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The interaction of genetic variants and DNA methylation of the interleukin-4 receptor gene increase the risk of asthma at age 18 years

Nelís Soto-Ramírez1, Syed Hasan Arshad26, John W Holloway23, Hongmei Zhang1, Eric Schauberger4, Susan Ewart5, Veeresh Patil26 and Wilfried Karmaus1*

Author Affiliations

1 Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, 800 Sumter Street, Columbia, SC, 29208, USA

2 Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Road, Southampton, SO17 1BJ, UK

3 Human Development and Health, Faculty of Medicine, University of Southampton, University Road, Southampton, SO17 1BJ, UK

4 Department of Pediatrics, Medical College of Wisconsin, 8701 W Watertown Plank Road, Milwaukee, WI, 53226, USA

5 Department of Large Animal Clinical Sciences, Michigan State University, 3700 East Gull Lake Drive, East Lansing, MI, 48824, USA

6 The David Hide Asthma and Allergy Research Centre, St Mary’s, Hospital, Parkhurst Road, Newport, Isle of Wight, PO30 5TG, UK

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Clinical Epigenetics 2013, 5:1  doi:10.1186/1868-7083-5-1

Published: 3 January 2013



The occurrence of asthma is weakly explained by known genetic variants. Epigenetic marks, DNA methylation (DNA-M) in particular, are considered to add to the explanation of asthma. However, no etiological model has yet been developed that integrates genetic variants and DNA-M. To explore a new model, we focused on one asthma candidate gene, the IL-4 receptor (IL4R). We hypothesized that genetic variants of IL4R in interaction with DNA-M at cytosine-phosphate-guanine (CpG) sites jointly alter the risk of asthma during adolescence. Blood samples were collected at age 18 years from 245 female cohort participants randomly selected for methylation analysis from a birth cohort (n = 1,456, Isle of Wight, UK). Genome-wide DNA-M was assessed using the Illumina Infinium HumanMethylation450 BeadChip.


Thirteen single nucleotide polymorphisms (SNPs) and twelve CpG sites of IL4R gene were analyzed. Based on linkage disequilibrium and association with asthma, eight SNPs and one CpG site were selected for further analyses. Of the twelve CpG sites in the IL4R gene, only methylation levels of cg09791102 showed an association with asthma at age 18 years (Wilcoxon test: P = 0.01). Log-linear models were used to estimate risk ratios (RRs) for asthma adjusting for uncorrelated SNPs within the IL4R gene and covariates. Testing for interaction between the eight SNPs and the methylation levels of cg09791102 on the risk for asthma at age 18 years, we identified the statistically significant interaction term of SNP rs3024685 × methylation levels of cg09791102 (P = 0.002; after adjusting for false discovery rate). A total of 84 participants had methylation levels ≤0.88, 112 participants between 0.89 and 0.90, and 35 between 0.91 and 0.92. For the SNP rs3024685 (‘CC’ vs. ‘TT’) at methylation levels of ≤0.85, 0.86, 0.90, 0.91, and 0.92, the RRs were 0.01, 0.04, 4.65, 14.76, 14.90, respectively (interaction effect, P = 0.0003).


Adjusting for multiple testing, our results suggest that DNA-M modulates the risk of asthma related to genetic variants in the IL4R gene. The strong interaction of one SNP and DNA-M is encouraging and provides a novel model of how a joint effect of genetic variants and DNA-M can explain occurrence of asthma.

Interleukin-4 receptor gene; DNA methylation; Genetic variants; Asthma; Epigenetics