CD14, endotoxin, and asthma risk: actions and interactions

Abstract

A functional single nucleotide polymorphism in the 5 genomic region of CD14 (CD14/-159) is one of the most widely tested genetic variations in relation to asthma and associated traits. The results of these studies have shown a remarkable, statistically significant heterogeneity, with some studies indicating the T-allele as a risk factor, others the C-allele, and others finding no association. Recent studies in which exposure to house-dust endotoxin or to domestic sources of microbial exposure were assessed concomitantly with CD14/-159 have shown a consistent, replicable gene-environment interaction. Specifically, results suggest that the C-allele is a risk factor for allergic phenotypes at low levels of exposure, whereas the T-allele is a risk factor at high levels of exposure. This finding seems to be explained by a genetically-determined heterogeneity for the protective effect of microbial exposure on allergic phenotypes, with homozygotes for the C-allele showing a much stronger negative association between exposure and allergic outcomes than carries of the other two genotypes. These results suggest that the often encountered, limited replicability of genetic associations may, at least in part, be due to complex interactions between genes and environment in determining asthma-related outcomes.

Figure 1.

Association between serum specific IgE against aeroallergens and CD14/−159 by exposure to endotoxin in house dust in the ALEX study (26). Sensitization was strongly and inversely associated with exposure among CC homozygotes (dark blue columns), whereas the association was much weaker among carriers of the other two genotypes (lighter blue columns). As a result, TT homozygotes were at risk for sensitization, as compared with the other two genotypes, whereas opposite (albeit not significant) trends were observed at lower levels of exposure. Reprinted by permission from Reference 26.

Figure 2.

Antagonistic interaction between house-dust endotoxin exposure and CD14/−159 genotypes as determinants of allergic sensitization in children enrolled in the Manchester Asthma and Allergy Study (28). As in Figure 1, the inverse relation between exposure and sensitization was strongest in CC homozygotes and less pronounced in the other two genotypes. Reprinted by permission from Reference 28.

Figure 3.

Association between total serum IgE and dust endotoxin exposure by CD14/−159 in adult participants in a Detroit cohort study (29). Gene–environment interactions are very similar to those described in Figures 1 and 2. Reprinted by permission from Reference 29.

Figure 4.

Schematic representation of the single nucleotide polymorphisms identified in the Innate Immunity Program for Genomic Applications (PGA) database (http://innateimmunity.net). The SNPs that tag for the four most frequent SNP bins among subjects of European origin are also included. Reprinted by permission from Reference .