Allergic Asthma: Influence of Genetic and Environmental Factors
2011; Elsevier BV; Volume: 286; Issue: 38 Linguagem: Inglês
10.1074/jbc.r110.197046
ISSN1083-351X
AutoresAnil B. Mukherjee, Zhongjian Zhang,
Tópico(s)Food Allergy and Anaphylaxis Research
ResumoAllergic asthma is a chronic airway inflammatory disease in which exposure to allergens causes intermittent attacks of breathlessness, airway hyper-reactivity, wheezing, and coughing. Allergic asthma has been called a “syndrome” resulting from a complex interplay between genetic and environmental factors. Worldwide, >300 million individuals are affected by this disease, and in the United States alone, it is estimated that >35 million people, mostly children, suffer from asthma. Although animal models, linkage analyses, and genome-wide association studies have identified numerous candidate genes, a solid definition of allergic asthma has not yet emerged; however, such studies have contributed to our understanding of the multiple pathways to this syndrome. In contrast with animal models, in which T-helper 2 (TH2) cell response is the dominant feature, in human asthma, an initial exposure to allergen results in TH2 cell-dependent stimulation of the immune response that mediates the production of IgE and cytokines. Re-exposure to allergen then activates mast cells, which release mediators such as histamines and leukotrienes that recruit other cells, including TH2 cells, which mediate the inflammatory response in the lungs. In this minireview, we discuss the current understanding of how associated genetic and environmental factors increase the complexity of allergic asthma and the challenges allergic asthma poses for the development of novel approaches to effective treatment and prevention. Allergic asthma is a chronic airway inflammatory disease in which exposure to allergens causes intermittent attacks of breathlessness, airway hyper-reactivity, wheezing, and coughing. Allergic asthma has been called a “syndrome” resulting from a complex interplay between genetic and environmental factors. Worldwide, >300 million individuals are affected by this disease, and in the United States alone, it is estimated that >35 million people, mostly children, suffer from asthma. Although animal models, linkage analyses, and genome-wide association studies have identified numerous candidate genes, a solid definition of allergic asthma has not yet emerged; however, such studies have contributed to our understanding of the multiple pathways to this syndrome. In contrast with animal models, in which T-helper 2 (TH2) cell response is the dominant feature, in human asthma, an initial exposure to allergen results in TH2 cell-dependent stimulation of the immune response that mediates the production of IgE and cytokines. Re-exposure to allergen then activates mast cells, which release mediators such as histamines and leukotrienes that recruit other cells, including TH2 cells, which mediate the inflammatory response in the lungs. In this minireview, we discuss the current understanding of how associated genetic and environmental factors increase the complexity of allergic asthma and the challenges allergic asthma poses for the development of novel approaches to effective treatment and prevention. Allergic Asthma: A Complex SyndromeAsthma is a highly prevalent (330 million people affected worldwide) chronic inflammatory disease of the conducting airways of the respiratory system (American Academy of Allergy, Asthma and Immunology and reviewed in Ref. 2Barnes P.J. Nat. Rev. Immunol. 2008; 8: 183-192Crossref PubMed Scopus (1028) Google Scholar). It is a complex syndrome in which allergen exposure often induces intermittent attacks of breathlessness, airway hyper-reactivity, wheezing, and coughing (3Locksley R.M. Cell. 2010; 140: 777-783Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar). During the past 6 decades, the worldwide incidence and severity of asthma have steadily increased. Allergic asthma is one aspect of atopic disease, which is also increasing. This disease has become an expanding burden on public health services in both industrialized and developing countries (1Garantziotis S. Schwartz D.A. Annu. Rev. Public Health. 2010; 31: 37-51Crossref PubMed Scopus (24) Google Scholar, 2Barnes P.J. Nat. Rev. Immunol. 2008; 8: 183-192Crossref PubMed Scopus (1028) Google Scholar, 3Locksley R.M. Cell. 2010; 140: 777-783Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar, 4Mannino D.M. Buist A.S. Lancet. 2007; 370: 765-773Abstract Full Text Full Text PDF PubMed Scopus (1457) Google Scholar, 5Pearce N. Aït-Khaled N. Beasley R. Mallol J. Keil U. Mitchell E. Robertson C. the ISAAC Phase Three Study GroupThorax. 2007; 62: 758-766Crossref PubMed Scopus (884) Google Scholar, 6Akinbami L.J. Advance Data from Vital and Health Statistics. National Center for Health Statistics, Hyattsville, MD2006: 1-24Google Scholar). It is estimated that >35 million people in the United States alone develop asthma during their lifetime, and more than three-fourths of these individuals suffer from allergies (1Garantziotis S. Schwartz D.A. Annu. Rev. Public Health. 2010; 31: 37-51Crossref PubMed Scopus (24) Google Scholar, 5Pearce N. Aït-Khaled N. Beasley R. Mallol J. Keil U. Mitchell E. Robertson C. the ISAAC Phase Three Study GroupThorax. 2007; 62: 758-766Crossref PubMed Scopus (884) Google Scholar). During the past 3 decades, much has been learned about the pathogenesis of allergen-induced airway inflammation, which is recognized as one of the predominant underlying causes of allergic asthma. Currently, it is recognized that allergic asthma is a complex disease that results from interactions between multiple genetic and environmental factors (7Holloway J.W. Yang I.A. Holgate S.T. J. Allergy Clin. Immunol. 2010; 125: S81-S94Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar). Moreover, the advances in molecular genetics and the use of animal models have advanced our understanding of the pathogenic mechanism(s) of various aspects of this complex disease, and it is expected that further advance in this area will facilitate the development of novel and more effective therapeutic approaches. It should be noted, however, that the mouse models of allergic asthma do not exactly replicate the human disease. In contrast to the mouse models, in which T-helper 2 (TH2) 2The abbreviations used are: TH2T-helper 2FcϵRFcϵ receptorDCdendritic cellAHRairway hyper-reactivityAPCantigen-presenting cellOVAovalbuminTregregulatory TUGuteroglobin. cell response is the dominant feature, the pathogenesis of human allergic asthma involves an initial exposure to an allergen that results in TH2 cell-dependent stimulation of the immune response that mediates the production of IgE and cytokines. Repeated exposure to allergen then activates mast cells, which release mediators that facilitate recruitment of other cell types, including TH2 cells, which mediate the inflammatory response in the airways (reviewed in Ref. 8Geha R.S. Jabara H.H. Brodeur S.R. Nat. Rev. Immunol. 2003; 3: 721-732Crossref PubMed Scopus (341) Google Scholar). Thus, although the TH2 axis plays a critical role in initiating the IgE response and airway inflammation, the presence of allergen-specific IgE does not necessarily culminate in asthma. In this minireview, we discuss what makes allergic asthma a complex disease in which genetic and environmental factors merge to cause pathogenesis.Current Understanding of Allergic Asthma PathogenesisAlthough several types of asthma have been recognized clinically, allergic asthma is the most common form of the disease (reviewed in Ref. 9Kim H.Y. DeKruyff R.H. Umetsu D.T. Nat. Immunol. 2010; 11: 577-584Crossref PubMed Scopus (448) Google Scholar). In susceptible individuals, the initiation of allergen sensitivity occurs at the mucosal surfaces, where environmental allergens meet the mucosal epithelia. The interaction of inhaled allergen(s) with sensitized immune cells in the airway results in allergic asthma. Allergic rhinitis, atopic dermatitis, and asthma, which constitute atopic conditions, occur in individuals with markedly increased levels of IgE antibodies (10Oettgen H.C. Geha R.S. J. Allergy Clin. Immunol. 2001; 107: 429-440Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar). The expression of high-affinity (FcϵRI) and low-affinity (FcϵRII; CD23) IgE receptors occurs in a wide variety of cell types, including dendritic cells (DCs) and B cells (Fig. 1). IgE bound to these receptors on B cells and DCs facilitates the uptake of allergen by these cells, promoting allergen presentation to T cells, which mediate secondary immune responses. The majority of IgE is bound by FcϵRI on mast cells as well as basophils, and IgE-bound FcϵRI cross-linking by a specific antigen mediates the release of inflammatory mediators (e.g. histamine and leukotrienes) by mast cells (Fig. 1), leading to the inflammatory response. The regulation of IgE production and its relationship to the development of TH2 cells that drive IgE responses have been reviewed (8Geha R.S. Jabara H.H. Brodeur S.R. Nat. Rev. Immunol. 2003; 3: 721-732Crossref PubMed Scopus (341) Google Scholar). An enhanced tendency toward airway hyper-reactivity (AHR) culminating in bronchial smooth muscle contraction, characteristically found in patients with asthma, is often linked to high IgE levels (11Postma D.S. Bleecker E.R. Amelung P.J. Holroyd K.J. Xu J. Panhuysen C.I. Meyers D.A. Levitt R.C. N. Engl. J. Med. 1995; 333: 894-900Crossref PubMed Scopus (709) Google Scholar). Moreover, it has been reported that, in cohorts of children with asthma and physiologic evidence of AHR, high serum levels of IgE are detectable (12Sears M.R. Burrows B. Flannery E.M. Herbison G.P. Hewitt C.J. Holdaway M.D. N. Engl. J. Med. 1991; 325: 1067-1071Crossref PubMed Scopus (698) Google Scholar). Although, in both animal models and humans, some component of asthmatic pathophysiology, especially acute reactions to allergen, may be IgE-mediated, the other features of this disease may arise independently of IgE. Thus, in atopic families, inhalation of allergens and subsequent production of IgE are associated with predisposition to allergic asthma. Furthermore, it is likely that IgE participates in triggering mast cell-mediated acute- and late-phase airflow obstruction (10Oettgen H.C. Geha R.S. J. Allergy Clin. Immunol. 2001; 107: 429-440Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar). Allergen exposure also triggers activation of bone marrow-derived and non-bone marrow-derived cells of the innate immune system, which eventually leads to the secretion of various cytokines (3Locksley R.M. Cell. 2010; 140: 777-783Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar). The recruitment of antigen-processing cells, most likely monocyte-derived DCs, initiates the pathway to inflammation. Recently, it was reported that basophils may also be involved in certain situations. Moreover, it has been reported that, in the airways of patients with asthma and especially in those patients suffering from allergic asthma, allergen-specific TH2 cells are readily detectable (13Robinson D.S. Hamid Q. Ying S. Tsicopoulos A. Barkans J. Bentley A.M. Corrigan C. Durham S.R. Kay A.B. N. Engl. J. Med. 1992; 326: 298-304Crossref PubMed Scopus (2551) Google Scholar). Recently, several excellent reviews were published on TH2 cell differentiation (14Zhu J. Yamane H. Paul W.E. Annu. Rev. Immunol. 2010; 28: 445-489Crossref PubMed Scopus (2203) Google Scholar, 15Paul W.E. Zhu J. Nat. Rev. Immunol. 2010; 10: 225-235Crossref PubMed Scopus (679) Google Scholar, 16Amsen D. Spilianakis C.G. Flavell R.A. Curr. Opin. Immunol. 2009; 21: 153-160Crossref PubMed Scopus (132) Google Scholar, 17Sokol C.L. Medzhitov R. Curr. Opin. Immunol. 2010; 22: 73-77Crossref PubMed Scopus (68) Google Scholar), which may be referred to for detail knowledge on this subject. The TH2 cells secrete cytokines, which promote the synthesis of allergen-specific IgE. These cytokines also promote presentation of antigens (allergens) to CD4+ T cells, which facilitate both DCs and T cells in eliciting TH2 cell responses (18Saenz S.A. Taylor B.C. Artis D. Immunol. Rev. 2008; 226: 172-190Crossref PubMed Scopus (389) Google Scholar, 19Finkelman F. Austen K.F. Frank M.M. Atkinson J.P. Cantor H. Samter's Immunologic Diseases. 6th Ed. Lippincott Williams & Wilkins, Philadelphia2001: 111-126Google Scholar). In addition, activated TH2 cells also secrete the cytokines IL-5, IL-9 and IL-13, which facilitate the recruitment of eosinophils and promote the growth of mast cells, respectively, ultimately stimulating AHR, characteristically found in asthma (9Kim H.Y. DeKruyff R.H. Umetsu D.T. Nat. Immunol. 2010; 11: 577-584Crossref PubMed Scopus (448) Google Scholar, 20Holgate S.T. Polosa R. Nat. Rev. Immunol. 2008; 8: 218-230Crossref PubMed Scopus (484) Google Scholar). However, recent experiments indicate that TH2 cells fail to produce IL-4, IL-5, or IL-13 without CD11c+ DCs (9Kim H.Y. DeKruyff R.H. Umetsu D.T. Nat. Immunol. 2010; 11: 577-584Crossref PubMed Scopus (448) Google Scholar, 21van Rijt L.S. Jung S. Kleinjan A. Vos N. Willart M. Duez C. Hoogsteden H.C. Lambrecht B.N. J. Exp. Med. 2005; 201: 981-991Crossref PubMed Scopus (518) Google Scholar). Interestingly, adoptively transferred, bone marrow-derived, antigen-loaded DCs or DCs in lungs can induce the TH2 cell response (22Lambrecht B.N. De Veerman M. Coyle A.J. Gutierrez-Ramos J.C. Thielemans K. Pauwels R.A. J. Clin. Invest. 2000; 106: 551-559Crossref PubMed Scopus (436) Google Scholar), suggesting that lung DCs are the major antigen-presenting cells (APCs) and are essential for TH2 cell response during allergen-mediated airway inflammation.In addition to the recruitment of TH2 cells, allergen challenge also facilitates the recruitment of other inflammatory cells such as mast cells, basophils, and eosinophils. However, a recent report indicates that, in addition to being inflammatory, these cells also participate as APCs and initiate or enhance TH2 cell responses (9Kim H.Y. DeKruyff R.H. Umetsu D.T. Nat. Immunol. 2010; 11: 577-584Crossref PubMed Scopus (448) Google Scholar). Among the three cell types, mast cells can initiate immediate hypersensitivity responses by releasing histamines in response to both IgE-mediated adaptive and innate immune responses. Moreover, mast cells can be activated via cross-linking of allergen-specific IgE (23Prussin C. Metcalfe D.D. J. Allergy Clin. Immunol. 2006; 117: S450-S456Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar) or via Toll-like receptor ligands or cytokines such as IL-33 (24Silver M.R. Margulis A. Wood N. Goldman S.J. Kasaian M. Chaudhary D. Inflamm. Res. 2010; 59: 207-218Crossref PubMed Scopus (105) Google Scholar). Furthermore, in addition to releasing histamines and cysteinyl leukotrienes, mast cells secrete various cytokines such as IL-1, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, IL-16, TGF-β, and TNF-α and chemokines such as TCA-3, RANTES, MCP-1, and MIP-1α (reviewed in Ref. 25Barrett N.A. Austen K.F. Immunity. 2009; 31: 425-437Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar). In Fig. 2, the pathways that lead to allergic asthma are summarized.FIGURE 2Possible pathways to allergic asthma. Allergens reaching the airways via inhaled air are taken up and processed by DCs that are primed by thymic stromal lymphopoietin (TSLP) secreted by airway epithelial cells. These allergens also cause the mast cells to release CCL17 and CCL22. CCL17 and CCL22 act on CCR4 (CC chemokine receptor 4), which mediates chemotactic migration of TH2 cells. TH2 cells play critical roles in orchestrating the allergen-induced inflammatory response by releasing IL-4 and IL-13. These interleukins also stimulate IgE production by B cells. These activated B cells also produce IL-5 (required for eosinophilic inflammation) and IL-9 (stimulator of mast cell proliferation). Airway epithelial cells release CCL11, stimulating recruitment of eosinophils via CCR3. Individuals suffering from allergic asthma may have defective Treg cells, which favor further TH2 cell proliferation and differentiation. Allergens also stimulate activation of sensitized mast cells by cross-linking surface-bound IgE molecules. In turn, activated mast cells secrete mediators of bronchoconstriction such as histamines, prostaglandin D2, and cysteinyl leukotrienes (2Barnes P.J. Nat. Rev. Immunol. 2008; 8: 183-192Crossref PubMed Scopus (1028) Google Scholar).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Genetic Susceptibility to Allergy and AsthmaAs stated above, asthma and asthma-related syndromes are complex diseases in which an interplay of strong genetic and environmental components leads to pathogenesis (reviewed in Refs. 7Holloway J.W. Yang I.A. Holgate S.T. J. Allergy Clin. Immunol. 2010; 125: S81-S94Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar and 26Vercelli D. Nat. Rev. Immunol. 2008; 8: 169-182Crossref PubMed Scopus (477) Google Scholar, 27Ober C. Hoffjan S. Genes Immun. 2006; 7: 95-100Crossref PubMed Scopus (519) Google Scholar, 28Wills-Karp M. Ewart S.L. Nat. Rev. Genet. 2004; 5: 376-387Crossref PubMed Scopus (120) Google Scholar, 29Cookson W. Nat. Rev. Immunol. 2004; 4: 978-988Crossref PubMed Scopus (327) Google Scholar, 30Guerra S. Martinez F.D. Annu. Rev. Med. 2008; 59: 327-341Crossref PubMed Scopus (50) Google Scholar, 31Bossé Y. Hudson T.J. Annu. Rev. Med. 2007; 58: 171-184Crossref PubMed Scopus (62) Google Scholar, 32Vercelli D. J. Allergy Clin. Immunol. 2010; 125: 347-348Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar). It is well known that many individuals are predisposed to developing allergic reactions to substances that do not generally elicit immune response. These atopic individuals are thought to be genetically predisposed to develop hypersensitivity to substances such as pollens, antibiotics, and perfumes. Numerous studies have shown that atopy is familial in nature. Elevated levels of IgE have been detected in patients with allergic diseases (7Holloway J.W. Yang I.A. Holgate S.T. J. Allergy Clin. Immunol. 2010; 125: S81-S94Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar), and IgE production is tightly controlled. Recently, it was reported that NF-IL3, a transcriptional regulator, may control IgE production (33Rothman P.B. Trans. Am. Clin. Climatol. Assoc. 2010; 121: 156-171PubMed Google Scholar). Early studies reported the prevalence of allergic disease in first degree relatives of affected individuals (34Sibbald B. Horn M.E. Brain E.A. Gregg I. Thorax. 1980; 35: 671-674Crossref PubMed Scopus (113) Google Scholar, 35Taylor B Broom B.C. Ann. Allergy. 1981; 47: 197-199PubMed Google Scholar). Subsequently, studies in monozygotic and dizygotic twins have shown a positive correlation with regard to allergic disease traits such as total serum IgE levels, methacholine sensitivity in the lungs, and skin test results being 2-fold higher among monozygotic twins than dizygotic twins. Moreover, children of asthmatic parents are more likely to develop asthma than those of parents without any history of atopy. Studies on atopic disease in human and animal populations have facilitated the identification of susceptibility genes encoding class II MHC, FcϵRIβ, RANTES, IL-4 receptor α, β-adrenergic receptor, T cell receptor α, and mast cell chymase. Furthermore, evidence suggests that genetic loci on human chromosomes 5, 6, and 11 are likely to harbor atopy genes. A thorough review of the molecular genetics of allergic diseases provides insight into the complexity of the atopic disease and why the identification of specific atopy genes remains challenging (reviewed in Ref. 36Ono S.J. Annu. Rev. Immunol. 2000; 18: 347-366Crossref PubMed Scopus (105) Google Scholar).During the past decade, knowledge on asthma genetics has progressed significantly, and several genes or gene loci associated with asthma- and/or atopy-related syndromes have been identified. However, most of these genes have only modest effects, and the majority of these genes have not been systematically tested to determine whether the results are replicable in different populations. Several excellent reviews on the genetics of allergy and asthma have been published (2Barnes P.J. Nat. Rev. Immunol. 2008; 8: 183-192Crossref PubMed Scopus (1028) Google Scholar, 7Holloway J.W. Yang I.A. Holgate S.T. J. Allergy Clin. Immunol. 2010; 125: S81-S94Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar, 26Vercelli D. Nat. Rev. Immunol. 2008; 8: 169-182Crossref PubMed Scopus (477) Google Scholar, 27Ober C. Hoffjan S. Genes Immun. 2006; 7: 95-100Crossref PubMed Scopus (519) Google Scholar, 28Wills-Karp M. Ewart S.L. Nat. Rev. Genet. 2004; 5: 376-387Crossref PubMed Scopus (120) Google Scholar, 29Cookson W. Nat. Rev. Immunol. 2004; 4: 978-988Crossref PubMed Scopus (327) Google Scholar, 30Guerra S. Martinez F.D. Annu. Rev. Med. 2008; 59: 327-341Crossref PubMed Scopus (50) Google Scholar, 31Bossé Y. Hudson T.J. Annu. Rev. Med. 2007; 58: 171-184Crossref PubMed Scopus (62) Google Scholar, 32Vercelli D. J. Allergy Clin. Immunol. 2010; 125: 347-348Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar). In this minireview, we discuss only those genes that have shown functional and immunological links for susceptibility to asthma and allergy. In general, asthma susceptibility genes are classified into four main groups (reviewed in Refs. 7Holloway J.W. Yang I.A. Holgate S.T. J. Allergy Clin. Immunol. 2010; 125: S81-S94Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar, 26Vercelli D. Nat. Rev. Immunol. 2008; 8: 169-182Crossref PubMed Scopus (477) Google Scholar, and 32Vercelli D. J. Allergy Clin. Immunol. 2010; 125: 347-348Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar): (i) innate immunity and immunoregulatory genes; (ii) genes associated with TH2 cell differentiation and effector functions; (iii) genes associated with mucosal immunity and epithelial biology; and (iv) genes linked to lung function, airway remodeling, and severity of the disease (7Holloway J.W. Yang I.A. Holgate S.T. J. Allergy Clin. Immunol. 2010; 125: S81-S94Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar, 26Vercelli D. Nat. Rev. Immunol. 2008; 8: 169-182Crossref PubMed Scopus (477) Google Scholar, 32Vercelli D. J. Allergy Clin. Immunol. 2010; 125: 347-348Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar). The interactions among the genes in the first three groups and those identified by positional cloning have been reviewed in detail (32Vercelli D. J. Allergy Clin. Immunol. 2010; 125: 347-348Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar) and are summarized in Fig. 3. The genes included in the first group have been discovered through association studies and are thought to be involved in triggering the immune response and stimulating differentiation of CD4+ T helper cells. These genes encode pattern recognition receptors CD14 (monocyte differentiation antigen 14), NOD1 (nucleotide-binding, oligomerization domain-containing 1), NOD2, TLR2 (Toll-like receptor 2), TLR4, TLR6, and TLR10; cytokines regulating immune responses such as TGF-β1 and IL-10; the transcription factor STAT3 (signal transducer and activator of transcription 3); molecules that facilitate antigen presentation such as the HLA-DR, HLA-DP, and HLA-DQ alleles; and the prostaglandin receptor. Asthma susceptibility genes that belong to the second group regulate TH2 cell differentiation and TH2 cell effector functions (26Vercelli D. Nat. Rev. Immunol. 2008; 8: 169-182Crossref PubMed Scopus (477) Google Scholar): FCER1B, GATA3 (GATA-binding protein 3), IL4, IL4RA (interleukin-4 receptor α-chain), IL5, IL5RA, IL12B, IL13, STAT6, and TBX21 (T-box 21; also known as T-bet). Several genes are expressed in epithelial cells and are included in the third group. These genes encode chemokines CCL5 (CC chemokine ligand 5), CCL11, CCL24, and CCL26; factors involved in maintaining the integrity of the epithelial cell barrier (FLG (filaggrin) and SPINK5 (serine protease inhibitor Kazal-type 5)); antimicrobial peptide DEFB1 (defensin β1); and anti-inflammatory protein CC10/CC16 (Clara cell-specific 16 kDa protein; also known as SCGB1A1 and uteroglobin). The fourth group of asthma susceptibility genes has been identified by positional cloning. It includes ADAM33 (a disintegrin and metalloproteinase domain 33), COL29A1 (collagen type XXIX α-1; also called COL6A5 (collagen type VI α-5)), DPP10 (dipeptidyl peptidase 10), GPRA (G-protein-coupled receptor for asthma susceptibility; also known as NPSR1 and GPRA154), HLA-G, IRAKM (interleukin-1 receptor-associated kinase M), and PHF11 (plant homeodomain finger protein 11), which are expressed in the epithelium and/or smooth muscle cells.FIGURE 3Genes identified by association studies or positional cloning. The genes that are associated with asthma/atopy are divided into four groups (26Vercelli D. Nat. Rev. Immunol. 2008; 8: 169-182Crossref PubMed Scopus (477) Google Scholar). A, the first group of genes is associated with triggering the allergic response via differentiation of CD4+ T helper cells. This group includes genes encoding CD14, TLR2, TLR4, TLR6, TLR10, NOD1, and NOD2, which are known as pattern recognition receptors. This group also includes genes that encode immunoregulatory cytokines such as IL-10 and TGF-β1; the transcription factor STAT3; antigen-presenting facilitator genes such as the HLA-DR, HLA-DQ, and HLA-DP alleles; and prostaglandin E receptor 2. B, the second group of genes includes GATA3, TBX21, IL4, IL13, IL4RA, FCER1B, IL5, IL5RA, STAT6, and IL12B, which regulate TH2 cell differentiation and effector functions. C, the third group includes genes encoding chemokines CCL5, CCL11, CCL24, and CCL26; antimicrobial peptide DEFB1; anti-inflammatory protein CC16 (also called UG); and factors responsible for maintaining the epithelial cell barrier such as SPINK5 and FLG. The positional cloning method has been used to identify the following genes expressed in the epithelia and smooth muscles: ADAM33, COL29A1, DPP10, GPRA, HLA-G, IRAKM, and PHF11 (26Vercelli D. Nat. Rev. Immunol. 2008; 8: 169-182Crossref PubMed Scopus (477) Google Scholar).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Several genes (including ADAM33, DPP10, PHF11, TIM-1, GPRA, OPN3, ORMDL3, and PDE4D) that are associated with atopy and asthma have been identified via association studies and positional cloning (37Agrawal D.K. Shao Z. Curr. Allergy Asthma Rep. 2010; 10: 39-48Crossref PubMed Scopus (115) Google Scholar). The genes encoding the T cell immunoglobulin domain, the mucin-like domain (TIM) family (38McIntire J.J. Umetsu S.E. Akbari O. Potter M. Kuchroo V.K. Barsh G.S. Freeman G.J. Umetsu D.T. DeKruyff R.H. Nat. Immunol. 2001; 2: 1109-1116Crossref PubMed Scopus (435) Google Scholar, 39McIntire J.J. Umetsu D.T. DeKruyff R.H. Springer Semin. Immunopathol. 2004; 25: 335-348Crossref PubMed Scopus (104) Google Scholar), and ADAM33 on human chromosome 20p13 are associated with asthma and AHR (40Van Eerdewegh P. Little R.D. Dupuis J. Del Mastro R.G. Falls K. Simon J. Torrey D. Pandit S. McKenny J. Braunschweiger K. Walsh A. Liu Z. Hayward B. Folz C. Manning S.P. Bawa A. Saracino L. Thackston M. Benchekroun Y. Capparell N. Wang M. Adair R. Feng Y. Dubois J. FitzGerald M.G. Huang H. Gibson R. Allen K.M. Pedan A. Danzig M.R. Umland S.P. Egan R.W. Cuss F.M. Rorke S. Clough J.B. Holloway J.W. Holgate S.T. Keith T.P. Nature. 2002; 418: 426-430Crossref PubMed Scopus (941) Google Scholar). In addition to association studies and positional cloning, genome-wide association studies have also been carried out to identify asthma susceptibility genes (27Ober C. Hoffjan S. Genes Immun. 2006; 7: 95-100Crossref PubMed Scopus (519) Google Scholar, 28Wills-Karp M. Ewart S.L. Nat. Rev. Genet. 2004; 5: 376-387Crossref PubMed Scopus (120) Google Scholar, 29Cookson W. Nat. Rev. Immunol. 2004; 4: 978-988Crossref PubMed Scopus (327) Google Scholar, 30Guerra S. Martinez F.D. Annu. Rev. Med. 2008; 59: 327-341Crossref PubMed Scopus (50) Google Scholar, 31Bossé Y. Hudson T.J. Annu. Rev. Med. 2007; 58: 171-184Crossref PubMed Scopus (62) Google Scholar, 32Vercelli D. J. Allergy Clin. Immunol. 2010; 125: 347-348Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar). This method utilizes SNPs for screening across the whole genome to identify novel disease susceptibility genes without the bias of prior knowledge. However, because of the lack of biological correlates, in some instances, the genes identified by this method have raised questions about the true relevance of these genes to the disease (32Vercelli D. J. Allergy Clin. Immunol. 2010; 125: 347-348Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar). Three independent reports were published recently (41Wu H. Romieu I. Shi M. Hancock D.B. Li H. Sienra-Monge J.J. Chiu G.Y. Xu H. del Rio-Navarro B.E. London S.J. J. Allergy Clin. Immunol. 2010; 125: 321-327Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 42Mathias R.A. Grant A.V. Rafaels N. Hand T. 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