Role of DNA Methylation in mediating the environmental and genetic effects in asthma

Abstract

Genetics and environmental exposures at critical developmental windows, play an important role in the development of asthma. Genetically, asthma is a complex trait with known genes only explaining part of the heritability. Mechanisms by which environmental exposures lead to development of asthma are not clearly understood. Epigenetic marks, particularly DNA methylation can be influenced by both environmental exposures and genotype, thus may play a role in mediating the effects of genes and environment in asthma.
In 1989, the Isle of Wight Birth Cohort (IOWBC) was established to study the risk factors for the development of asthma and allergy. In this cohort, prenatal smoking exposure, IL13 SNPs (single-nucleotide-polymorphism) and methylation were seen to interact in a two-step analysis; methylation at cg13566430 was influenced by interaction of maternal smoking during pregnancy and rs20541, in stage-2, genotype at rs1800925 interacted with methylation at cg13566430 significantly affecting airflow limitation and reactivity. Interaction of DNA Methylation at cg09791102 and rs3024685 in the IL4R influence the risk of asthma.
A multigenerational cohort was established by recruiting children of the IOWBC into the Third Generation Study with a focus on transgenerational epigenetics of asthma. An intergenerational effect of prenatal smoking exposure was seen; combined maternal and grandmaternal smoking during pregnancy was significantly associated with infant wheeze in grandchildren and methylation at cg04180046 (MYO1G) and cg05575921 (AHRR). An Epigenome-wide association study (EWAS) of cord blood DNA methylation in third generation showed differential methylation at 5 CpG sites (False-discovery-rate <0.1) in relation to maternal asthma. Pathway analysis using the top 100 sites from the EWAS showed possible enrichment of T cell differentiation and activation pathways.
Findings from the thesis provide support to the concept of role of DNA methylation in mediating genetic and environmental effects in asthma and the Third Generation Study will provide valuable information for future studies in the field.

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