Over 100 years have passed since it was first recognized that asthma and allergic diseases have a genetic component. The genetic involvement was suggested from observations that allergic subjects had a higher incidence of positive family histories of disease when compared to families without disease [1, 2]. More recent studies have shown that a child has a 33% chance of developing allergies if one parent has allergies and a 70% chance if both parents are allergic. Evidence for linkage to asthma is not as robust, as there is only a 15% chance of a child developing asthma if one parent has the disease. While the concept of allergic disorders having a familial predisposition has been recognized, defining the genetic mechanism has proven more challenging. It is now accepted that allergies and asthma are not only complex genetic disorders, defined as disorders that have numerous contributing genes, each having variable degrees of involvement in any given individual, but also multi-factorial in origin, involving interaction of genetic and environmental factors. Environmental exposures include allergen exposure, second hand cigarette smoke, pollutants, low birth weight and infectious agents. This review will first discuss gene association studies and explore some of the problems associated with them. The focus will then shift towards the future of genetic studies in asthma and allergy including pharmacogenetics, gene-environmental interactions, gene—gene interactions and epigenetics.
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References
Cooke RA, van der Veer A (1916) Human sensitization. J Immunol 1:201–205
Coca AF, Cooke RA (1923) On the classification of the phenomenon of hypersensitiveness. J Immunol 8:163–182
Daniels SE, Bhattacharrya S, James A, et al. (1996) A genome-wide search for quantitative trait loci underlying asthma. Nature 383:247–250
Ober C, Cox NJ, Abney M, et al. (1998) Genome-wide search for asthma susceptibility loci in a founder population. The Collaborative Study on the Genetics of Asthma. Hum Mol Genet 7:1393–1398
Wjst M, Fischer G, Immervoll T, et al. (1999) A genome-wide search for linkage to asthma. German Asthma Genetics Group. Genomics 58:1–8
Moffatt MF, Sharp PA, Faux JA, et al. (1992) Factors confounding genetic linkage between atopy and chromosome 11q. Clin Exp Allergy 22:1046–1051
(CSGA) CSotGoA (1997) A genome-wide search for asthma susceptibility loci in ethnically diverse populations. Nat Genetics 15:389–392
Van Eerdewegh P, Little RD, Dupuis J, et al. (2002) Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 418:426–430
Howard TD, Postma DS, Jongepier H, et al. (2003) Association of a disintegrin and metallo-protease 33 (ADAM33) gene with asthma in ethnically diverse populations. J Allergy Clin Immunol 112:717–722
Werner M, Herbon N, Gohlke H, et al. (2004) Asthma is associated with single-nucleotide polymorphisms in ADAM33. Clin Exp Allergy 34:26–31
Jongepier H, Boezen HM, Dijkstra A, et al. (2004) Polymorphisms of the ADAM33 gene are associated with accelerated lung function decline in asthma. Clin Exp Allergy 34:757–760
Holgate ST, Davies DE, Rorke S, et al. (2004) Identification and possible functions of ADAM33 as an asthma susceptibility gene. Clin Exp All Rev 4:49–55
Thomas NS, Wilkinson J, Holgate ST (1997) The candidate region approach to the genetics of asthma and allergy. Am J Respir Crit Care Med 156:S144–S151
Ulevitch RJ, Tobias PS (1995) Receptor-dependent mechanisms of cell stimulation by bacte rial endotoxin. Annu Rev Immunol 13:437–457
Baldini M, Lohman IC, Halonen M, et al. (1999) A polymorphism in the 5 flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E. Am J Respir Cell Mol Biol 20:976–983
LeVan TD, Bloom JW, Bailey TJ, et al. (2001) A common single nucleotide polymorphism in the CD14 promoter decreases the affinity of Sp protein binding and enhances transcriptional activity. J Immunol 167:5838–5844
Vercelli D (2002) Genetics of IL-13 and functional relevance of IL-13 variants. Curr Opin Allergy Clin Immunol 2:389–393
Borish L, Steinke JW (2003) Cytokines and chemokines. J Allergy Clin Immunol 111:S460–S475
Howard TD, Whittaker PA, Zaiman AL, et al. (2001) Identification and association of poly morphisms in the interleukin-13 gene with asthma and atopy in a Dutch population. Am J Respir Cell Mol Biol 25:377–384
Cameron L, Webster RB, Strempel JM, et al. (2006) Th2 cell-selective enhancement of human IL-13 transcription by IL-13–1112C > T, a polymorphism associated with allergic inflamma tion. J Immunol 177:8633–8642
Taussig LM, Wright AL, Morgan WJ, et al. (1989) The Tucson Children's Respiratory Study. I. Design and implementation of a prospective study of acute and chronic respiratory illness in children. Am J Epidemiol 129:1219–1231
von Mutius E, Weiland SK, Fritzsch C, et al. (1998) Increasing prevalence of hay fever and atopy among children in Leipzig, East Germany. Lancet 351:862–866
Arima K, Umeshita-Suyama R, Sakata Y, et al. (2002) Upregulation of IL-13 concentration in vivo by the IL-13 variant associated with bronchial asthma. J Allergy Clin Immunol 109:980–987
Malmstrom K, Rodriguez-Gomez G, Guerra J, et al. (1999) Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma. Ann Intern Med 130:487–495
Weiss ST, Lake SL, Silverman ES, et al. (2004) Asthma steroid pharmacogenetics: a study strategy to identify replicated treatment responses. Proc Am Thorac Soc 1:364–367
Tantisira KG, Lake S, Silverman ES, et al. (2004) Corticosteroid pharmacogenetics: associa tion of sequence variants in CRHR1 with improved lung function in asthmatics treated with inhaled corticosteroids. Hum Mol Genet 13:1353–1359
In KH, Asano K, Beier D, et al. (1997) Naturally occurring mutations in the human 5-lipoxy-genase gene promoter that modify transcription factor binding and reporter gene transcription. J Clin Invest 99:1130–1137
Silverman ES, Du J, De Sanctis GT, et al. (1998) Egr-1 and Sp1 interact functionally with the 5-lipoxygenase promoter and its naturally occurring mutants. Am J Respir Cell Mol Biol 19:316–323
Drazen JM, Yandava CN, Dube L, et al. (1999) Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nature Genetics 22:168–170.
Sanak M, Simon H-U, Szczeklik A (1997) Leukotriene C4 synthase promoter polymorphism and risk of aspirin-induced asthma. Lancet 350:1599–1600
de Alarcon A, Steinke JW, Caughey R, et al. (2006) Expression of leukotriene C4 synthase and plasminogen activator inhibitor 1 gene promoter polymorphisms in sinusitis. Am J Rhinol 20:545–549
Sampson AP, Siddiqui S, Buchanan D, et al. (2000) Variant LTC4 synthase allele modifies cysteinyl leukotriene synthesis in eosinophils and predicts clinical response to zafirlukast. Thorax 55:S28–S31
Sayers I, Barton S, Rorke S, et al. (2004) Allelic association and functional studies of promoter polymorphism in the leukotriene C4 synthase gene (LTC4S) in asthma. Thorax 58:417–424
Hawkins GA, Tantisira K, Meyers DA, et al. (2006) Sequence, haplotype, and association analysis of ADRbeta2 in a multiethnic asthma case-control study. Am J Respir Crit Care Med 174:1101–1119
Israel E, Drazen JM, Liggett SB, et al. (2000) The effect of polymorphisms of the β2-adrenergic receptor on the response to regular use of albuterol in asthma. Am J Respir Crit Care Med 162:75–80
Israel E, Chinchilli VM, Ford JG, et al. (2004) Use of regularly scheduled albuterol in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial. Lancet 364:1464–1466
Cho SH, Oh SY, Bahn JW, et al. (2005) Association between bronchodilating response to short-acting beta-agonist and non-synonymous single-nucleotide polymorphisms of beta-adrenoceptor gene. Clin Exp Allergy 35:1162–1167
Green SA, Turki J, Innis M, et al. (1994) Amino-terminal polymorphisms of the human β2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry 33:9414–9419
Perera BJ (2003) Salmeterol multicentre asthma research trial (SMART): interim analy sis shows increased risk of asthma related deaths. Ceylon Med J 48:99
Tantisira KG, Small KM, Litonjua AA, et al. (2005) Molecular properties and pharma-cogenetics of a polymorphism of adenylyl cyclase type 9 in asthma: interaction between beta-agonist and corticosteroid pathways. Hum Mol Genet 14:1671–1677
Eder W, von Mutius E (2004) Hygiene hypothesis and endotoxin: what is the evidence? Curr Opin Allergy Clin Immunol 4:113–117
Fageras Bottcher M, Hmani-Aifa M, Lindstrom A, et al. (2004) A TLR4 polymorphism is associated with asthma and reduced lipopolysaccharide-induced interleukin-12(p70) responses in Swedish children. J Allergy Clin Immunol 114:561–567
Zambelli-Weiner A, Ehrlich E, Stockton ML, et al. (2005) Evaluation of the CD14/-260 polymorphism and house dust endotoxin exposure in the Barbados Asthma Genetics Study. J Allergy Clin Immunol 115:1203–1209
Hoffjan S, Nicolae D, Ostrovnaya I, et al. (2005) Gene-environment interaction effects on the development of immune responses in the 1st Year of life. Am J Hum Genet 76:696–704
Eder W, Klimecki W, Yu L, et al. (2004) Toll-like receptor 2 as a major gene for asthma in children of European farmers. J Allergy Clin Immunol 113:482–488
Gilliland FD, Li YF, Saxon A, et al. (2004) Effect of glutathione-S-transferase M1 and P1 genotypes on xenobiotoc enhancement of allergic responses: randomised, placebo-controlled crossover study. Lancet 363:119–125
Gauderman WJ, Avol E, Lurmann F, et al. (2005) Childhood asthma and exposure to traffic and nitrogen dioxide. Epidemiology 16:737–743
Li YF, Gauderman WJ, Avol E, et al. (2006) Associations of tumor necrosis factor G-308A with childhood asthma and wheezing. Am J Respir Crit Care Med 173:970–976
Howard TD, Koppelman GH, Xu J, et al. (2003) Gene-gene interaction in asthma: IL4RA and IL13 in a Dutch population with asthma. Am J Hum Genet 70:230–236
Chan IH, Leung TF, Tang NL, et al. (2006) Gene-gene interactions for asthma and plasma total IgE concentration in Chinese children. J Allergy Clin Immunol 117:127–133
Kim HB, Lee YC, Lee SY, et al. (2006) Gene-gene interaction between IL-13 and IL-13Ralpha1 is associated with total IgE in Korean children with atopic asthma. J Hum Genet 51:1055–1062
Barnes KC, Grant A, Gao P, et al. (2006) Polymorphisms in the novel gene acyloxyacyl hydroxylase (AOAH) are associated with asthma and associated phenotypes. J Allergy Clin Immunol 118:70–77
Borish L, Steinke JW (2004) Beyond transcription factors. Allergy Clin Immunol Int 16:20–27
Jenuwein T, Allis CD (2001) Translating the histone code. Science 293:1074–1080
Zheng W-P, Flavell RA (1997) The transcription factor GATA-3 is necessary and suffi cient for Th2 cytokine gene expression in CD4 T cells. Cell 89:587–596
Szabo SJ, Kim ST, Costa GL, et al. (2000) A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100:655–669
Steinke JW (2004) Anti-interleukin-4 therapy. Immunol Allergy Clin N Am 24:599–614
Farrar JD, Asnagli H, Murphy KM (2002) T helper subset development: roles of instruc tion, selection, and transcription. J Clin Invest 109:431–435
Lighvani AA, Frucht DM, Jankovic D, et al. (2001) T-bet is rapidly induced by inter-feron-gamma in lymphoid and myloid cells. Proc Natl Acad Sci USA 98:15137–15142
Fields PE, Kim ST, Flavell RA (2002) Changes in histone acetylation at the IL-4 and IFN-γ loci accompany Th1/Th2 differentiation. J Immunol 169:647–650.
Li YF, Langholz B, Salam MT, et al. (2005) Maternal and grandmaternal smoking pat terns are associated with early childhood asthma. Chest 127:1232–1241.
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Steinke, J.W. (2009). Genetics of Hypersensitivity. In: Pawankar, R., Holgate, S.T., Rosenwasser, L.J. (eds) Allergy Frontiers: Epigenetics, Allergens and Risk Factors. Allergy Frontiers, vol 1. Springer, Tokyo. https://doi.org/10.1007/978-4-431-72802-3_13
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