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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 The field of genetics has evolved over the past decennia due
similarities and substantial differences. The Dutch hypothesis stipu- to completion of the HapMap project, applications to perform
lated that asthma and COPD have common genetic and environ- genomic studies with high-throughput techniques, and develop-
mental risk factors (allergens, infections, smoking), which ultimately ments of statistical analyses to test for association of a million
lead to clinical disease depending on the timing and type of en- single nucleotide polymorphisms (SNPs) at the same time and
vironmental exposures (Postma and Boezen, Chest 2004;126: to assess gene–gene and gene–environment interaction. The
96S2104S). Thus, a particular group of shared genetic factors may current challenge is to unravel the relation between variants
lead to asthma when combined with specific environmental factors in newly identified genes and their function to better design
that are met at a certain stage in life, whereas combination with
treatments of respiratory diseases.
other environmental factors, or similar environmental factors at
Genetic studies initially addressed single genes that are
a different stage in life, will lead toward COPD. Multiple genes have
candidates for disease development and/or performed linkage
been found for asthma and COPD. In addition to genes unique to
these diseases, some shared genetic risk factors exist. Moreover, analyses followed by positional cloning in families of an affected
there are both common host risk factors and environmental risk proband. Recently, genome-wide association studies (GWAS)
factors for asthma and COPD. Here we put forward, based on the have identified novel genes, mostly without known function as-
data available, that genes that affect lung development in utero and sociated with diseases. However, these findings do not easily
lung growth in early childhood in interaction with environmental lead to a genetic test for a specific disease, because the positive
detrimental stimuli, such as smoking and air pollution, are contrib- predictive value of a single-gene test is limited and multiple
uting to asthma in childhood and the ultimate development of genes and environmental factors have to be incorporated (2).
COPD. Additional genes and environmental factors then drive This requires methods to model all these risk factors at the same
specific immunological mechanisms underlying asthma, and others time, and large cohort sizes with all data available for validation
may contribute to the ultimate development of specific subtypes of of the test. This review gives a bird’s-eye view of the past and
COPD (i.e., airway disease with mucous hypersecretion, small airway present of genetics in asthma and COPD in the context of their
disease, and emphysema). The genetic predisposition to the de- common and differential origins.
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 DUTCH HYPOTHESIS
prospects. In 1961, Orie and colleagues postulated the Dutch hypothesis,
Keywords: asthma; COPD; genetics; risk factors
which stipulates that asthma and COPD have genetic and
environmental risk factors such as allergens, infections, and
Genetic factors contribute to the development of lung diseases smoking in common, which then ultimately lead to clinical
such as cystic fibrosis, sarcoidosis, interstitial fibrosis, lung disease depending on the timing and type of environmental
cancer, asthma, and chronic obstructive pulmonary disease exposure (3). This has led to a wide variety of research in-
(COPD). Cystic fibrosis is a monogenic disease, most frequently vestigating similarities and differences between asthma and
caused by a deletion of three nucleotides from the CFTR gene. COPD in cross-sectional studies. However, this type of study
In contrast, asthma and COPD are complex diseases wherein will never give the answer to whether this hypothesis has a valid
multiple genes and their interaction with environmental factors basis. Only when investigating genes, environmental exposures,
contribute to disease development. Thus, there is not a one-to- and the timing of these environmental stimuli will we un-
one relationship between a gene and a disease. derstand whether asthma and COPD have similar, different,
Notwithstanding this complexity, genetic studies have dis- or both similar and different underlying genetic and environ-
covered genes and pathways contributing to disease develop- mental factors. At this time we can make a (small) step forward,
ment, and some of them are targets for therapy (1). because we have increased our knowledge on both genetic and
environmental factors for asthma and COPD development.
(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 AND COPD
Groningen, Hanzeplein 1, PO Box 30001, 9700 RB Groningen, The Netherlands.
In the search for risk factors for asthma and COPD, a distinction
can be made between host factors (genetic predisposition, sex)
This article has an online supplement, which is accessible from this issue’s table of
contents at
and environmental factors (smoking, air pollution). Many
studies have tried to assess risk factors of asthma and found
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 evidence that, for example, atopy (4), hyperresponsiveness (5),
Internet address: (passive) smoking (6, 7), air pollution (8), and respiratory tract
Pulmonary Perspective 1589

infections (9) could be considered as single risk factors. There many of these genes have not been replicated, which is needed
are additional protective factors, such as breastfeeding (10), to reflect whether finding of this gene is a true observation,
maternal diet (11), and farming conditions (12). Smoking is the there is a group that is replicated many times: ADAM33,
predominant risk factor for development of COPD. However, ADRB2, CD14, FCER1B, HLA-DRB1, HLA-DQB1, IL4,
recent studies have shown that there are a considerable number IL13, IL4RA, and TNF (19). Meta-analyses do not always find
of people who develop COPD without having smoked ciga- these genes as being significantly associated with asthma, but
rettes (13). This signifies that indoor and outdoor air pollution when comparing different meta-analyses and large replication
(14) and other environmental triggers, such as maternal smok- studies, ADAM33, IL13, IL4RA, TNF, and TBXA2R appear as
ing (15, 16), may be important as well. As for asthma, airway consistent genes and may represent common major asthma
hyperresponsiveness (AHR) and low lung function are impor- genes (19). Because multiple interactions between genes may
tant determinants of COPD development (17). Table 1 shows occur in disease development, it is important to perform
an overview of common and different environmental risk statistical interaction analyses between genes in biologically
factors of asthma and COPD. Of interest, host factors such as plausible pathways of asthma development. Nevertheless, the
hyperresponsiveness, family history of asthma, and low lung number of studies actually investigating gene–gene interactions
function are common risk factors for asthma and COPD, as are in pathways so far is limited. The Toll-like receptor–related
environmental stimuli such as environmental tobacco smoke pathway is such a pathway (including CD14) and was investi-
and air pollution. It is difficult in this respect to dissect whether gated in more than 3,000 children (20). Several genes in this
maternal smoking during pregnancy, and parental smoking pathway were associated with atopy and/or asthma as a single
during early childhood confer separate risks. Hence, many gene, such as IL1RL1 (also found with GWAS), BPI, NOD1,
studies report on environmental tobacco smoke (ETS) exposure NOD2, and MAP3K7IP1 (20). Of interest, multifactor dimen-
in general (Figure 1). 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
Candidate genes are generally selected for their known bi- asthma (20). An important finding was that an SNP in a gene
ological function, differential expression in tissues or cells located in this pathway may not be associated with asthma on its
involved in the pathogenesis of a disease, and/or based on own, but the SNP does so in interaction with other SNPs in
findings in relevant animal models. Association studies aim to genes in this pathway.
show that affected individuals in a population are more likely to
have a particular variant of a gene than healthy controls in the COPD
same population. Association between the gene variant(s) and Candidate genes involved in established pathogenetic pathways
disease may imply causality. However, association can also have been investigated for their association with COPD (i.e.,
occur if the allele is in linkage disequilibrium with another oxidative stress, protease–antiprotease imbalance, chemokines,
polymorphism in the same or a nearby gene that is the real cytokines, and extracellular matrix breakdown and repair).
causative polymorphism, or in the case of population admixture. COPD results from accelerated lung function decline; thus it
Even discrepant findings may not exclude a gene to be is plausible to investigate genes in association with accelerated
important in disease development. In atopy, for instance, one lung function decline in general populations. Some candidate
allele in the CD14 gene has been reported as a risk for disease genes have been identified in this way, such as ADRB2,
in one study and as protective in another study. Although this CHRNA5, CSF3, EPHX1, IL1RN/IL1B, IL4R, IL6, IL8, IL10,
initially was interpreted as nonreplication of a gene, it later INFg, ADAM33, MMP1, GSTP1, GSTT1, GSTM1, HMOX1,
became apparent that other environmental levels of exposure and SERPINA1 (21–26).
may underlie the discrepancy (18). An additional list of genes has been associated with COPD
in case-control studies, wherein a COPD diagnosis was based on
Asthma FEV1/FVC less than 70% and FEV1 less than 80% predicted, or
There are at least 1,000 papers published examining SNPs in less than 75% predicted. These genes involve, among others,
genes that are candidates for asthma and allergy. Although 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.

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) ( 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
airway obstruction with chronic bronchitis. It is therefore not
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 —
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 1591

LINKAGE ANALYSIS AND POSITIONAL CLONING associated markers on the genome (41). Subsequent studies
have replicated the association between rs7216389 and child-
In diseases wherein the underlying biochemical or physiological hood asthma in ethnically diverse populations (42). Functional
disorder is unknown, linkage analysis is one of the methods used studies revealed that the asthma-associated haplotype affects
to identify novel genes. Linkage analysis is performed in nucleosome distribution and that this regulatory region governs
families, preferably in families with many members. A set of the transcriptional activity of at least three genes (ZPBP2,
polymorphic markers is spread out over the entire genome and GSDMB, and ORMDL3) in the chromosome 17q12-q21 region
their linkage (i.e., coinheritance) with a trait is tested. For (43). The recently published large GWAS on asthma of the
example, it is tested whether a certain marker allele located on Gabriel consortium found rs2305480 at the ORMDL3/GSDMB
chromosome 5q that is present in a proband with asthma is also locus to be specifically associated with childhood-onset asthma
present in offspring with asthma and not in offspring without (44). This study reported additional genome-wide significant
asthma. associations with asthma for rs3771166 within the IL18R1 gene,
Asthma a gene in linkage disequilibrium with IL1RL1, where significant
association was found with several polymorphisms: rs9273349 in
In 1996 the first genome-wide search for asthma susceptibility the HLA-DQ region; rs1342326 flanking IL33; rs744910 within
genes was presented and showed six potential linkages (31). the SMAD3 gene; and rs2284033 within IL2RB. Other genes or
Twenty-two different linkage studies for asthma or its related gene regions previously identified by GWAS are DENND1B
phenotypes have been performed in populations across the at chromosome 1q, IL1RL1 at 2q12, HLA-Dr/DQ region at
world (32). Although the results are difficult to compare due to 5q, PDE4D at 5q12, RAD50-IL13 region on chromosome
the use of different phenotypes, markers, and P values, they 5q, WDR36 at 5q22, TLE4 at 9q21.31, and MYB at 6q23
show consistent results in some regions (i.e., chromosome 5q, (44–49).
6p, 11q, 12q, 13q, and 21q) (33). By this method several genes Furthermore a GWAS in a population from African ancestry
have been identified, for example ADAM33, DPP10, GPRA, showed DPP10 (2q), PRNP at 20pter-p12 and ADRA1B (5q) to
HLA-G, PHF11, PTGDR, PLAUR, and PCDH1 (31, 33–37). be significantly associated with asthma, without replication in
Despite these successes, linkage studies are performed less fre- European populations, although DPP10 had been found with
quently, because they are time consuming and expensive and positional cloning in previous studies (50).
their power is limited. Of importance, meta-analyses of linkage
studies have replicated loci associated with AHR, but not with COPD
asthma, suggesting this is due to heterogeneity of asthma as The two reported GWAS on COPD identified variants in the
a disease (32). 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
One genome scan linkage study has been published in COPD, smoking status. Other studies have found a cross-sectional
performed in the Boston Early-Onset COPD Study, showing association of the same variants with the level of lung function
that chromosomes 2q, 12p, and 19q are likely locations of and COPD (defined by airway obstruction) and lung cancer
COPD susceptibility genes (38). (51–53). The gene is associated with the presence and severity
of emphysema as well, an association independent of pack-
Asthma and COPD
years. Therefore, it was suggested that the nAChR cluster is
Because only one linkage study has been published in COPD, causally involved in alveolar destruction as a potentially shared
looking for overlap in chromosomal regions that are linked to pathogenic mechanism in lung cancer and COPD. However,
both asthma and COPD is of limited value, and available because this gene is also associated with nicotine addiction and
studies showed no overlap whatsoever. smoking is a risk factor for COPD itself, it is not clear from
these cross-sectional studies whether the effect of the nAChR
GWAS variants determine COPD development directly or indirectly
via smoking addiction. Longitudinal analyses on the association
GWAS are applied to identify novel genetic variants that are of the nAChR variants with changes in smoking habits and
associated with disease. Contrary to candidate gene approaches, course of lung function will be needed to elucidate whether the
GWAS are hypothesis-free, because the markers that are set gene is involved in lung function loss per se, as suggested, or
throughout the genome are merely used to identify loci associ- only through the effects of nicotine addiction.
ated with the disease and are not selected based on their assumed
biological function (39). On the basis of phase I HapMap data, Asthma and COPD
it was shown that approximately 500,000 of these markers are So far, no common genes have been identified for both asthma
required to capture all common SNPs in human populations (40). and COPD using GWAS. This might be due to a number of
Current technologies can evaluate more than 1,000,000 SNPs reasons, the first one being that the number of GWAS so far
simultaneously, interrogating the entire genome in one assay. is relatively limited, specifically in COPD. A second, more
theoretical explanation for the lack of overlap might be the
Asthma nature of most GWAS performed so far, which focus on one
To date, several GWAS have been performed on asthma. The disease outcome (e.g., either on asthma or COPD) in popula-
first GWAS on asthma identified a region on 17q12-12 including tions that are specifically selected to study these outcomes.
the genes ORMDL3 and GSDMB (41). Several genes were Comparing the top hits of these distinct GWAS in different
identified in this linkage block, and still it has not been fully populations may not constitute the most appropriate way to
elucidated which SNP in this region is the culprit of the study shared genes in a GWA approach. A more fruitful
association with asthma. ORMDL3 was suggested to be impor- method might be searching for shared genetics of asthma and
tant because gene expression studies in Epstein-Barr Virus- COPD by performing a GWAS in one underlying population,
transformed lymphoblastoid B-cell–derived cell lines showed which includes both individuals with asthma and those with
transcript levels from ORMDL3 to be associated with disease- COPD.

THE GENETICS OF LUNG FUNCTION: OVERLAP WITH function growth. Importantly, children exposed to in utero
ASTHMA OR COPD? smoking carrying GSTM2 risk alleles had lower lung function
growth (65). In a subset of this cohort, GSTM1 and GSTP1
The trajectory of lung function growth appears to be established genotypes were associated with lung function growth in children
early in life. Genes involved in lung development together with (66). The GST genes are considered to play a role in the de-
in utero exposures may have important implications for lung velopment of COPD as well, through their association with
function later in life and may influence the development of accelerated lung function decline in the general adult popula-
asthma and COPD. Genes differentially expressed during in tion (67).
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 CONCLUSIONS
/b-catenin activity was found in COPD in humans and during Multiple genes have been found for asthma and COPD. In
COPD/emphysema development in mice (55). addition to genes unique to these diseases, some shared genetic
Two large GWAS in the general population, studying in- risk factors exist. Moreover, there are common host risk factors
dividuals with predominantly normal lung function, suggest and environmental risk factors for asthma and COPD. Based on
several novel genes related to FEV1 and FEV1/FVC ratio (56, the data available, we put forward that genes that affect lung
57). The number one locus identified in these two papers was development in utero and lung growth in early childhood in
near HHIP. It is of interest that HHIP was previously identified interaction with environmental detrimental stimuli, such as
in two GWA papers as a COPD susceptibility gene (51, 52). A smoking and air pollution, are contributing to asthma in child-
number of other novel loci have been identified at different hood and the ultimate development of COPD (see Figure 1).
chromosomal locations, such as 4q24 (GSTCD), 2q35 (TNS1), Additional genes and environmental factors then drive specific
5q33 (HTR4), 6p21 (Ager), and 15q23 (THSD4) (56, 57). immunological mechanisms that underlie asthma (like the Th2/
However, the Gabriel consortium found no evidence for these Th1 balance) and mechanisms that may determine asthma
loci to influence susceptibility to asthma (44). A next step will subphenotypes and others may contribute to the ultimate
be to assess whether genes that are associated with COPD are development of specific subtypes of COPD. In this respect it
additionally associated with lung function at birth and/or growth seems important to dissociate airway disease with mucous
during childhood and subsequent asthma development. This hypersecretion, small airway disease, and emphysema in
may then add further to the notion that common genetic and COPD. The genetic predisposition to the derailment of certain
environmental factors contribute to asthma and COPD. 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: COMMON ORIGINS? asthma and COPD (i.e., gene–gene and gene–environment
So far GWA studies in asthma and COPD have not identified interaction) on a genome-wide scale and gene regulation, such
overlapping genes, suggesting that these diseases have—at least as epigenetics and modulations of gene expression and trans-
in part—a unique genetic setup. Yet, there are examples from lation. In the end this may lead to stratification of patients by
the candidate-gene approach that may illustrate a genetic over- their genetic makeup and open new therapeutic prospects.
lap in asthma and COPD (see Table E1 and Figure E1 in the Author Disclosure: D.S.P. received consultancy fees from AstraZeneca, Nycomed,
online supplement for an overview). These overlapping genes GlaxoSmithKline, and Boehringer and serves on the advisory board for Teva.
include ADAM33, GSTM1, GSTP1, IL13, TGFb, and TNF. D.S.P. received lecture fees from Nycomed and GlaxoSmithKline. D.S.P. received
grants from GlaxoSmithKline, Netherlands Asthma Foundation, and European
Examples like ADAM33 and members of the GST family are of Union. M.K. does not have a financial relationship with a commercial entity that
interest because they have been implicated in both lung function has an interest in the subject of this manuscript. H.M.B. does not have a financial
growth in childhood and lung function decline in adulthood. relationship with a commercial entity that has an interest in the subject of this
During lung development, ADAM33 is expressed in the manuscript. G.H.K. received lecture fees and a sponsored grant from Glaxo-
SmithKline. G.H.K. also received sponsored grants from Netherlands Asthma
mesenchymal progenitor cells that surround the primitive Foundation, European Union, and University Medical Center Groningen, the
tubular airway structures (58). ADAM33 polymorphisms were Netherlands.
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
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