Asthma and Chronic Obstructive Pulmonary Disease - ATS Journals

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 stipulated that asthma and COPD have common genetic and environmental risk factors (allergens, infections, smoking), which ultimately lead to clinical disease depending on the timing and type of environmental 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 contributing 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 derailment 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-toone relationship between a gene and a disease. Notwithstanding this complexity, genetic studies have discovered genes and pathways contributing to disease development, 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: [email protected] 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 developments 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 associated 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 investigating 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 understand whether asthma and COPD have similar, different, or both similar and different underlying genetic and environmental 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

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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 cigarettes (13). This signifies that indoor and outdoor air pollution (14) and other environmental triggers, such as maternal smoking (15, 16), may be important as well. As for asthma, airway hyperresponsiveness (AHR) and low lung function are important 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 biological 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

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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 investigated 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 dimensionality 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 obstructive pulmonary disease.

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

Perinatal factors

Environmental exposures in childhood

Environmental exposures in adulthood

COPD

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

Family history of COPD Family history asthma/atopy (71) Genetic constitution Airway hyperresponsiveness (17, 71) Low lung function (17)

Maternal smoking (72)

Lower respiratory tract infections (13, 71) Maternal smoking (16) Indoor air pollution (13) Occupational exposures (13) Cigarette smoking (71) Outdoor air pollution (8) Indoor air pollution (13)

Definition of abbreviation: COPD 5 chronic obstructive pulmonary disease.

SERPINE2, SFTPB, SMOC2, TGFB1, and TNF (27). However, recent meta-analyses on published candidate gene studies on COPD using strict and well-defined criteria to include studies showed that there are only a few genes reaching statistical significance for their association with COPD, namely: GSTM1, TGFB1, TNF, SOD3, IL1RN, VNTR, TNFA, GSTP1, and EPHX1 (27, 28) (http://caes.webfactional.com/copddb/ copd). It is of interest to note that these genes are positioned in biologically plausible pathways of oxidative stress response and defense against oxidative stress, like GSTM1, TGFB1, TNF, SOD3, TNFA, GSTP1, and EPHX1. These studies have provided insight into genetic susceptibility to COPD. So far the only environmental factor studied substantially in relation to COPD is smoking, and lately the role of gene-bysmoking interaction has received attention. More recently, gene–environmental interaction was expanded to nutritional factors. Higher vitamin C intake has been reported to be associated with better lung function. It was shown that for every level of vitamin C intake, lung function was worse if smokers had an SNP in the GCL gene, a detoxifying gene associated 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 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 , 70%) usually do not find identical genetic variants. This is probably because genes associated with small airway fibrosis are likely different from genes determining emphysema. Moreover, some patients with COPD show evidence for both emphysema and small airway obstruction. It is now widely acknowledged that COPD is a heterogeneous disease (30). Some patients with COPD may have predominantly cough and phlegm, and others may have dyspnea (on exertion); some patients express predominantly emphysema, others express airway disease or any combination. It can be envisaged that these disease phenotypes are different in their genetic origins and constitute unique diseases. Thus, genetic GWAS only analyzing lung function as a COPD phenotype will not dissect the full spectrum, and many genes will go undetected that are relevant for emphysema, chronic mucous hypersecretion, or small airway disease. Also,

GWAS encompassing patients with all different subphenotypes may dissect the overlapping genes, just as is aimed for with asthma and COPD. Table 2 shows the current data available with respect to candidate genes associated with accelerated lung function decline in the general population and COPD defined by lung function criteria, emphysema on CT, and airway wall changes on CT. We have also included information on the association with asthma of these candidate genes. Asthma and COPD

Common genes identified for both asthma and COPD using single candidate association studies are ADRB2, GSTM1, GSTP1, IL13, TGFB1, and TNF. This so far limited list of candidate genes underlying both asthma and COPD might be extended in the near future, because some genes identified in COPD have not been studied yet in asthma (e.g., SERPINA2) or too few studies have been performed up to now trying to replicate genes associated with asthma in COPD, and the other way around.

TABLE 2. GENES ASSOCIATED WITH DIFFERENT PHENOTYPES OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND WITH ASTHMA Gene ADRB2 CHRNA3 EPHX1 GSTP1 HMOX1 SERPINE2 TGFB1 TNFa

FEV1 COPD: COPD: CT: Airway Decline Lung Function CT Emphysema Wall Thickening Asthma 1 NT 1* 1 1* NT — —

— 1* 1* 1 1 1* 1* 1*

— 1 1† 1 1 1 # #

1 NT 1 — NT 1 1 NT

1 NT — 1 — NT 1 1

Definition of abbreviations: COPD 5 chronic obstructive pulmonary disease; CT 5 computed tomography; NT 5 not tested. Data from References 59–61, 70, 71. * Replicated genetic finding. † Loose replication because different Reference SNP (rs) numbers were associated. # 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 frequently, 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 associated 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 important because gene expression studies in Epstein-Barr Virustransformed lymphoblastoid B-cell–derived cell lines showed transcript levels from ORMDL3 to be associated with disease-

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associated markers on the genome (41). Subsequent studies have replicated the association between rs7216389 and childhood 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 packyears. 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 populations 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.

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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 individuals 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 overlap 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 substances, 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

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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 development of COPD as well, through their association with accelerated lung function decline in the general adult population (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 childhood 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 translation. 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 GlaxoSmithKline. G.H.K. also received sponsored grants from Netherlands Asthma Foundation, European Union, and University Medical Center Groningen, the Netherlands.

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