DNA methylation signature of interleukin 1 receptor type II in asthma
© Gagné-Ouellet et al. 2015
Received: 30 April 2015
Accepted: 13 July 2015
Published: 5 August 2015
Interleukin 1 and its receptors are associated with allergic diseases such as asthma. In the present study, we measured DNA methylation at the IL1R1 and IL1R2 gene loci and assessed for associations with asthma-related phenotypes and gene expressions. We found that asthmatic and atopic individuals have higher IL1R2 promoter DNA methylation than control subjects. Additionally, we observed a negative correlation between DNA methylation at the IL1R2 promoter and IL1R2 mRNA expression. These results suggest for the first time that IL1R2 promoter DNA methylation is associated with its gene repression in allergic diseases such as asthma.
KeywordsEpigenetics Methylation IL1 IL1R1 IL1R2 Asthma Atopy
Interleukin 1 (IL1) plays a key role in the inflammatory process of asthma . We reported the association of polymorphisms within the IL1 receptors type I (IL1R1) and type II (IL1R2) gene loci with asthma and atopy in the French Canadian Saguenay–Lac-Saint-Jean (SLSJ) asthma study [2, 3]. The IL1R2 gene expression signature in allergic asthma has also been described [4–6]. Epigenetics has received tremendous attention, and variations in DNA methylation (DNA-Me) in candidate genes have been reported associated with asthma and allergic related disorders [7–12]. These findings underline the relevance of genetic and epigenetic profiling to identify pathways associated with allergic diseases. Such a combined approach will facilitate the understanding of the functional impacts of genetic and epigenetic variations on transcription and molecular mechanisms involved in allergic diseases. In this study, we hypothesized that DNA-Me in the promoters of IL1R1 and IL1R2 is associated with asthma and/or atopy.
Clinical characteristics and methods
Clinical characteristics of individuals from the Saguenay–Lac-Saint-Jean asthma familial collection
All individuals (n = 93)
Controls (n = 25)
Asthmaticsa and/or atopicsb (n = 68)
Sex ratio (M:F)
Mean age, year (range)
<16 years old, n (%)
FEV1, % predicted (SD)c
PC20, mg/ml (SD)d
Serum IgE, μg/l (SD)e
Asthma, n (%)a
Atopy, n (%)b
With asthma, n (%)a
The association between IL1R1 and IL1R2 DNA-Me levels and asthma and/or atopy at each CpG was analyzed by logistic regression considering age and sex as covariates . Gene expression analysis by phenotype was not performed as control group sample size was insufficient (n = 4). The association between DNA-Me and mRNA levels was assessed by Spearman correlation. CpG dinucleotides with r > 0.6 were combined before they were tested for associations with asthma and/or atopy and for correlation with gene expressions. Δβ with p value < 0.05 was considered statistically significant. Statistical analyses were conducted using the statistical software SPSS (v11.5.0, IBM, USA).
Summary of DNA methylation analysis on promoter of two interleukin 1 receptors in whole blood samples from Saguenay–Lac-Saint-Jean asthma familial collection
IL1R1 promoter and exon 1
An epigenetic signature has also been identified for IL1R2 promoter in systemic lupus erythematosus (SLE) . The risk of allergic disorders was significantly increased in SLE patients, which suggests that these conditions share some common biomarkers . The negative correlation we observed between DNA-Me and gene expression levels for IL1R2 may be due to stoichiometry. Methylation may limit access of a transcription factor to DNA and hinders transcriptions . We identified potential binding sites for transcription factors relevant to asthma near the CpG dinucleotide sites of IL1R2 analyzed (Additional file 2: Figure S2) which could explain the inverse correlation between methylation and gene expression . Noteworthy is the potential binding site for nuclear factor kappa B/c-rel (NFKB) at the IL1R2 promoter; it is involved in inflammation through several pathways, including IL1 signalization . Given that IL1R2 acts as a decoy receptor to antagonize the bound ligand , our data prompted the speculation that hypermethylation of IL1R2 in asthma and atopy negatively regulates IL1R2 expression and less decoy receptors are available to reduce the downstream pro-inflammatory response of IL1 in the presence of unchanged IL1R1 level [22, 23]. Unlike IL1R1, IL1R2 does not have an intracellular domain and the formation of IL1-IL1R2 complex inactivates the IL1 downstream signaling cascade; hence, silences the role of IL1 in inflammation. Functional study will be needed to investigate the impact of observed epi-variations on the production of expressed receptors. This hypothesis could be attributed to both asthma and atopy as IL1R2 non-signaling receptor is suspected to influence Th2 imbalance , and both disorders are driven by Th2 allergic lung inflammation [25, 26].
To our knowledge, this is the first report of (1) a hypermethylation signature of IL1R2 promoter in asthma with or without atopy and (2) an inverse correlation between methylation at IL1R2 promoter and its gene expression. Together, they underline the relevance of IL1R2 as a potential biomarker of asthma and atopy. Further work is needed to understand the interactions between environmental exposures and epigenetic modifications like the ones identified in this study. Such understanding will aid the discovery of disease mechanisms associated and development of more effective therapies.
interleukin 1 receptor type 1
interleukin 1 receptor type 2
ribosomal protein, large, P0
systemic lupus erythematosus
- Δβ :
difference of methylation
The authors thank all families for their valuable participation. This study was supported by the Canadian Institutes of Health Research (CIHR) Catalyst Grant: Environments, Genes, and Chronic Disease. Catherine Laprise is the chairholder of the Canada Research Chair in Environment and Genetics of Respiratory Disorders and Allergy and Director of the Asthma Strategic Group of the Respiratory Health Network (RHN) of Fonds de recherche du Québec—Santé (FRQS) and researcher of the AllerGen NCE. Valérie Gagné-Ouellet received a Summer Student Research Training Award from the AllerGen NCE Inc. and a master degree studentship award from the RHN. Anne-Marie Boucher-Lafleur received a Summer Student Research Training Award from the AllerGen NCE Inc. Simon-Pierre Guay is the recipient of a Doctoral Research Award from the CIHR. Luigi Bouchard is a Junior Research Scholar from the FRQS and member of the FRQS-funded Centre de recherche clinique Étienne-Le Bel (affiliated with Centre hospitalier de l’Université de Sherbrooke).
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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