Genetics of allergic disease John W. Holloway, PhD, Ian A. Yang, MBBS, PhD, Stephen T. Holgate, MD, DSc, FMed Sci  Journal of Allergy and Clinical Immunology  Volume 125, Issue 2, Pages S81-S94 (February 2010) DOI: 10.1016/j.jaci.2009.10.071 Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Susceptibility genes for allergic disease. Group 1: sensing the environment. The group of genes encodes molecules that directly modulate the effect of environmental risk factors for allergic disease. For example, genes such as TLR2, TLR4, and CD14, encoding components of the innate immune system, interact with levels of microbial exposure to alter the risk of allergic immune responses.71 Polymorphisms of glutathione-S-transferase genes (GSTM1, GSTM2, GSTM3, GSTM5, GSTT1, and GSTP172,73) have been shown to modulate the effect of exposures involving oxidant stress, such as tobacco smoke and air pollution on asthma susceptibility. Group 2: barrier function. A high proportion of the novel genes identified for susceptibility to allergic disease through genome-wide linkage and association approaches have been shown to be expressed in the epithelium. This includes genes such as FLG,70 which directly affects dermal barrier function and is associated not only with increased risk of atopic dermatitis but also with increased atopic sensitization. Other susceptibility genes, such as ORMDL3/GSDML,34 PCDH1,24 and C11orf30,44 are also expressed in the epithelium and might have a role in possibly regulating epithelial barrier function. Group 3: regulation of (atopic) inflammation. This group includes genes that regulate TH1/TH2 differentiation and effector function (eg, IL13, IL4RA, and STAT674; TBX21 [encoding T-box transcription factor]75; and GATA376), as well as genes such as IRAKM,77 PHF11,21 and UPAR23 that potentially regulate both atopic sensitization and the level inflammation that occurs at the end-organ location for allergic disease. This also includes the genes shown to regulate the level of blood eosinophilia (IL1RL1, IL33, MYB, and WDR36).41 Group 4: tissue response genes. This group includes genes that modulate the consequences of chronic inflammation (eg, airway remodeling), such as ADAM3317 and PDE4D,39 which are expressed in fibroblasts and smooth muscle, and COL29A1,25 encoding a novel collagen expressed in the skin linked to atopic dermatitis. Some genes can affect more than 1 disease component. For example, IL13 regulates both atopic sensitization through IgE isotype switching but also has direct effects on the airway epithelium and mesenchyme, promoting goblet cell metaplasia and fibroblast proliferation.14 Adapted with permission from Rose-Zerilli MJ, Davis SA, Holgate ST, Holloway JW. The genetics of allergic disease and asthma. In: Leung DYM, Sampson H, Geha R, Szefler SJ, editors. Pediatric allergy: principles and practice. 2nd ed. St Louis: Mosby; 2009. Journal of Allergy and Clinical Immunology 2010 125, S81-S94DOI: (10.1016/j.jaci.2009.10.071) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions