Interaction of genetic and environmental factors in childhood asthma and allergy

Sammanfattning: Asthma and allergy are the most common chronic childhood diseases. Their occurrences are influenced by both genetic and environmental factors, although the underlying mechanisms are not fully understood. The overall aim of this thesis was to study the role of genetic polymorphisms and epigenetic alterations in interaction with environmental factors related to childhood respiratory and allergic disease. Epidemiological data from the Swedish prospective birth cohort BAMSE and other European and North American cohorts were analyzed, in addition to material from functional studies and bioinformatics resources. Study I included 14,495 children from five European and one North American birth cohorts. Early mold exposure at home was associated with increased risk of early wheezing and childhood nasal symptoms. Effect modification by the functional GSTP1 single nucleotide polymorphism (SNP) Ile105Val could not be confirmed. However, stratification by genotype revealed statistically significant associations between mold exposure and childhood nasal symptoms confined to Ile/Ile carriers. The previously identified asthma-associated gene NPSR1 was investigated in Study II. Differential DNA methylation in the NPSR1 promoter region was associated with adult severe asthma (CpG site 5) (n=171), and childhood allergic asthma (CpG sites 1 and 4) (n=546) but not with non-allergic asthma. Current and former smoking in adults was associated with increased DNA methylation (CpG sites 1 and 8) as compared with never- smoking. The season of blood sampling was associated with differential methylation at CpG site 5, whereas no such associations were seen for season of birth. Study III aimed to identify genetic regions of importance in the association between traffic air pollution exposure (NO2) and childhood asthma, with further functional analyses of identified loci. A genome-wide interaction study (GWIS) in 1,534 children from three European birth cohorts, with look-up of SNPs with interaction p < 1x10-4 in two North American cohorts (n = 1,602 and 186, respectively), revealed significant interaction for eight SNPs in four different loci. Two of the identified genes, ADCY2 and DLG2, have previously been associated with lung function and COPD. Functional follow-up showed an inverse association between NO2 exposure at birth and DNA methylation in one CpG site of DLG2 in 8-year-olds. Short-term diesel exposure in adults revealed inverse associations with DLG2 DNA methylation in eight additional CpG sites and positive associations in two CpG sites. One of the SNPs identified in the look-up evaluation, rs686237, was found to strongly influence B4GALT5 expression in adult lung tissue. Interaction between rs686237 and NO2 exposure at birth in relation to B4GALT5 gene expression was detected in blood from 16- year-olds. Associations between dietary antioxidant intake and development of asthma and allergic disease were investigated in 2,359 children in Study IV. An inverse association was identified for new onset sensitization to inhalant allergens between 8 and 16 years of age. The association was stronger among children exposed to low levels of current traffic air pollution (NOx), with a significant interaction between antioxidant intake and current NOx. In conclusion, the results in this thesis imply that genetic variants can influence associations between environmental exposures, such as mold and traffic air pollution, and asthma and allergic disease. Interactions between environmental factors may also influence disease development. Further, there seems to be a link between environmental exposures and epigenetic as well as transcriptomic events, which warrant further investiogations.

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