Introduction:
DNA methylation (DNAm) is a dynamic epigenetic modification that refers
to the bonding of a methyl (CH3) group to the
5th carbon of a Cytosine base to form
5-methyl-Cytosine
(5mC)1. This process
primarily occurs at Cytosine-phosphate-Guanine (CpG)
dinucleotides2. DNAm is
altered by factors such as environmental exposures (e.g.
smoking3, pesticide
exposures4), disease
(including asthma5),
cell type6,
sex7 and
age2. As such, the study
of DNAm has great potential to help characterize the impact of
gene-environment interactions on the development of disease.
There is growing interest in considering aging as more than just the
passing of calendar years but, rather, as a life-long process beginning
at birth and influenced by an accumulation of environmental exposures
and disease. Consistent patterns of age-associated DNAm changes have
been
identified2,8-11,
resulting in the development of epigenetic
clocks12 that reflect
biological aging (e.g. susceptibility to disease, fragility and early
mortality). These ’clocks’ refer to mathematical algorithms that use
DNAm levels at select CpG sites to calculate epigenetic age
(EA)13. A variety of
disease
phenotypes14-18,
including asthma and
allergy19,20,
have demonstrated associations with epigenetic age acceleration (EAA),
where epigenetic age is different than chronological, or actual, age
(CA).
EAA captures biological aging which may be faster or slower than
calendar time. A key question is whether EAA is established during
childhood and impacts disease risk in later life. This aligns with the
Developmental Origins of Health and Disease
(DOHaD)21 hypothesis
that prenatal and early life exposures during the first 1000 days cause
DNAm changes that influence the likelihood of disease in later life.
This premise has led to a focus on the study of epigenetic aging in
relation to prenatal and childhood exposures (Fig.1A ). There is
evidence of differential methylation in cord blood due to in
utero exposures, including elevated maternal
BMI22, air
pollution23, and the
widely reported and replicated effects of maternal
smoking24(Table 1 ). In addition, maternal smoking has been linked to
increased EAA well into childhood (years
6-11)4.
Asthma is a complex phenotype influenced by genetic and environmental
factors, that demonstrates age and sex specific prevalence
patterns25. Childhood
asthmatics are predominately male (65%), while 65% of adult asthmatics
are female
(Fig.1B )25.
There are two main asthma subtypes – allergic and non-allergic.
Allergic asthmatics have an additional allergic disease (e.g., atopy or
eczema), whereas non-allergic asthmatics have asthma without additional
allergic disease. Understanding the relationship between EAA and
asthma26 may clarify
the mechanisms whereby early life exposures affect methylation and
disease susceptibility.