The genetics of asthma and allergic disease: a 21st century perspective

Abstract

Asthma and allergy are common conditions with complex etiologies involving both genetic and environmental contributions. Recent genome-wide association studies (GWAS) and meta-analyses of GWAS have begun to shed light on both common and distinct pathways that contribute to asthma and allergic diseases. Associations with variation in genes encoding the epithelial cell-derived cytokines, interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP), and the IL1RL1 gene encoding the IL-33 receptor, ST2, highlight the central roles for innate immune response pathways that promote the activation and differentiation of T-helper 2 cells in the pathogenesis of both asthma and allergic diseases. In contrast, variation at the 17q21 asthma locus, encoding the ORMDL3 and GSDML genes, is specifically associated with risk for childhood onset asthma. These and other genetic findings are providing a list of well-validated asthma and allergy susceptibility genes that are expanding our understanding of the common and unique biological pathways that are dysregulated in these related conditions. Ongoing studies will continue to broaden our understanding of asthma and allergy and unravel the mechanisms for the development of these complex traits.

Fig. 1. Genetic architecture of asthma and allergic diseases

Examples are shown for (A) Monogenic diseases with allergic phenotypes that are caused by highly penetrant rare (<1%) mutations. These disease genes can be discovered by linkage studies in families segregating the disease. (B) Complex diseases or phenotypes with low frequency (1-5%) risk alleles with intermediate effect sizes. The relative paucity of genes in his category reflects the limited ability for re-sequencing studies in the past. (C) Complex diseases and phenotypes with common disease risk alleles (>5%) with very low effect sizes and penetrances can be discovered by GWAS. Modified from references (179, 183).