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Endotoxin Exposure, CD14, and Allergic Disease

An Interaction between Genes and the Environment

Academic Division of Medicine and Surgery South, North West Lung Centre, Wythenshawe Hospital; and Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, United Kingdom

Correspondence and requests for reprints should be addressed to Adnan Custovic, M.D., Ph.D., North West Lung Centre, Wythenshawe Hospital, Manchester M23 9LT, UK. E-mail: adnan.custovic{at}manchester.ac.uk

Rationale: High endotoxin exposure may reduce the risk of allergic sensitization.

Objective: To determine the relationship between a promoter polymorphism in the CD14 gene (CD14/–159 C to T) and endotoxin exposure in relation to the development of allergic sensitization, eczema, and wheeze within the setting of a birth cohort.

Methods: We genotyped 442 children (CD14/–159 C to T; rs2569190). We assessed children for allergic sensitization (IgE > 0.2 kU/L to at least one of seven allergens), eczema (physical examination), and parentally reported wheeze. Endotoxin was measured in house dust.

Main Results: Genotype frequencies were consistent with other populations (TT, 25%; CT, 47%; CC, 28%). Sensitization (present in 33% of children) was not associated with genotype. For children with TT and CT genotypes, there was no association between endotoxin and sensitization (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.71–1.23; p = 0.7; and OR, 0.90; 95% CI, 0.77–1.04; p = 0.16, respectively) or endotoxin and eczema (OR, 0.99; 95% CI, 0.81–1.20; p = 0.89; and OR, 1.38; 95% CI, 0.83–2.30; p = 0.22, respectively). In children with the genotype CC, increasing endotoxin load was associated with a marked and significant reduction in the risk of sensitization (OR, 0.70; 95% CI, 0.55–0.89; p = 0.004) and eczema (OR, 0.73; 95% CI, 0.56–0.95; p = 0.02). However, we observed an increased risk of nonatopic wheeze with increasing endotoxin exposure in children with the CC genotype (OR, 1.42; 95% CI, 1.01–1.99; p = 0.04) but not other genotypes. No effect was seen for atopic wheeze.

Conclusions: Increasing endotoxin exposure is associated with reduced risk of allergic sensitization and eczema but with increased risk of nonatopic wheeze in children with the CC genotype at –159 of the CD14 gene. The impact of environmental endotoxin may be enhanced in individuals with this genotype.

Key Words: allergy • asthma • genetics