Introduction
Asthma is a chronic airway disorder that affects more than 300 million
people around the world. Asthma cannot be completely cured with the
available treatment up to now. However, some asthma patients may grow
out of this disease, which is called asthma remission.
The remission rate of asthma varies from 35% to 60% according to
different studies, and asthma remission is more common in patients with
childhood onset asthma1. There are two types of asthma
remission, one is defined by absence of asthma symptoms and medication
for at least one year, which is called “clinical remission” (ClinR).
Some ClinR subjects may still have airway hyperresponsiveness (AHR) or a
low lung function. Therefore, “complete remission” (ComR) was put
forward 2. In addition to criteria of ClinR, ComR has
to meet additional criteria of normal lung function and absence of AHR.
This is a more rare phenomenon, that takes place in 5%-22% of
asthmatics3.
Asthma remission is associated with both genetic and environmental
factors. Environmental factors including breast feeding and having pets
in childhood were reported to be positively associated with asthma
remission4. A recent genome-wide association study
(GWAS) identified one SNP (single nucleotide polymorphism) that was
associated with ClinR and three SNPs with ComR. One of these SNPs was
also associated with expression of known asthma genes includingILRL1 and IL13 in lung tissue5.
Epigenetic mechanisms such as DNA methylation may help to build a link
between genetic factors and the environment. DNA methylation can be
regulated by SNPs, and can reflect environmental exposures, ageing, cell
type constitution and activation6. DNA methylation
refers to the addition of a methyl-group to cytosine, resulting in a CpG
site, which may relate to the regulation of gene
expression7. Epigenome-wide association studies (EWAS)
have provided insights into the development of asthma and its remission.
CpG sites associated with asthma in both blood and nasal epithelial
cells have been identified, such as CpG sites located in DICER1,
STX3, and LIPIN1 in blood cells, and CDHR3, FBXL7 andNTRK1 in nasal epithelial cells8,9. Vermeulenet al. identified 4 CpG sites and 42 regions that were
differentially methylated between remission and persistent asthma
(PersA) in bronchial biopsies, and top CpG sites were annotated to genes
including ACKR2 and DGKQ by gene
expression10.
Although this latter paper provided a proof of concept of the relation
between asthma remission and DNA methylation, bronchial biopsies are not
easy to obtain for further studies. DNA methylation in whole blood and
nasal epithelium is a good proxy for bronchial epithelium and can
therefore also help to understand the mechanism of asthma remission.
Here, we hypothesize that epigenetic mechanisms may be involved in
asthma remission, reflected in different DNA methylation patterns in
whole blood and nasal epithelium. To test this hypothesis, we performed
an EWAS of whole blood and nasal DNA in subjects with PersA, ClinR and
ComR. We investigated a longitudinal cohort in which asthma was
initially carefully defined and the remission status was assessed during
follow-up (median 39 years). We subsequently replicated the whole blood
DNA results in two independent cohorts, and also verified the top
results from whole blood DNA in cells obtained by nasal brushing.