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The interplay of DNA methylation over time with Th2 pathway genetic variants on asthma risk and temporal asthma transition

The interplay of DNA methylation over time with Th2 pathway genetic variants on asthma risk and temporal asthma transition
The interplay of DNA methylation over time with Th2 pathway genetic variants on asthma risk and temporal asthma transition
Background

Genetic effects on asthma of genes in the T-helper 2 (Th2) pathway may interact with epigenetic factors including DNA methylation. We hypothesized that interactions between genetic variants and methylation in genes in this pathway (IL4, IL4R, IL13, GATA3, and STAT6) influence asthma risk, that such influences are age-dependent, and that methylation of some CpG sites changes over time in accordance with asthma transition. We tested these hypotheses in subsamples of girls from a population-based birth cohort established on the Isle of Wight, UK, in 1989.

Results

Logistic regression models were applied to test the interaction effect of DNA methylation and SNP on asthma within each of the five genes. Bootstrapping was used to assess the models identified. From 1,361 models fitted at each age of 10 and 18 years, 8 models, including 4 CpGs and 8 SNPs, showed potential associations with asthma risk. Of the 4 CpGs, methylation of cg26937798 (IL4R) and cg23943829 (IL4) changes between ages 10 and 18 (both higher at 10; P?=?9.14?×?10?6 and 1.07?×?10?5, respectively).

At age 10, the odds of asthma tended to decrease as cg12405139 (GATA3) methylation increased (log-OR?=??12.15; P?=?0.049); this effect disappeared by age 18. At age 18, methylation of cg09791102 (IL4R) was associated with higher risk of asthma among subjects with genotype GG compared to AG (P?=?0.003), increased cg26937798 methylation among subjects with rs3024685 (IL4R) genotype AA (P?=?0.003) or rs8832 (IL4R) genotype GG (P?=?0.01) was associated with a lower asthma risk; these CpGs had no effect at age 10. Increasing cg26937798 methylation over time possibly reduced the risk of positive asthma transition (asthma-free at age 10???asthma at age 18; log-OR?=??3.11; P?=?0.069) and increased the likelihood of negative transition (asthma at age 10???asthma-free at age 18; log-OR?=?3.97; P?=?0.074).

Conclusions

The interaction of DNA methylation and SNPs in Th2 pathway genes is likely to contribute to asthma risk. This effect may vary with age. Methylation of some CpGs changed over time, which may influence asthma transition.
asthma risk, asthma transition, DNA methylation and SNP interaction, Th2 pathway
1868-7075
1-11
Zhang, Hongmei
9f774048-54d6-4321-a252-3887b2c76db0
Tong, Xin
0e86225e-f4e1-49b5-ac04-4a2a6b9a202b
Holloway, John W.
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Rezwan, Faisal I.
203f8f38-1f5d-485b-ab11-c546b4276338
Lockett, Gabrielle A.
4d92a28c-f54c-431b-81f6-e82ad9057d7a
Patil, Veeresh
25d44602-ebc7-4487-879a-c50500be203a
Ray, Meredith
b08cd74f-e4f5-4e7b-b7e9-8874fd23be77
Everson, Todd M.
0639cdab-214c-4fd3-8181-bfca14ad58ef
Soto-Ramírez, Nelís
3526295b-e2ec-4cf3-bc74-088d10943f45
Arshad, S
917e246d-2e60-472f-8d30-94b01ef28958
Ewart, Susan
28667421-3cf7-43d7-b1c3-ca27564938f7
Karmaus, Wilfried
281d0e53-6b5d-4d38-9732-3981b07cd853
Zhang, Hongmei
9f774048-54d6-4321-a252-3887b2c76db0
Tong, Xin
0e86225e-f4e1-49b5-ac04-4a2a6b9a202b
Holloway, John W.
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Rezwan, Faisal I.
203f8f38-1f5d-485b-ab11-c546b4276338
Lockett, Gabrielle A.
4d92a28c-f54c-431b-81f6-e82ad9057d7a
Patil, Veeresh
25d44602-ebc7-4487-879a-c50500be203a
Ray, Meredith
b08cd74f-e4f5-4e7b-b7e9-8874fd23be77
Everson, Todd M.
0639cdab-214c-4fd3-8181-bfca14ad58ef
Soto-Ramírez, Nelís
3526295b-e2ec-4cf3-bc74-088d10943f45
Arshad, S
917e246d-2e60-472f-8d30-94b01ef28958
Ewart, Susan
28667421-3cf7-43d7-b1c3-ca27564938f7
Karmaus, Wilfried
281d0e53-6b5d-4d38-9732-3981b07cd853

Zhang, Hongmei, Tong, Xin, Holloway, John W., Rezwan, Faisal I., Lockett, Gabrielle A., Patil, Veeresh, Ray, Meredith, Everson, Todd M., Soto-Ramírez, Nelís, Arshad, S, Ewart, Susan and Karmaus, Wilfried (2014) The interplay of DNA methylation over time with Th2 pathway genetic variants on asthma risk and temporal asthma transition. Clinical Epigenetics, 6 (1), 1-11. (doi:10.1186/1868-7083-6-8).

Record type: Article

Abstract

Background

Genetic effects on asthma of genes in the T-helper 2 (Th2) pathway may interact with epigenetic factors including DNA methylation. We hypothesized that interactions between genetic variants and methylation in genes in this pathway (IL4, IL4R, IL13, GATA3, and STAT6) influence asthma risk, that such influences are age-dependent, and that methylation of some CpG sites changes over time in accordance with asthma transition. We tested these hypotheses in subsamples of girls from a population-based birth cohort established on the Isle of Wight, UK, in 1989.

Results

Logistic regression models were applied to test the interaction effect of DNA methylation and SNP on asthma within each of the five genes. Bootstrapping was used to assess the models identified. From 1,361 models fitted at each age of 10 and 18 years, 8 models, including 4 CpGs and 8 SNPs, showed potential associations with asthma risk. Of the 4 CpGs, methylation of cg26937798 (IL4R) and cg23943829 (IL4) changes between ages 10 and 18 (both higher at 10; P?=?9.14?×?10?6 and 1.07?×?10?5, respectively).

At age 10, the odds of asthma tended to decrease as cg12405139 (GATA3) methylation increased (log-OR?=??12.15; P?=?0.049); this effect disappeared by age 18. At age 18, methylation of cg09791102 (IL4R) was associated with higher risk of asthma among subjects with genotype GG compared to AG (P?=?0.003), increased cg26937798 methylation among subjects with rs3024685 (IL4R) genotype AA (P?=?0.003) or rs8832 (IL4R) genotype GG (P?=?0.01) was associated with a lower asthma risk; these CpGs had no effect at age 10. Increasing cg26937798 methylation over time possibly reduced the risk of positive asthma transition (asthma-free at age 10???asthma at age 18; log-OR?=??3.11; P?=?0.069) and increased the likelihood of negative transition (asthma at age 10???asthma-free at age 18; log-OR?=?3.97; P?=?0.074).

Conclusions

The interaction of DNA methylation and SNPs in Th2 pathway genes is likely to contribute to asthma risk. This effect may vary with age. Methylation of some CpGs changed over time, which may influence asthma transition.

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More information

Published date: 15 April 2014
Keywords: asthma risk, asthma transition, DNA methylation and SNP interaction, Th2 pathway
Organisations: Human Development & Health, Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 364496
URI: https://eprints.soton.ac.uk/id/eprint/364496
ISSN: 1868-7075
PURE UUID: ba3978eb-6e6a-4565-9b35-8c7bcf42158e
ORCID for John W. Holloway: ORCID iD orcid.org/0000-0001-9998-0464
ORCID for Faisal I. Rezwan: ORCID iD orcid.org/0000-0001-9921-222X

Catalogue record

Date deposited: 01 May 2014 15:49
Last modified: 06 Jun 2018 12:59

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Contributors

Author: Hongmei Zhang
Author: Xin Tong
Author: Gabrielle A. Lockett
Author: Veeresh Patil
Author: Meredith Ray
Author: Todd M. Everson
Author: Nelís Soto-Ramírez
Author: S Arshad
Author: Susan Ewart
Author: Wilfried Karmaus

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