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.