studies revealed that the asthma-associated haplotype affects
nucleosome distribution and that this regulatory region governs
the transcriptional activity of at least three genes (ZPBP2,
GSDMB, and ORMDL3) in the chromosome 17q12-q21 region
(43). The recently published large GWAS on asthma of the
Gabriel consortium found rs2305480 at the ORMDL3/GSDMB
locus to be specifically associated with childhood-onset asthma
(44). This study reported additional genome-wide significant
associations with asthma for rs3771166 within the IL18R1 gene,
a gene in linkage disequilibrium with IL1RL1, where significant
association was found with several polymorphisms: rs9273349 in
the HLA-DQ region; rs1342326 flanking IL33; rs744910 within
the SMAD3 gene; and rs2284033 within IL2RB. Other genes or
gene regions previously identified by GWAS are DENND1B
at chromosome 1q, IL1RL1 at 2q12, HLA-Dr/DQ region at
5q, PDE4D at 5q12, RAD50-IL13 region on chromosome
5q, WDR36 at 5q22, TLE4 at 9q21.31, and MYB at 6q23
(44–49).
Furthermore a GWAS in a population from African ancestry
showed DPP10 (2q), PRNP at 20pter-p12 and ADRA1B (5q) to
be significantly associated with asthma, without replication in
European populations, although DPP10 had been found with
positional cloning in previous studies (50).
COPD
The two reported GWAS on COPD identified variants in the
nicotinic acetylcholine receptors (nAChR) subunit genes such
as CHRNA3/5 and CHRNB3/4 (51, 52). These SNPs have been
associated cross-sectionally with nicotine dependency and
smoking status. Other studies have found a cross-sectional
association of the same variants with the level of lung function
and COPD (defined by airway obstruction) and lung cancer
(51–53). The gene is associated with the presence and severity
of emphysema as well, an association independent of pack-
years. Therefore, it was suggested that the nAChR cluster is
causally involved in alveolar destruction as a potentially shared
pathogenic mechanism in lung cancer and COPD. However,
because this gene is also associated with nicotine addiction and
smoking is a risk factor for COPD itself, it is not clear from
these cross-sectional studies whether the effect of the nAChR
variants determine COPD development directly or indirectly
via smoking addiction. Longitudinal analyses on the association
of the nAChR variants with changes in smoking habits and
course of lung function will be needed to elucidate whether the
gene is involved in lung function loss per se, as suggested, or
only through the effects of nicotine addiction.
Asthma and COPD
So far, no common genes have been identified for both asthma
and COPD using GWAS. This might be due to a number of
reasons, the first one being that the number of GWAS so far
is relatively limited, specifically in COPD. A second, more
theoretical explanation for the lack of overlap might be the
nature of most GWAS performed so far, which focus on one
disease outcome (e.g., either on asthma or COPD) in popula-
tions that are specifically selected to study these outcomes.
Comparing the top hits of these distinct GWAS in different
populations may not constitute the most appropriate way to
study shared genes in a GWA approach. A more fruitful
method might be searching for shared genetics of asthma and
COPD by performing a GWAS in one underlying population,
which includes both individuals with asthma and those with
COPD.
1592 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
THE GENETICS OF LUNG FUNCTION: OVERLAP WITH
ASTHMA OR COPD?
The trajectory of lung function growth appears to be established
early in life. Genes involved in lung development together with
in utero exposures may have important implications for lung
function later in life and may influence the development of
asthma and COPD. Genes differentially expressed during in
utero airway development, such as Wnt signaling genes, have
been shown to be associated with impaired lung function in
children with asthma (54). In addition, decreased Wnt signaling
/b-catenin activity was found in COPD in humans and during
COPD/emphysema development in mice (55).
Two large GWAS in the general population, studying in-
dividuals with predominantly normal lung function, suggest
several novel genes related to FEV1 and FEV1/FVC ratio (56,
57). The number one locus identified in these two papers was
near HHIP. It is of interest that HHIP was previously identified
in two GWA papers as a COPD susceptibility gene (51, 52). A
number of other novel loci have been identified at different
chromosomal locations, such as 4q24 (GSTCD), 2q35 (TNS1),
5q33 (HTR4), 6p21 (Ager), and 15q23 (THSD4) (56, 57).
However, the Gabriel consortium found no evidence for these
loci to influence susceptibility to asthma (44). A next step will
be to assess whether genes that are associated with COPD are
additionally associated with lung function at birth and/or growth
during childhood and subsequent asthma development. This
may then add further to the notion that common genetic and
environmental factors contribute to asthma and COPD.
ASTHMA AND COPD: COMMON ORIGINS?
So far GWA studies in asthma and COPD have not identified
overlapping genes, suggesting that these diseases have—at least
in part—a unique genetic setup. Yet, there are examples from
the candidate-gene approach that may illustrate a genetic over-
lap in asthma and COPD (see Table E1 and Figure E1 in the
online supplement for an overview). These overlapping genes
include ADAM33, GSTM1, GSTP1, IL13, TGFb, and TNF.
Examples like ADAM33 and members of the GST family are of
interest because they have been implicated in both lung function
growth in childhood and lung function decline in adulthood.
During lung development, ADAM33 is expressed in the
mesenchymal progenitor cells that surround the primitive
tubular airway structures (58). ADAM33 polymorphisms were
associated with lung function in 3- to 5-year-old children (59)
and interacted with in utero smoking on the development of low
lung function and AHR (60). In adulthood, ADAM33 SNPs
were associated with accelerated FEV1 decline in asthma (61)
and the general population (62), which implied that the gene is
a risk factor for the development of COPD in still-healthy
subjects. The role of ADAM33 in COPD became even more
apparent by results showing that a number of SNPs are also
associated with the severity of AHR and airway inflammation in
patients with COPD (63). Although the function of ADAM33 is
still largely unknown, a recent study has indicated a role of
a soluble ADAM33 variant in angiogenesis (64).
The Glutathione S transferase (GST) genes are involved in
detoxification pathways. This gene family consists of four
members (designated A, M, P, and T), and each family member
has several members. Whole gene deletions of GSTM1 and
GSTT1 may result in impaired detoxification of toxic sub-
stances, such as those involved in air pollution and cigarette
smoke.
A study on 2,108 8-year-old children showed that genetic
variation across the GST mu locus is associated with 8-year lung
VOL 183 2011
function growth. Importantly, children exposed to in utero
smoking carrying GSTM2 risk alleles had lower lung function
growth (65). In a subset of this cohort, GSTM1 and GSTP1
genotypes were associated with lung function growth in children
(66). The GST genes are considered to play a role in the de-
velopment of COPD as well, through their association with
accelerated lung function decline in the general adult popula-
tion (67).
CONCLUSIONS
Multiple genes have been found for asthma and COPD. In
addition to genes unique to these diseases, some shared genetic
risk factors exist. Moreover, there are common host risk factors
and environmental risk factors for asthma and COPD. Based on
the data available, we put forward that genes that affect lung
development in utero and lung growth in early childhood in
interaction with environmental detrimental stimuli, such as
smoking and air pollution, are contributing to asthma in child-
hood and the ultimate development of COPD (see Figure 1).
Additional genes and environmental factors then drive specific
immunological mechanisms that underlie asthma (like the Th2/
Th1 balance) and mechanisms that may determine asthma
subphenotypes and others may contribute to the ultimate
development of specific subtypes of COPD. In this respect it
seems important to dissociate airway disease with mucous
hypersecretion, small airway disease, and emphysema in
COPD. The genetic predisposition to the derailment of certain
pathways may further help to define subgroups of asthma and
COPD. The next steps in genomics era will help to further
unravel the common and disease-specific backgrounds of
asthma and COPD (i.e., gene–gene and gene–environment
interaction) on a genome-wide scale and gene regulation, such
as epigenetics and modulations of gene expression and trans-
lation. In the end this may lead to stratification of patients by
their genetic makeup and open new therapeutic prospects.
Author Disclosure: D.S.P. received consultancy fees from AstraZeneca, Nycomed,
GlaxoSmithKline, and Boehringer and serves on the advisory board for Teva.
D.S.P. received lecture fees from Nycomed and GlaxoSmithKline. D.S.P. received
grants from GlaxoSmithKline, Netherlands Asthma Foundation, and European
Union. M.K. does not have a financial relationship with a commercial entity that
has an interest in the subject of this manuscript. H.M.B. does not have a financial
relationship with a commercial entity that has an interest in the subject of this
manuscript. G.H.K. received lecture fees and a sponsored grant from Glaxo-
SmithKline. G.H.K. also received sponsored grants from Netherlands Asthma
Foundation, European Union, and University Medical Center Groningen, the
Netherlands.
References
1. Postma D, Koppelman G. Genetics of asthma: where are we and where
do we go? Proc Am Thorac Soc 2009;6:283–287.
2. Koppelman GH, te Meerman GJ, Postma DS. Genetic testing for
asthma. Eur Respir J 2008;32:775–782.
3. Postma DS, Boezen HM. Rationale for the Dutch hypothesis. Allergy
and airway hyperresponsiveness as genetic factors and their interac-
tion with environment in the development of asthma and COPD.
Chest 2004;126:96S2104S.
4. Pearce N, Pekkanen J, Beasley R. How much asthma is really attribut-
able to atopy? Thorax 1999;54:268–272.
5. Anto JM, Sunyer J, Basagana X, Garcia-Esteban R, Cerveri I, de Marco
R, Heinrich J, Janson C, Jarvis D, Kogevinas M, et al. Risk factors of
new-onset asthma in adults: a population-based international cohort
study. Allergy 2010;65:1021–1030.
6. Strachan DP, Cook DG. Health effects of passive smoking. 6. Parental
smoking and childhood asthma: longitudinal and case-control studies.
Thorax 1998;53:204–212.
7. McLeish AC, Zvolensky MJ. Asthma and cigarette smoking: a review
of the empirical literature. J Asthma 2010;47:345–361.
8. Brunekreef B, Forsberg B. Epidemiological evidence of effects of coarse
airborne particles on health. Eur Respir J 2005;26:309–318.
Pulmonary Perspective
9. Busse WW, Lemanske RF Jr, Gern JE. Role of viral respiratory
infections in asthma and asthma exacerbations. Lancet 2010;376:
826–834.
10. Scholtens S, Gehring U, Brunekreef B, Smit HA, de Jongste JC,
Kerkhof M, Gerritsen J, Wijga AH. Breastfeeding, weight gain in
infancy, and overweight at seven years of age: the prevention and
incidence of asthma and mite allergy birth cohort study. Am J
Epidemiol 2007;165:919–926.
11. Willers SM, Wijga AH, Brunekreef B, Kerkhof M, Gerritsen J, Hoekstra
MO, de Jongste JC, Smit HA. Maternal food consumption during
pregnancy and the longitudinal development of childhood asthma.
Am J Respir Crit Care Med 2008;178:124–131.
12. Douwes J, Brooks C, Pearce N. Protective effects of farming on allergies
and asthma: have we learnt anything since 1873? Expert Rev Clin
Immunol 2009;5:213–219.
13. Salvi SS, Barnes PJ. Chronic obstructive pulmonary disease in non-
smokers. Lancet 2009;374:733–743.
14. Andersen ZJ, Hvidberg M, Jensen SS, Ketzel M, Loft S, Sorensen M,
Tjonneland A, Overvad K, Raaschou-Nielsen O. Chronic obstructive
pulmonary disease and long-term exposure to traffic-related air
pollution: a cohort study. Am J Respir Crit Care Med 2011;183:455–
461.
15. Boy E, Bruce N, Delgado H. Birth weight and exposure to kitchen wood
smoke during pregnancy in rural Guatemala. Environ Health Perspect
2002;110:109–114.
16. Svanes C, Sunyer J, Plana E, Dharmage S, Heinrich J, Jarvis D,
DeMarco R, Norback D, Raherison C, Villani S, et al. Early life
origins of chronic obstructive pulmonary disease. Thorax 2010;65:
14–20.
17. Postma DS, de Vries K, Koeter GH, Sluiter HJ. Independent influence
of reversibility of air-flow obstruction and nonspecific hyperreactivity
on the long-term course of lung function in chronic air-flow obstruc-
tion. Am Rev Respir Dis 1986;134:276–280.
18. Martinez FD. CD14, endotoxin, and asthma risk: actions and interac-
tions. Proc Am Thorac Soc 2007;4:221–225.
19. Undarmaa S, Mashimo Y, Hattori S, Shimojo N, Fujita K, Miyatake A,
Doi S, Kohno Y, Okamoto Y, Hirota T, et al. Replication of genetic
association studies in asthma and related phenotypes. J Hum Genet
2010;55:342–349.
20. Reijmerink NE, Bottema RW, Kerkhof M, Gerritsen J, Stelma FF, Thijs
C, van Schayck CP, Smit HA, Brunekreef B, Koppelman GH, et al.
TLR-related pathway analysis: novel gene-gene interactions in the
development of asthma and atopy. Allergy 2010;65:199–207.
21. Molfino NA. Genetic predisposition to accelerated decline of lung
function in COPD. Int J Chron Obstruct Pulmon Dis 2007;2:117–119.
22. He J, Shumansky K, Connett JE, Anthonisen NR, Paré PD, Sandford
AJ. Association of genetic variations in the CSF2 and CSF3 genes
with lung function in smoking-induced COPD. Eur Respir J 2008;32:
25–34.
23. Joos L, McIntyre L, Ruan J, Connett JE, Anthonisen NR, Weir TD,
Pare PD, Sandford AJ. Association of IL-1beta and IL-1 receptor
antagonist haplotypes with rate of decline in lung function in smokers.
Thorax 2001;56:863–866.
24. He J, Connett JE, Anthonisen NR, Sandford AJ. Polymorphisms in the
IL13, IL13RA1, and IL4RA genes and rate of decline in lung function
in smokers. Am J Respir Cell Mol Biol 2003;28:379–385.
25. He JQ, Foreman MG, Shumansky K, Zhang X, Akhabir L, Sin DD, Man
SF, DeMeo DL, Litonjua AA, Silverman EK, et al. Associations of
IL6 polymorphisms with lung function decline and COPD. Thorax
2009;64:698–704.
26. van Diemen C, Postma D, Vonk J, Bruinenberg M, Schouten J, Boezen
HM. A disintegrin and metalloprotease 33 polymorphisms and lung
function decline in the general population. Am J Respir Crit Care Med
2005;172:329–333.
27. Castaldi PJ, Cho MH, Cohn M, Langerman F, Moran S, Tarragona
N, Moukhachen H, Venugopal R, Hasimja D, Kao E, et al. The
COPD genetic association compendium: a comprehensive online
database of COPD genetic associations. Hum Mol Genet 2010;19:
526–534.
28. Smolonska J, Wijmenga C, Postma DS, Boezen HM. Meta-analyses on
suspected COPD genes: a summary of 20 years’ research. Am J Respir
Crit Care Med 2009;180:618–631.
29. Siedlinski M, Postma D, van Diemen C, Blokstra A, Smit H, Boezen
HM. Lung function loss, smoking, vitamin C intake, and polymor-
phisms of the glutamate-cysteine ligase genes. Am J Respir Crit Care
Med 2008;178:13–19.
1593
30. Rennard SI, Vestbo J. The many ‘‘small COPDs’’: COPD should be an
orphan disease. Chest 2008;134:623–627.
31. Daniels SE, Bhattacharrya S, James A, Leaves NI, Young A, Hill MR,
Faux JA, Ryan GF, le Souef PN, Lathrop GM, et al. A genome-wide
search for quantitative trait loci underlying asthma. Nature 1996;383:
247–250.
32. Bouzigon E, Forabosco P, Koppelman GH, Cookson WO, Dizier MH,
Duffy DL, Evans DM, Ferreira MA, Kere J, Laitinen T, et al. Meta-
analysis of 20 genome-wide linkage studies evidenced new regions
linked to asthma and atopy. Eur J Hum Genet 2010;18:700–706.
33. Bouzigon E, Corda E, Aschard H, Dizier MH, Boland A, Bousquet J,
Chateigner N, Gormand F, Just J, Le Moual N, et al. Effect of 17q21
variants and smoking exposure in early-onset asthma. N Engl J Med
2008;359:1985–1994.
34. Van EP, Little RD, Dupuis J, Del Mastro RG, Falls K, Simon J, Torrey
D, Pandit S, McKenny J, Braunschweiger K, et al. Association of the
ADAM33 gene with asthma and bronchial hyperresponsiveness.
Nature 2002;418:426–430.
35. Zhang Y, Leaves NI, Anderson GG, Ponting CP, Broxholme J, Holt R,
Edser P, Bhattacharyya S, Dunham A, Adcock IM, et al. Positional
cloning of a quantitative trait locus on chromosome 13q14 that
influences immunoglobulin E levels and asthma. Nat Genet 2003;34:
181–186.
36. Barton SJ, Koppelman GH, Vonk JM, Browning CA, Nolte IM, Stewart
CE, Bainbridge S, Mutch S, Rose-Zerilli MJ, Postma DS. PLAUR
polymorphisms are associated with asthma, PLAUR levels and lung
function decline. J Allergy Clin Immunol 2009;123:1406–1415.
37. Koppelman G, Meyers D, Howard T, Zheng SL, Hawkins G, Ampleford
E, Xu J, Koning H, Bruinenberg M, Nolte I, et al. Identification of
PCDH1 as a novel susceptibility gene for bronchial hyperresponsive-
ness. Am J Respir Crit Care Med 2009;180:929–935.
38. Silverman EK, Mosley JD, Palmer LJ, Barth M, Senter JM, Brown A,
Drazen JM, Kwiatkowski DJ, Chapman HA, Campbell EJ, et al.
Genome-wide linkage analysis of severe, early-onset chronic obstruc-
tive pulmonary disease: airflow obstruction and chronic bronchitis
phenotypes. Hum Mol Genet 2002;11:623–632.
39. Boezen HM. Genome-wide association studies: what do they teach us
about asthma and chronic obstructive pulmonary disease? Proc Am
Thorac Soc 2009;6:701–703.
40. The International HapMap Consortium. A haplotype map of the human
genome. Nature 2005;437:1299–1320.
41. Moffatt M, Kabesch M, Liang L, Dixon A, Strachan D, Heath S, Depner
M, von Berg A, Bufe A, Rietschel E, et al. Genetic variants regulating
ORMDL3 expression contribute to the risk of childhood asthma.
Nature 2007;448:470–473.
42. Halapi E, Gudbjartsson DF, Jonsdottir GM, Bjornsdottir US, Thorleifsson
G, Helgadottir H, Williams C, Koppelman GH, Heinzmann A, Boezen
HM, et al. A sequence variant on 17q21 is associated with age at onset
and severity of asthma. Eur J Hum Genet 2010;18:902–908.
43. Verlaan DJ, Berlivet S, Hunninghake GM, Madore AM, Larivière M,
Moussette S, Grundberg E, Kwan T, Ouimet M, Ge B, et al. Allele-
specific chromatin remodeling in the ZPBP2/GSDMB/ORMDL3
locus associated with the risk of asthma and autoimmune disease.
Am J Hum Genet 2009;85:377–393.
44. Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S,
von Mutius E, Farrall M, Lathrop M, Cookson WO. GABRIEL
Consortium. A large-scale, consortium-based genomewide associa-
tion study of asthma. N Engl J Med 2010;363:1211–1221.
45. Sleiman P, Flory J, Imielinski M, Bradfield J, Annaiah K, Willis-Owen S,
Wang K, Rafaels N, Michel S, Bonnelykke K, et al. Variants of
DENND1B Associated with Asthma in Children. N Engl J Med 2010;
362:36–44.
46. Li X, Howard T, Zheng S, Haselkorn T, Peters S, Meyers D, Bleecker E.
Genome-wide association study of asthma identifies RAD50–IL13
and HLA-DR/DQ regions. J Allergy Clin Immunol 2010;125:328–335.
47. Himes B, Hunninghake G, Baurley J, Rafaels N, Sleiman P, Strachan D,
Wilk J, Willis-Owen S, Klanderman B, Lasky-Su J, et al. Genome-
wide association analysis identifies PDE4D as an asthma-susceptibility
gene. Am J Hum Genet 2009;84:581–593.
48. Gudbjartsson D, Bjornsdottir U, Halapi E, Helgadottir A, Sulem P,
Jonsdottir G, Thorleifsson G, Helgadottir H, Steinthorsdottir V,
Stefansson H, et al. Sequence variants affecting eosinophil numbers
associate with asthma and myocardial infarction. Nat Genet 2009;18:
902–908.
49. Hancock DB, Romieu I, Shi M, Sienra-Monge JJ, Wu H, Chiu GY, Li H,
del Rio-Navarro BE, Willis-Owen SA, Weiss ST, et al. Genome-wide
1594 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
association study implicates chromosome 9q21.31 as a susceptibility
locus for asthma in Mexican children. PLoS Genet 2009;5:e1000623.
50. Mathias R, Grant A, Rafaels N, Hand T, Gao L, Vergara C, Tsai Y,
Yang M, Campbell M, Foster C, et al. A genome-wide association
study on African-ancestry populations for asthma. J Allergy Clin
Immunol 2010;125:336–346.
51. Pillai SG, Ge D, Zhu G, Kong X, Shianna KV, Need AC, Feng S, Hersh
CP, Bakke P, Gulsvik A, et al. A genome-wide association study in
chronic obstructive pulmonary disease (COPD): identification of two
major susceptibility loci. PLoS Genet 2009;5:e1000421.
52. Cho M, Boutaoui N, Klanderman B, Sylvia J, Ziniti J, Hersh C, DeMeo
D, Hunninghake G, Litonjua A, Sparrow D, et al. Variants in
FAM13A are associated with chronic obstructive pulmonary disease.
Nat Genet 2010;42:200–202.
53. Wang JC, Cruchaga C, Saccone NL, Bertelsen S, Liu P, Budde JP, Duan
W, Fox L, Grucza RA, Kern J, et al. COGEND collaborators and
GELCC collaborators. Risk for nicotine dependence and lung cancer
is conferred by mRNA expression levels and amino acid change in
CHRNA5. Hum Mol Genet 2009;18:3125–3135.
54. Sharma S, Tantisira K, Carey V, Murphy AJ, Lasky-Su J, Celedon JC,
Lazarus R, Klanderman B, Rogers A, Soto-Quiros M, et al. A role for
Wnt signaling genes in the pathogenesis of impaired lung function in
asthma. Am J Respir Crit Care Med 2010;181:328–336.
55. Kneidinger N, Yildirim AO, Callegari J, Takenaka S, Stein MM,
Dumitrascu R, Bohla A, Bracke KR, Morty RE, Brusselle GG,
et al. Activation of the WNT/fbetag-catenin pathway attenuates
experimental emphysema. Am J Respir Crit Care Med (In press)
56. Repapi E, Sayers I, Wain L, Burton P, Johnson T, Obeidat M, Zhao J,
Ramasamy A, Zhai G, Vitart V, et al. Genome-wide association study
identifies five loci associated with lung function. Nat Genet 2010;42:
36–44.
57. Hancock D, Eijgelsheim M, Wilk J, Gharib S, Loehr L, Marciante K,
Franceschini N, van Durme Y, Chen T, Barr RG, et al. Meta-analyses
of genome-wide association studies identify multiple loci associated
with pulmonary function. Nat Genet 2010;42:45–52.
58. Haitchi HM, Bassett DJ, Bucchieri F, Gao X, Powell RM, Hanley NA,
Wilson DI, Holgate ST, Davies DE. Induction of a disintegrin and
metalloprotease 33 during embryonic lung development and the
influence of IL-13 or maternal allergy. J Allergy Clin Immunol
2009;124:590–597, 597.e1–11.
59. Simpson A, Maniatis N, Jury F, Cakebread JA, Lowe LA, Holgate ST,
Woodcock A, Ollier WE, Collins A, Custovic A, et al. Polymorphisms
in a disintegrin and metalloprotease 33 (ADAM33) predict impaired
early-life lung function. Am J Respir Crit Care Med 2005;172:55–60.
60. Reijmerink NE, Kerkhof M, Koppelman GH, Gerritsen J, de Jongste
JC, Smit HA, Brunekreef B, Postma DS. Smoke exposure interacts
with ADAM33 polymorphisms in the development of lung function
and hyperresponsiveness. Allergy 2009;64:898–904.
61. Jongepier H, Boezen HM, Dijkstra A, Howard TD, Vonk JM, Koppelman
GH, Zheng SL, Meyers DA, Bleecker ER, Postma DS. Polymorphisms
of the ADAM33 gene are associated with accelerated lung function
decline in asthma. Clin Exp Allergy 2004;34:757–760.
62. van Diemen CC, Postma DS, Aulchenko YS, Snijders PJLM, Oostra
BA, van Duijn CM, Boezen HM. Novel strategy to identify genetic
VOL 183 2011
risk factors for COPD severity: a genetic isolate. Eur Respir J 2010;35:
768–775.
63. Gosman MM, Boezen HM, van Diemen CC, Snoeck-Stroband JB,
Lapperre TS, Hiemstra PS, Ten Hacken NH, Stolk J, Postma DS.
A disintegrin and metalloprotease 33 and chronic obstructive pulmo-
nary disease pathophysiology. Thorax 2007;62:242–247.
64. Puxeddu I, Pang YY, Harvey A, Haitchi HM, Nicholas B, Yoshisue H,
Ribatti D, Clough G, Powell RM, Murphy G, et al.. The soluble form
of a disintegrin and metalloprotease 33 promotes angiogenesis:
implications for airway remodeling in asthma. J Allergy Clin Immunol
2008;121:1400–1406, 1406.e1–4.
65. Breton CV, Vora H, Salam MT, Islam T, Wenten M, Gauderman WJ,
Van den Berg D, Berhane K, Peters JM, Gilliland FD. Variation in
the GST mu locus and tobacco smoke exposure as determinants of
childhood lung function. Am J Respir Crit Care Med 2009;179:601–
607.
66. Gilliland FD, Gauderman WJ, Vora H, Rappaport E, Dubeau L.
Effects of glutathione-S-transferase M1, T1, and P1 on childhood
lung function growth. Am J Respir Crit Care Med 2002;166:710–
716.
67. Imboden M, Downs SH, Senn O, Matyas G, Brandli O, Russi EW,
Schindler C, Ackermann-Liebrich U, Berger W, Probst-Hensch NM;
SAPALDIA Team. Glutathione S-transferase genotypes modify lung
function decline in the general population: SAPALDIA cohort study.
Respir Res 2007;8:2.
68. McCallister JW, Mastronarde JG. Sex differences in asthma. J Asthma
2008;45:853–861.
69. Haland G, Carlsen KC, Sandvik L, Devulapalli CS, Munthe-Kaas MC,
Pettersen M, Carlsen KH. ORAACLE. Reduced lung function at
birth and the risk of asthma at 10 years of age. N Engl J Med 2006;355:
1682–1689.
70. Scholtens S, Wijga A, Seidell J, Brunekreef B, de Jongste J, Gehring U,
Postma D, Kerkhof M, Smit H. Overweight and changes in weight
status during childhood in relation to asthma symptoms at 8 years of
age. J Allergy Clin Immunol 2009;123:1312–1318.
71. de Marco R, Accordini S, Marcon A, Cerveri I, Anto JM, Gislason T,
Heinrich J, Janson C, Jarvis D, Kuenzli N, et al; European Commu-
nity Respiratory Health Survey (ECRHS). Risk factors for chronic
obstructive pulmonary disease in a European cohort of young adults.
Am J Respir Crit Care Med (In press)
72. Stein RT, Holberg CJ, Sherrill D, Wright AL, Morgan WJ, Taussig L,
Martinez FD. Influence of parental smoking on respiratory symptoms
during the first decade of life: the Tucson Children’s Respiratory
Study. Am J Epidemiol 1999;149:1030–1037.
73. Roduit C, Scholtens S, de Jongste JC, Wijga AH, Gerritsen J, Postma
DS, Brunekreef B, Hoekstra MO, Aalberse R, Smit HA. Asthma at 8
years of age in children born by caesarean section. Thorax 2009;64:
107–113.
74. Gehring U, Wijga AH, Brauer M, Fischer P, de Jongste JC, Kerkhof M,
Oldenwening M, Smit HA, Brunekreef B. Traffic-related air pollution
and the development of asthma and allergies during the first 8 years of
life. Am J Respir Crit Care Med 2010;181:596–603.
75. Malo JL, Chan-Yeung M. Agents causing occupational asthma. J Allergy
Clin Immunol 2009;123:545–550.