Abstract: Asthma and allergic diseases are complex conditions caused by a combination of genetic and environmental factors. More than 100 genes have been associated with asthma and related conditions through candidate gene approaches, but issues of insufficient replication have made conclusions difficult to draw. Despite this, several overarching themes in the biology and pathogenesis of asthma have been revealed as a result of this work. In mid-2007, the first genome wide association study (GWAS) targeting asthma was published, and in the intervening years more than a dozen such studies have been reported examining asthma, allergic diseases, and related intermediate phenotypes and quantitative traits. A few previously suspected genetic variants have been confirmed in these studies as asthma susceptibility loci, or as loci contributing to disease severity or response to treatment. Additionally, unexpected and largely uncharacterized genes have been identified as new susceptibility loci for asthma, altering lung function or perturbing immune function. In this review, we summarize these GWAS, as well as the functional themes and characteristics underlying asthma that have been revealed through decades of genetic and genomic research.
Asthma is a chronic inflammatory condition of the lungs, characterized by excessive responsiveness of the lungs to stimuli, in the forms of infections, allergens, and environmental irritants. During an asthma attack, lung airways will produce excess mucus and swell, and muscles around the airways will tighten leading to airway obstruction, tightness in the chest, coughing, and wheezing. Data from the National Institutes of Health suggests that 50% of U.S. asthma cases are attributable to specific allergies. Currently, 22.9 million Americans suffer from asthma, and the prevalence has increased dramatically since 1980. Asthma is the leading chronic illness in U.S. children, with 6.8 million affected in 2006 (American Lung Association, 2008). Twin studies have shown that there is a genetic element to asthma susceptibility, with heritability of the condition estimated at between 0.36 and 0.77 (Duffy et al., 1990; Harris et al., 1997; Koppelman et al., 1999; Nieminen et al., 1991). The first study to link a genetic locus (chromosome 11q13) to asthma was published in 1989 (Deichmann et al., 1999). Since then more than 100 candidate genes described in more than 1,000 publications have been found in connection to asthma or an associated phenotype, like elevated IgE levels, bronchial hyperresponsiveness, or eosinophilia.
An Overview of the Analysis of the Genetic Contributions in Asthma
Researchers have been successful in identifying the genetic underpinning of many single-gene disorders. It has been comparatively difficult to identify the genetic basis of complex genetic disorders, such as asthma, allergies, and autoimmune disease, with multifactorial inheritance and significant environmental contributors. Three study designs are routinely employed to investigate genetic contributions in complex diseases: genome-wide linkage studies, candidate gene association studies, and genome-wide association studies.
Linkage studies: Genome-wide linkage study design focuses on families affected by the disease of interest. With less genetic recombination occurring between closely related individuals, it is possible to screen the entire genome with a panel of relatively few, evenly spaced markers, searching for variants that are either unique to or over-represented in affected individuals. If such a region is found, it is said to be linked with the disease trait, and the genes within this region can become candidates for further analysis, including association study followed by positional cloning of the gene. Unlike the candidate gene association study (see below), this study design allows for the identification of genes and pathways previously not suspected of contributing to the disease in question. However, because large families of affected individuals are needed, these studies are expensive and difficult to conduct. Moreover, while they are effective at identifying genes with low frequency variants with high penetrance and large effects, they often lack the statistical power to identify genes of modest effect that are attributed to common alleles. This is in contrast to genome-wide association studies (discussed below), which are best suited to the identification of common variants with lower penetrance and smaller effects. In this way, linkage studies and association studies are used to address different questions, and are, in fact, complementary.
Approximately 20 genome-wide linkage screens have been reported in different populations investigating chromosomal regions that are linked to asthma and atopy, or related phenotypes like elevated IgE levels, wheezing, and bronchial hyperresponsiveness. A number of chromosomal regions have been repeatedly identified across multiple studies that contain genes of biological relevance to asthma and allergic disease, including the cytokine cluster on chromosome 5q [containing interleukin 3 (IL3), IL5, and granulocyte/macrophage colony-stimulating factor (GMCSF)], FCER1B on 11q, IFNG (interferon γ) and STAT6 on 12q, and IL4R (the IL-4Rα chain, also part of the IL-13R) on 16p. Linkage studies followed by positional cloning approaches have resulted in the identification of a handful of novel asthma susceptibility genes, including CYFIP2 (Noguchi et al., 2005), DPP10 (Allen et al., 2003), HLAG (Nicolae et al., 2005), PHF11 (Zhang et al., 2003), GPRA (Laitinen et al., 2004), and ADAM33 (Van Eerdewegh et al., 2002). GPRA (G protein-coupled receptor for asthma) and ADAM33 (a disintegrin and metalloproteinase domain-containing protein 33) have generated considerable interest, as their expression in bronchial smooth muscle cells suggests roles in the pathobiology of asthma and pulmonary allergic disease (Laitinen et al., 2004).
Candidate gene studies: In a candidate gene association study, a particular gene (or set of genes) is selected for study based on its biological plausibility or suspected role in the phenotype of interest. The incidence of variants in this gene is compared between a group of individuals affected with the phenotype (cases) and a group of controls. The strength of such a design lies in the statistical power and relative ease of recruiting large cohorts, compared to family-based studies. The main limitations of such a design are its inability to identify novel or unsuspected genes and pathways contributing to the pathogenesis of a disorder, and its susceptibility to unknown population structures in cases or controls. Candidate gene association studies are best suited to identifying common genetic variants of modest effect (Risch and Merikangas, 1996).
More than 1,000 papers have been published with candidate gene studies examining asthma and related phenotypes, identifying more than 100 candidate genes. However, surprisingly few of these candidate gene discoveries have been rigorously replicated, and many have been examined and failed replication in subsequent studies. The loci identified in candidate gene studies of asthma and associated phenotypes have been extensively reviewed elsewhere (Ober and Hoffjan, 2006; Vercelli, 2008; Zhang et al., 2008). Among genes identified in candidate studies are receptors for detection of microbial products (TLRs, CD14, CARD15, among others); various cytokines and cytokine signaling proteins involved in T cell survival, proliferation, and differentiation; genes involved in lung function, development, and response to stimuli (ADRB2, CFTR, SPINK5, etc.); genes involved in epithelial barrier function and innate immunity (FLG and DEFB1) (Levy et al., 2005; Palmer et al., 2007); genes believed to be involved in the responses to environmental exposures (GSTM1, GSTP1, and GSTT1) (Halapi and Hakonarson, 2004; Hoffjan et al., 2003; Kabesch, 2005; Vercelli, 2008). Genes that have been extensively replicated include the beta2 adrenergic receptor gene (Liggett, 1995; Martinez et al., 1997; Potter et al., 1993); the cytokines, receptors, signaling proteins, and transcription factors involved in TH1 (T helper 1) and TH2 differentiation of T cells, like IL4, IL4RA, IFNG, IFNGR1, STAT6, GATA3, and TBX21 (Basehore et al., 2004; Haller et al., 2009; Munthe-Kaas et al., 2008; Pykäläinen et al., 2005; Randolph et al., 2004; Suttner et al., 2009; Tantisira et al., 2004; Zhou et al., 2009); and genes involved in the cellular responses that characterize atopic disease, such as IL13 and its receptor and the FCER1B gene (Howard et al., 2002; Kabesch et al., 2006; Potaczek et al., 2009; Vladich et al., 2005; Wu et al., 2010).
Genome wide association studies: Rapid advances in microarray technology that now permit the high-throughput genotyping of hundreds of thousands of single nucleotide polymorphisms (SNPs) has allowed for the development of a third type of study, the genome-wide association study (GWAS). In this design many SNPs are compared across the entire genome between cases and controls. Like the candidate gene association study, this design facilitates the collection of a large number of cases and controls for analysis, increasing statistical power. In contrast, however, it permits a hypothesis-free search for gene variants associated with disease, revealing new targets for researchers. As mentioned above, GWAS are well-suited for discovery of common alleles with relatively small effects.
In 2007, the first GWAS focused on bronchial asthma as an endpoint was reported (Moffatt et al., 2007), identifying multiple markers on chromosome 17q21 reproducibly associated with childhood-onset asthma. The findings were replicated in German and British cohorts. Independent replication of the 17q21 association has been reported in multiple populations of diverse ethnic backgrounds (Bisgaard et al., 2009; Galanter et al., 2008; Leung et al., 2009; Sleiman et al., 2008; Tavendale et al., 2008).
Variable expression of two genes within this region, ORMDL3 and GSDML, was linked to asthma susceptibility (Moffatt et al., 2007). ORMDL3 is a member of a gene family that encodes transmembrane proteins anchored in the endoplasmic reticulum (Cantero-Recasens et al., 2010). GSDML encodes a member of the gasdermin proteins that are expressed in epithelial cells and regulate apoptosis. Functional data will be required to identify the causal gene; however, this finding does represent the first step in unraveling the complex genetics underlying asthma susceptibility in a hypothesis-independent manner.
A case-control GWAS of North American asthmatics of European ancestry from the Childhood Asthma Management Program (CAMP) cohort has also recently been published. Whereas no loci reached genome-wide significance in their discovery cohort, the strongest association was to variants of the PDE4D gene on chromosome 5q12. In seven Caucasian replication cohorts, two out of seven PDE4D SNPs were marginally associated. No significant associations were observed at the PDE4D locus in populations of African ancestry (Himes et al., 2009). PDE4D is a lung-expressed phosphodiesterase that has been implicated in airway contractility; as such it is a plausible asthma candidate gene that warrants further investigation. In a separate study, genome-wide association data from the CAMP cohort was investigated for replication of previously reported candidate gene associations. Approximately 30 genes were investigated with five SNP-based associations replicating in the IRAK‑3, PHF11, IL10, ITGB3, and IL4R genes (Rogers et al., 2009).
Another GWAS on allergic asthma was recently reported, with children 6 years of age, whose mothers had participated in an earlier study of asthma in pregnancy (Perinatal Risk of Asthma in Infants with Asthmatic Mothers - PRAM). An initial genome-wide association screen was performed on small numbers of cases and controls of mixed ethnic descent, and the most significant SNPs were further analyzed in a larger collection of samples. Although no single SNP achieved genome-wide significance, one SNP in an intron of PDE11A was cited as potentially interesting. PDE11A encodes a phosphodiesterase related to PDE4D, suggesting that this family of proteins may play a broader role in asthma pathogenesis (DeWan et al., 2010).
A genome-wide association was also reported on two independent populations of African descent ascertained through the Genomic Research on Asthma in the African Diaspora (GRAAD) consortium, which included African American asthmatics and controls from the Baltimore-Washington, DC area and African Caribbean asthmatics and their family members from Barbados (Mathias et al., 2010). A meta-analysis of the two populations did not yield any genome-wide significant associations, illustrating the complexity of identifying associations for a complex disease in admixed and heterogeneous populations.
An association was reported between several SNPs in the transducin-like enhancer of split 4 (TLE4) gene on chromosome 9q with asthma in a population of 492 Mexican children with asthma, but these associations also did not reach genome-wide significance (Hancock et al., 2009). They were able to replicate these findings in an independent cohort of 177 Mexican case-parent trios. TLE4 had not previously been linked to the pathogenesis of asthma, but does play a role in early B cell development (Milili et al., 2002).
A GWAS from our group was recently reported on a series of pediatric asthma patients consisting of North American cases of European ancestry with persistent asthma requiring daily inhaled glucocorticoids for symptom control, and matched controls without asthma. In addition to the previously reported 17q21 locus, we uncovered association to a novel asthma locus on chromosome 1q31 in the discovery cohort and replicated the finding in an independent cohort of Northern European ancestry. The locus contains DENND1B, a gene that is expressed by natural killer (NK) cells and dendritic cells (Sleiman et al., 2010). Homologs of the DENND1B protein have been shown to interact with the TNFα receptor (Al-Zoubi et al., 2001). To determine whether the 1q31 locus also contributes to asthma in children of African ancestry, we also tested for association of the chromosome 1q31 locus and asthma in African American cases and ancestrally matched controls. A total of 17 of 20 SNPs were significantly associated with asthma, although the associated allele at each SNP was the alternative allele to that associated with asthma in the discovery set. Allele reversal at shared risk loci can be attributed to differences in the underlying genomic architecture at the loci between populations of different ancestry and as a result are being tagged differently. This locus has since been replicated in inflammatory bowel disease.
Six GWAS have been reported using intermediate phenotypes and quantitative traits, rather than asthma itself, as study endpoints. The first report used genome-wide associations to identify variants that modulate serum protein levels (Ober et al., 2008). A promoter SNP in the CHI3L1 gene that encodes the chitinase-like protein YKL-40 was shown to be a major determinant of elevated serum YKL‑40 levels and was also shown to associate with asthma, bronchial responsiveness, and pulmonary function in the Hutterite population. A GWAS showed significant association of the FCER1A and RAD50 genes with expression of CHI3L1, and evidence for association of the STAT6 gene with IgE levels. IgE levels are closely correlated with the clinical expression and severity of both asthma and allergy. The RAD50 variants were further shown to be associated with increased risk of asthma and atopic eczema (Weidinger et al., 2008).
Eosinophils are leukocytes that play an important role in the initiation and propagation of inflammatory signals. This makes them likely mediators of inflammatory disease and a GWAS was performed examining blood eosinophil counts. Five loci reached genome-wide association significance, one of which, IL1RL1, was also shown to be associated with asthma in a collection of 10 different populations (Gudbjartsson et al., 2009).
One genome-wide association has been reported on chronic obstructive pulmonary disease (COPD) and further three studies reported genome-wide association for lung function using a quantitative metric of lung function as a measure of airflow obstruction. Altered lung function, and airflow obstruction in particular, is associated with both asthma and COPD. Two SNPs at the α-nicotinic acetylcholine receptor (CHRNA 3/5) surpassed genome wide significance in the study and replicated in two of three independent cohorts. The CHRNA 3/5 locus had previously been associated with lung cancer and nicotine dependence (Berrettini et al., 2008; Saccone et al., 2007). The authors also reported that SNPs at the HHIP locus on chromosome 4 showed association and were consistently replicated across the study cohorts but did not reach genome-wide significance (Pillai et al., 2009). In the first of the three lung function GWAS that included 7,691 Framingham heart study participants, the only locus to surpass genome-wide significance for association with FEV1/FVC ratio and replicate in an independent cohort of 835 Family Heart Study participants was HHIP (Wilk et al., 2009).
The final two studies resulted in the identification of eleven novel loci associated with measures of lung function; both studies also replicated the previously reported association of the HHIP locus (Hancock et al., 2010; Repapi et al., 2010). These novel loci will not only shed further light on the pathways associated with pulmonary function but may also provide potential targets for respiratory disease such as asthma and COPD.
Themes Revealed by Genetic Analysis of Asthma Susceptibility
The numerous genome-wide linkage, candidate gene, and genome-wide association studies performed on asthma and asthma related phenotypes have resulted in an increasing large list of genes implicated in asthma susceptibility and pathogenesis. This list has been neatly categorized into four broad functional groups by several recent reviewers (Holloway et al., 2010; Swarr and Hakonarson, 2010; Vercelli, 2008). With this approach in mind, several themes have emerged (Figure 1).
Epithelial barrier function
Studies of asthma genetics have raised new interest in the body’s first line of immune defense, the epithelial barrier, in the pathogenesis of asthma. Mutations in the filaggrin gene (FLG) were initially identified in the rare single-gene disorder ichthyosis vulgaris (Smith et al., 2006), but subsequently loss of function variants were reported to be strongly associated with atopic dermatitis, eczema, and asthma, both dependent and independent of atopic dermatitis (Marenholz et al., 2006; Morar et al., 2007; Palmer et al., 2006; Palmer et al., 2007). Filaggrin, a protein involved in keratin aggregation, is not expressed in the bronchial mucosa (Ying et al., 2006), which has lead others to suggest that asthma susceptibility in patients with loss-of-function FLG variants may be due to allergic sensitization that occurs after breakdown of the epithelial barrier (Hudson, 2006).
Several epithelial genes with important roles in innate and adaptive immune function have also been implicated in asthma. These genes include defensin-beta1 (an antimicrobial peptide), uteroglobin/Clara cell 16-kD protein (CC16) (an inhibitor of dendritic cell-mediated TH2-cell differentiation), and several chemokines (CCL-5, -11, -24, and -26) involved in the recruitment of T-cells and eosinophils (Laing et al., 2009; Lee et al., 2008; Levy et al., 2005; Min et al., 2005; Raby et al., 2006b; Sengler et al., 2003; Zhang et al., 2010). Variations in SPINK5, a serine protease inhibitor limited to the epithelium and the causative factor in Netherton Syndrome (Chavanas et al., 2000), have been associated with asthma, but with conflicting results (Genuneit et al., 2009; Kabesch et al., 2004; Liu et al., 2009; Walley et al., 2001).
Environmental sensing and immune detection
A second class of associated genes is involved in detection of pathogens and allergens. These genes include pattern recognition receptors and extracellular receptors, such as CD14, toll-like receptor 2 (TLR2), TLR4, TLR6, TLR10; and intracellular receptors, such as nucleotide-binding oligomerization domain containing 1 (NOD1/CARD4) (Eder et al., 2006; Eder et al., 2004; Hysi et al., 2005; Kabesch et al., 2004; Kormann et al., 2008; Smit et al., 2009). Additional studies have strongly associated variations in the HLA class II genes with asthma and allergen-specific IgE responses (Li et al., 2010). These molecules are important in the immune response and shaping of the T cell repertoire; their involvement in an immune-mediated inflammatory disorder like asthma is unsurprising.
TH2-mediated cell response
TH2 ‑cell mediated adaptive immune responses have been widely recognized as a crucial component of allergic disease. Genes involved in TH2 ‑cell differentiation and function have been extensively studied in asthma candidate-gene association studies, and as one might expect, SNPs in many of these genes have been associated with asthma and other allergic phenotypes. Genes important for TH1 versus TH2 T cell polarization, like GATA3, TBX21, IL4, IL4RA, STAT6, and IL12B, have been implicated with asthma and allergy (Basehore et al., 2004; Genuneit et al., 2009; Haller et al., 2009; Howard et al., 2002; Kabesch et al., 2006; Munthe-Kaas et al., 2008; Pykäläinen et al., 2005; Raby et al., 2006a; Randolph et al., 2004; Suttner et al., 2009; Tantisira et al., 2004; Zhou et al., 2009). The genes encoding IL-13 and the beta-chain of the IgE receptor FcεR1 are well replicated contributors to asthma susceptibility (Genuneit et al., 2009; Howard et al., 2002; Li et al., 2010; Potaczek et al., 2009; Vladich et al., 2005; Wu et al., 2010). These two molecules play critical roles in allergic disease.
Finally, a variety of genes involved in mediating the response to allergic inflammation and oxidant stress on the tissue level appear to be important contributors to asthma susceptibility. Examples include ADAM33, a disintegrin and metalloprotease expressed in lung fibroblasts and smooth muscle cells; the alpha-1 chain of type 29 collagen (COL29A1); leukotriene C4 synthase (LTC4S); glutathione-S-transferase (GSTP1, GSTM1); arachidonate 5-lipoxygenase (ALOX-5); and nitric oxide synthase 1 (NOS1) (Duroudier et al., 2009; Hollá et al., 2002; Minelli et al., 2010; Piacentini et al., 2010; Sayers et al., 2003; Tamer et al., 2004; Van Eerdewegh et al., 2002; Via et al., 2010). Some studies have implicated variations in the beta-2 adrenergic receptor (ADRB2) as modulators of response to inhaled bronchodilators (Hawkins et al., 2008; Moore et al., 2009) but a recent randomized, double-blind, placebo-controlled trial refutes these results (Wechsler et al., 2009).
The many studies that have been aimed at asthma and allergies have revealed much about the genetic variants that underlie susceptibility to the condition as well as its severity. It is through this work that we have come to appreciate the importance of the barrier function of epithelium and molecules involved in the sensing and effector arms of innate immunity. Additionally, we have a much better picture of the critical roles played by both TH2 skewing and the molecules involved in development and remodeling of the lungs. The recent application of GWAS to asthma, with the possibility of discovering new genes that are currently unsuspected in asthma pathobiology, has the potential to greatly and rapidly expand our knowledge of the factors contributing to this complex genetic disease. However, the identification of unsuspected genes brings with it a new set of problems, as entire crops of functional studies will be required to explain and understand how these molecules contribute to asthma and related phenotypes. The recent identifications of ORMDL3 (Galanter et al., 2008; Moffatt et al., 2007; Sleiman et al., 2008; Tavendale et al., 2008) and DENND1B (Sleiman et al., 2010) highlight this issue. ORMDL3 encodes a transmembrane protein that resides in the endoplasmic reticulum. Recently, it has been described as a sensor of calcium concentrations and a mediator of cellular stress (Cantero-Recasens et al., 2010). It has been hypothesized that this function may give ORMDL3 a role in regulating inflammation, but much more work will be required to understand how it contributes to asthma. Even less is known of DENND1B. A presumably cytosolic protein with a conserved DENN domain, the molecule encoded by this locus has thus far only been described in a neuronal cell system and by overexpression in COS-7 cells, in which it localized to endosomes and interacted with clathrin, indicating a role in endocytosis and vesicular trafficking (Marat and McPherson, 2010). The DENN domain itself has been shown to have guanonucleotide exchange activity toward RAB35, a small GTPase involved in vesicle movement. DENND1B mRNA is highly expressed in natural killer cells, T lymphocytes, and a subset of dendritic cells (Sleiman et al., 2010), suggesting a function within the immune system, and the protein is homologous to proteins that regulate MAP kinase (Majidi et al., 2000; Majidi et al., 1998) and TNF receptor signaling (Al-Zoubi et al., 2001). However, much work remains in elucidating the contribution of this molecule to the asthmatic phenotype. Additionally, a large challenge is presented by understanding the effects of interactions between genes and between genetic factors and environmental risks and exposures (Martinez, 2005; Ober and Thompson, 2005; Vercelli, 2003). It is likely that considerable breakthroughs in our understanding of the genetics of asthma will come only with the development of tools and study designs to analyze the networks of factors that contribute to a complex genetic disease like asthma. Next-generation sequencing will undoubtedly play an important role in this process.
The authors report no conflicts of interest.
Patrick M.A. Sleiman, Ph.D., and Hakon Hakonarson, M.D., Ph.D. (Director of The Center for Applied Genomics), The Center for Applied Genomics, The Abramson Research Center of the Joseph Stokes Jr. Research Institute, The Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, 1216E Abramson Research Center, 3615 Civic Center Blvd., Philadelphia, Pennsylvania 19104, USA.
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