Early-life exposure to sibling modifies the relationship between CD14 polymorphisms and allergic sensitization.

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.

The interaction between farming/rural environment and TLR2, TLR4, TLR6 and CD14 genetic polymorphisms in relation to early- and late-onset asthma.

Asthma phenotypes based on age-of-onset may be differently influenced by the interaction between variation in toll-like receptor (TLR)/CD14 genes and environmental microbes. We examined the associations between single-nucleotide polymorphisms (SNP) in the TLR/CD14 genes and asthma, and their interaction with proxies of microbial exposure (childhood farm exposure and childhood rural environment). Ten SNPs in four genes (TLR2, TLR4, TLR6, CD14) were genotyped for 1,116 participants from the Tasmanian Longitudinal Health Study (TAHS). Using prospectively collected information, asthma was classified as never, early- (before 13 years) or late-onset (after 13 years). Information on childhood farm exposure/childhood rural environment was collected at baseline. Those with early-onset asthma were more likely to be males, had a family history of allergy and a personal history of childhood atopy. We found significant interaction between TLR6 SNPs and childhood farm exposure. For those with childhood farm exposure, carriers of the TLR6-rs1039559 T-allele (p-interaction = 0.009) and TLR6-rs5743810 C-allele (p-interaction = 0.02) were associated with lower risk of early-onset asthma. We suggest the findings to be interpreted as hypothesis-generating as the interaction effect did not withstand correction for multiple testing. In this large, population-based longitudinal study, we found that the risk of early- and late-onset asthma is differently influenced by the interaction between childhood farming exposure and genetic variations.

Hormonal contraception increases risk of asthma among obese but decreases it among nonobese subjects: a prospective, population-based cohort study.

Epidemiological data on asthma suggest a sex difference that varies with age. Hormonal effects have been suggested as a possible explanation for these differences but there is a scarcity of evidence on these relationships. Our objective was to examine the relationship between reproductive factors and asthma risk among females and to examine whether body mass index (BMI) modifies this relationship. Female participants in the 2004 fifth decade follow-up postal survey of the Tasmanian Longitudinal Health Study formed the study population. Reproductive history and data on hormonal contraceptive (HC) use were collected on 2764 females. Multiple logistic regression was used to assess the association between the reproductive factors and current asthma. The mean age of participants was 43 years and the prevalence of middle-aged current asthma was 12.8%. Females with very early menarche (≤10 years) had higher odds of middle-aged current asthma (OR 1.91, 95% CI 1.14-3.2). Pregnancy history (number of births and age at first pregnancy) were not associated with current asthma risk at 44 years. Ever having used HCs, years of use and age started using HCs were not individually associated with current asthma risk. However, body mass index significantly modified the relationship between HC use and asthma. We found increasing years of pill use was associated with a significantly increased risk of current asthma in overweight/obese women but a reduced risk in normal weight women (interaction p=0.015). Hormonal effects from use of HCs and early menarche may contribute to the sex differential in asthma risk. Our findings suggest that in obese women with a history of long-term HC use may be at an increased risk of chronic respiratory disease, and regular monitoring for asthma and asthma symptoms may be recommended.