Early-life exposure to sibling modifies the relationship between CD14 polymorphisms and allergic sensitization.
Lau MYZ., Dharmage SC., Burgess JA., Win AK., Lowe AJ., Lodge CJ., Perret J., Hui J., Thomas PS., Giles G., Thompson BR., Abramson MJ., Walters EH., Matheson MC., investigators of the TAHS and MACS None.
BACKGROUND: Markers of microbial exposure are thought to be associated with risk of allergic sensitization; however, the associations are inconsistent and may be related to gene-environment interactions. OBJECTIVE: To examine the relationship between polymorphisms in the CD14 gene and allergic sensitization and whether sibling exposure, as a marker of microbial exposure, modified this relationship. METHODS: We used data from the Tasmanian Longitudinal Health Study and the Melbourne Atopy Cohort Study. Two CD14 polymorphisms were genotyped. Allergic sensitization was defined by a positive response to a skin prick test. Sibling exposure was measured as cumulative exposure to siblings before age 6 months, 2 and 4 years. Logistic regression and multi-level mixed-effects logistic regression were used to examine the associations. Effect estimates across the cohorts were pooled using random-effects meta-analysis. RESULTS: CD14 SNPs were not individually associated with allergic sensitization in either cohort. In TAHS, cumulative sibling exposure before age 6 months, 2 and 4 years was each associated with a reduced risk of allergic sensitization at age 45 years. A similar effect was observed in MACS. Meta-analysis across the two cohorts showed consistent evidence of an interaction between cumulative sibling exposure before 6 months and the rs5744455-SNP (P = 0.001) but not with the rs2569190-SNP (P = 0.60). The pooled meta-analysis showed that the odds of sensitization with increasing cumulative exposure to sibling before 6 months of age was 20.9% smaller in those with the rs5744455-C-allele than the T-allele (OR = 0.83 vs 1.05, respectively). CONCLUSION AND CLINICAL RELEVANCE: Cumulative sibling exposure reduced the risk of sensitization from childhood to middle age in genetically susceptible individuals.