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.
Introduction
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 ) and STAT6 on 12q, and IL4R (the IL-4R 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; Pyklinen 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.
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The Genetics of Asthma and Allergic Disorders - Michael E ...