Host defense genes in asthma and sepsis and the role of the environment

Abstract

There is growing evidence that innate immunity genes contribute to asthma pathogenesis. At the core of the innate immune response are ubiquitous, soluble fragments of bacterial lipopolysaccharide or endotoxin, and chronic exposure to domestic endotoxin has been shown to influence asthma severity. Asthmatic and atopic individuals are more sensitive to endotoxin than nonallergic individuals, suggesting a role for genetics in the innate immunity response, and the potential for gene-environment interactions. Variants in genes associated with classic innate immunity-related disorders, such as sepsis, may be unique candidates for asthma susceptibility. Candidate genes for asthma and allergic diseases co-associated with sepsis including innate immunity receptors and related molecules (CD14, TLR4 and AOAH) and novel genes such as MYLK provide good examples of pleitropic effects of innate immunity genes, where variants conferring risk to specific traits (i.e. sepsis) under one set of genetic and environmental circumstances confer a reduced risk in a different (but possibly related) clinical outcome (i.e. allergic asthma), and support the 'common variant/multiple disease' hypothesis. Collectively, these observations suggest a greater role for the innate immunity response in allergic asthma than previously assumed, and implicate host defense genes in disease pathology.