Genome-wide association studies (GWASs) have uncovered more than 40 susceptibility genes for the allergic skin condition atopic eczema (also known as atopic dermatitis) and for allergic asthma (Fig. 14.6). Some of the susceptibility genes are common to both atopic eczema and allergic asthma, suggesting that some aspects of the atopic diathesis (that is, predisposition) are governed by similar genetic factors regardless of the organs that are the targets of the allergic response. For example, specific alleles at the IL-33 receptor and IL-13 loci show strong association with both allergic asthma and atopic eczema. This sharing of genetic risk alleles by allergic asthma and atopic eczema is consistent with the finding that these two disorders are commonly found together in atopic families, with some family members manifesting both disorders, while other family members may manifest only atopic eczema or allergic asthma, but not both. There are, however, alleles of many genes (especially genes that regulate skin-barrier function) that show linkage to atopic eczema without enhancing the risk for allergic asthma or allergic rhinoconjunctivitis, indicating that other genetic factors contribute importantly to the phenotype of allergic responsiveness any individual may express. In addition, there are many ethnic differences in the susceptibility genes for a given allergic disease. Several of the chromosome regions associated with allergy or asthma are also associated with the inflammatory disease psoriasis and with autoimmune diseases, suggesting that these loci contain genes that are involved in exacerbating inflammation.
One candidate susceptibility gene for both allergic asthma and atopic eczema resides at chromosome 11q12–13 and encodes the β subunit of the high-affinity IgE receptor FcεRI. Another region of the genome associated with allergic disease, 5q31–33, contains at least four types of candidate genes that might be responsible for increased susceptibility. First, there is a cluster of tightly linked genes for cytokines that enhance IgE class switching, eosinophil
Fig. 14.6 Susceptibility loci for asthma. Loci that have shown linkage on the basis of GWAS or targeted gene analysis are listed, separated into genes that are expressed in epithelial cells of the airways, genes that regulate the differentiation and/or function of CD4 T cells and ILC2s, and genes with other miscellaneous or unknown functions.
survival, and mast-cell proliferation, all of which help to produce and maintain an IgE-mediated allergic response. This cluster includes the genes for IL-3, IL-4, IL-5, IL-9, IL-13, and granulocyte–macrophage colony-stimulating factor (GM-CSF). In particular, genetic variation in the promoter region of the gene encoding IL-4 has been associated with raised IgE levels in atopic individuals. The variant promoter directs increased expression of a reporter gene in experimental systems and thus might produce increased IL-4 in vivo. Atopy has also been associated with a gain-of-function mutation of the α subunit of the IL-4 receptor, with the mutation causing increased signaling after ligation of the receptor.