Perinatal Epigenetic Programming of the Development or Sparing of Childhood Asthma

Asthma prevalence is increasing worldwide, especially is children. There are 5 to 25 % of children having asthma in different countries. It is no exception in Taiwan that prevalence of childhood asthma has increased 9 times from 1.3% in 1970s to the current 10-14%. This poses a significant public health problem, and highlights the need for better understanding of the molecular and genetic basis for prevention of the disease. Evidence accumulated has demonstrated that many genes in different chromosomes are implicated in childhood asthma in different populations. Recent epidemiological studies, including ours, have indicated the importance of gene-environment interactions on the development of allergy sensitization. In particular, our recent analysis of a large perinatal cohort population with 1211 pregnant women and their offspring has provided evidence that prenatal IgE production reflected on umbilical cord blood IgE (CBIgE) elevation and infant eczema were significantly associated with gene-gender and gene-maternal interactions, suggesting that asthma is not a pure genetic disease, but is significantly affected by gene-environment interactions as early in perinatal stage. However, the mechanism by which the parental and environmental factors influence the development of childhood asthma is unclear. As progress in genomic studies of human diseases, it is known that gene expression is not totally dependent of genetic sequences. Different genes in different developmental stages varied its expression by epigenetic modification with methylation at CpG islands under influence of environmental factors, especially during perinatal stage. It is of significance to note that antenatal epigenetic program has often been implicated in the development of several complex diseases, including metabolic syndrome and hypertension. Interestingly, recent reports suggested that the induction of allergy-related T helper 2 (Th2) cytokines, such as IL-4 and IL-13, is vulnerable to epigenetic control, although its relevance to the genesis of allergic diseases is, at present, unclear. We hypothesize that antenatal epigenetic programming of the IL-4/IL-13 loci and/or other allergy-associated genes occurs in utero and proceeds transiently or persistently into childhood for the development or sparing of childhood asthma. Using our cohort population, we intend to prove this hypothesis through a series of experimental designs to investigate the epigenetic programming of allergy-associated genes and its functional involvement in childhood asthma. In the current proposal, we will pursue the following specific aims: 1) To explore if epigenetic programming in a panel of allergy-associated gene(s) occurs in utero and is related to genetic (paternal or maternal) imprint or the effect of selective environmental factors, as well as to examine their impact on the levels of cord blood IgE (CBIgE). 2) To investigate whether the antenatal epigenetic program of allergy-associated genes can proceed into childhood and correlate to perinatal allergy sensitization with elevated total and specific IgE levels. 3) To examine if a dynamic (persistent or transient) epigenetic programming of allergy genes (e.g. IL-13 & FoxP3) and environment-sensitive genes (e.g. redox genes) is involved in the development or sparing of childhood asthma. This will be confirmed by a functional epigenetic study showing a decrease in allergy reaction by erasing epigenetic program in asthmatic children. We anticipate that fetuses are susceptible to antenatal epigenetic program of allergy-associated genes associated with elevated CBIgE levels, and that a persistent, but not transient, perinatal epigenetic program in allergy-associated genes and redox status contributes to the development of childhood asthma. It is hoped that this study will be the first study in the literature to prove the epigenetic mechanisms in the genesis of childhood asthma. We also hope that, in the future, early prevention of allergy and asthma may be made possible by screening and/or erasing perinatal epigenetic control of allergy-associated genes. This study thus will be informative in the design of further studies in asthma and other complex diseases, with an aim being to define the prenatal or perinatal epigenetic programming and offer a rational design for prophylactic and therapeutic strategies.

Project ID:PA9706-1121
External Project ID:NSC97-3112-B182-006