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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

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

Results: 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).

Conclusions: 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.
1868-7075
1
Soto-Ramírez, Nelís
3526295b-e2ec-4cf3-bc74-088d10943f45
Arshad, Syed Hasan
917e246d-2e60-472f-8d30-94b01ef28958
Holloway, John W
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Zhang, Hongmei
9f774048-54d6-4321-a252-3887b2c76db0
Schauberger, Eric
465a4658-a065-470e-b7dc-0b713f911922
Ewart, Susan
28667421-3cf7-43d7-b1c3-ca27564938f7
Patil, Veeresh
25d44602-ebc7-4487-879a-c50500be203a
Karmaus, Wilfried
281d0e53-6b5d-4d38-9732-3981b07cd853
Soto-Ramírez, Nelís
3526295b-e2ec-4cf3-bc74-088d10943f45
Arshad, Syed Hasan
917e246d-2e60-472f-8d30-94b01ef28958
Holloway, John W
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Zhang, Hongmei
9f774048-54d6-4321-a252-3887b2c76db0
Schauberger, Eric
465a4658-a065-470e-b7dc-0b713f911922
Ewart, Susan
28667421-3cf7-43d7-b1c3-ca27564938f7
Patil, Veeresh
25d44602-ebc7-4487-879a-c50500be203a
Karmaus, Wilfried
281d0e53-6b5d-4d38-9732-3981b07cd853

Soto-Ramírez, Nelís, Arshad, Syed Hasan, Holloway, John W, Zhang, Hongmei, Schauberger, Eric, Ewart, Susan, Patil, Veeresh and Karmaus, Wilfried (2013) The interaction of genetic variants and DNA methylation of the interleukin-4 receptor gene increase the risk of asthma at age 18 years. Clinical Epigenetics, 5 (1), 1. (doi:10.1186/1868-7083-5-1). (PMID:23286427)

Record type: Article

Abstract

Background: 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.

Results: 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).

Conclusions: 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.

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More information

e-pub ahead of print date: 3 January 2013
Published date: 2013
Organisations: Human Development & Health, Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 347145
URI: http://eprints.soton.ac.uk/id/eprint/347145
ISSN: 1868-7075
PURE UUID: f1240515-b6b5-40e5-92da-172ac363b238
ORCID for John W Holloway: ORCID iD orcid.org/0000-0001-9998-0464

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Date deposited: 22 Jan 2013 12:53
Last modified: 08 Jan 2022 02:46

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Contributors

Author: Nelís Soto-Ramírez
Author: John W Holloway ORCID iD
Author: Hongmei Zhang
Author: Eric Schauberger
Author: Susan Ewart
Author: Veeresh Patil
Author: Wilfried Karmaus

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