Genetic and environmental interaction in allergy and asthma

Abstract

Asthma is an inflammatory disorder of the airways involving coordinate up-regulation of T(H)2-type cytokines encoded in a cluster on chromosome 5q(31-33) on T cells and inflammatory cells. There is also a requirement for local airway susceptibility factors that, together with T(H)2 polarization, results in hyperresponsiveness, variable airflow obstruction, and, over time, remodeling of the airway wall. Asthma has strong genetic and environmental components that interact both in the induction and subsequent expression of the disease phenotypes. Multiple genes are involved and probably interact. Whole genome screens are beginning to identify gene-rich regions of special relevance to asthma and atopy, although a novel disease-related gene has yet to be discovered from these. By contrast, there are a plethora of candidate genes whose function in relation to disease pathophysiologic mechanisms and response to treatment are known. Two examples are polymorphisms involving IL-4 receptors and the enzymes controlling cysteinyl leukotriene production. Abnormal signaling between the epithelium, which is in contact with the environment, and the underlying (myo)fibroblasts and dendritic cells indicating reactivation of the epithelial mesenchymal trophic unit, which is involved in fetal lung development and branching, provide a basis for asthma that encapsulates both T(H)2 polarization and airway wall remodeling.

Fig. 1

Eigenvector plot shows relationship between various clinical phenotypes and the summated scores for asthma and atopy derived by principal-component regression analysis.

Fig. 2

Different approaches to identify susceptibility genes: random genome search with microsatellite markers (upper), microsatellite markers close to a known gene (lower left), and mutation analysis of known gene or its promoter (lower right).

Fig. 3

IL-4 activates a number of signaling pathways, including signal transduction and activators of transcription (STAT) 6 and IRS (insulin receptor substrate) 1 through IL-4 receptor (IL-4R). IL-4R is composed of α chain (IL-4Rα) and γ (γc) α chain; however, other forms do exist because of formation of heterogeneous structures with a component of α γ chain, which is shared with the IL-2r IL-13 receptor (IL-13α₁) Signal transduction through IL-4R is thought to involve activation of IRS1/2 and STAT6, which leads to cell proliferation and activation of gene transcription. A number of polymorphisms have been identified within the IL-4Rα gene and several of these result in amino acid coding changes. Several of these polymorphisms have been shown to have effects on IL4 signal transduction. However, the precise effects of each polymorphism and combinations of these polymorphisms are still unclear.