Applications of the First-Generation Epigenetic Clocks to Asthma
and Allergic Disease Research
The asthma phenotype, and in particular, allergic asthma, presents a
test case for the utility of the epigenetic clock in studying prenatal
and childhood traits and exposures over the lifespan. Asthma often
begins in the early years and may be transient. The clinical
presentation is heterogeneous, especially in early childhood, making
timely diagnosis
difficult19. Wheeze in
young children may resolve without intervention or may persist and
transition into asthma. In addition, there is an unexplained switch in
the sex-specific prevalence of asthma between childhood and
adolescence25.
According to the atopic march
theory78, asthma and
allergic diseases begin in infancy, with the first presenting symptoms
being eczema/atopic dermatitis, progressing to infant food allergies,
then asthma and allergic rhinitis. The atopic march is thought to be
initiated by environmental exposures, and it has been proposed that the
impact of environmental exposures may be reflected in DNAm, explaining
the heterogeneity of
asthma19,20.
Genetic variants have been shown to account for ~61-75%
of susceptibility to
asthma79,80. Numerous
genome-wide association studies have demonstrated associations between
the HLA region and asthma and allergic disease. The remaining
~25-40% of the risk is thought to be due to
environmental factors. Epigenome Wide Association Studies (EWAS) have
repeatedly implicated DNAm in both childhood and adult
asthma5,81,82.
One exposure of particular interest is viral infection, which may have
either a punitive or protective effect, depending upon the age when
infected and viral subtype. Infection may skew the immune response
towards the Th2 pattern observed in
allergy50,83,84.
For example, infection with the respiratory syncytial virus (RSV) in
infancy is associated with increased risk for asthma, and this effect
appears to be mediated through changes in
DNAm83-85. Differential
methylation at three CpG sites, mapped to airway and immune response
genes, can separate (with area under the curve (AUC) =1) children who
will develop recurrent wheeze and asthma subsequent to an RSV infection
from those who recover
normally85.
The few available studies show a positive association between allergy
and asthma and
EAA19,20.
Peng et al. found that EEAA was linked to asthma and allergic
disease (i.e. atopy, food allergy) in Project Viva – a longitudinal
birth cohort which included 408 mother-child pairs with blood DNAm data
at mid-childhood (mean age: 7.8 years, range: 6.7-10.2
years)19. Epigenetic
age as predicted by the pan-tissue Horvath clock and IEAA have also been
associated with allergic
disease19: the Peng
study found a 1.21 increase in the odds of developing atopic disease and
food allergy and 1.16 increase in the odds for asthma at mid-childhood
for every one year increase in
EA19. These results
were independently replicated. A study examining DNAm of nasal
epithelium cells of 547 Project Viva participants (mean age=12.9,
range:11.9-15.3 years) showed increased EAA in children with asthma
(0.74 years) and allergic asthma (1.30 years)20.
The epigenetic clock may provide a greater understanding of the
sex-specific asthma prevalence between childhood and adulthood25,86.
It is believed that hormonal fluctuations during puberty, menstruation,
pregnancy and menopause are associated with asthma pathogenesis,
exacerbations and disease
severity25(Fig.1B&C ). Sex hormones are key to determining immune
response87; thus, an
epigenetic clock that captures early development and puberty may be
crucial to understanding the relationship between EAA and asthma
(Fig. 1C ). EAA has been shown to be affected by biological sex
with males having higher acceleration rates compared to
females77. This pattern
is seen at mid-childhood (~year 7) with persistence into
adolescence (~year 17) and
adulthood61.
A study by Patel et al. identified 13 CpG sites with sex-specific
methylation that were associated with the acquisition of asthma between
the ages of 10 and
1888. Ten of these
sites were replicated in an independent cohort. Epigenetic clocks may
unravel the relationships between DNAm, asthma and sex, and how they are
associated with the mechanisms of sex-reversal in asthma prevalence.