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Oral contraceptives modify the effect of GATA3 polymorphisms on the risk of asthma at the age of 18 years via DNA methylation

Oral contraceptives modify the effect of GATA3 polymorphisms on the risk of asthma at the age of 18 years via DNA methylation
Oral contraceptives modify the effect of GATA3 polymorphisms on the risk of asthma at the age of 18 years via DNA methylation
Background: The prevalence of asthma in girls increases after puberty. Previous studies have detected associations between sex hormones and asthma, as well as between sex hormones and T helper 2 (Th2) asthma-typical immune responses. Therefore, we hypothesized that exogenous or endogenous sex hormone exposure (represented by oral contraceptive pill (OCP) use and early menarche, respectively) are associated with DNA methylation (DNA-M) of the Th2 transcription factor gene, GATA3, in turn affecting the risk of asthma in girls, possibly in interaction with genetic variants.

Blood samples were collected from 245 female participants aged 18 years randomly selected for methylation analysis from the Isle of Wight birth cohort, UK. Information on use of OCPs, age at menarche, and concurrent asthma were assessed by questionnaire. Genome-wide DNA-M was determined using the Illumina Infinium HumanMethylation450 beadchip. In a first stage, we tested the interaction between sex hormone exposure and genetic variants on DNA-M of specific cytosine-phosphate-guanine (CpG) sites. In a second stage, we determined whether these CpG sites interact with genetic variants in GATA3 to explain the risk of asthma.

Results: Interactions between OCP use and seven single nucleotide polymorphisms (SNPs) of GATA3 were analyzed for 14 CpG sites (stage 1). The interaction between OCP use and SNP rs1269486 was found to be associated with the methylation level of cg17124583 (P?=?0.002, false discovery rate (FDR) adjusted P?=?0.04). DNA-M of this same CpG site was also influenced by the interaction between age at menarche and rs1269486 (P?=?0.0017). In stage 2, we found that cg17124583 modified the association of SNP rs422628 with asthma risk at the age of 18 years (P?=?0.006, FDR adjusted P?=?0.04). Subjects with genotype AG showed an increase in average risk ratio (RR) from 0.31 (95% CI: 0.10 to 0.8) to 11.65 (95% CI: 1.71 to 79.5) when methylation level increased from 0.02 to 0.12, relative to genotype AA.

Conclusion: A two-stage model consisting of genetic variants in the GATA3 gene, OCP use, age at menarche, and DNA-M may explain how sex hormones in women can increase the asthma prevalence after puberty.
1868-7075
17
Guthikonda, Kranthi
40998d59-60cd-4781-8b18-a998b837ba90
Zhang, Hongmei
9f774048-54d6-4321-a252-3887b2c76db0
Nolan, Vikki G.
57314de8-d38c-4ba3-8c43-99ba061c1ba7
Soto-Ramírez, Nelís
3526295b-e2ec-4cf3-bc74-088d10943f45
Ziyab, Ali H.
12905e44-3fd1-47c2-98e5-35320e89815b
Ewart, Susan
28667421-3cf7-43d7-b1c3-ca27564938f7
Arshad, Hasan S.
917e246d-2e60-472f-8d30-94b01ef28958
Patil, Veeresh
b898b9a7-db31-4c1c-b0f0-4165b3e4d29c
Holloway, John W.
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Lockett, Gabrielle A.
4d92a28c-f54c-431b-81f6-e82ad9057d7a
Karmaus, Wilfried
281d0e53-6b5d-4d38-9732-3981b07cd853
Guthikonda, Kranthi
40998d59-60cd-4781-8b18-a998b837ba90
Zhang, Hongmei
9f774048-54d6-4321-a252-3887b2c76db0
Nolan, Vikki G.
57314de8-d38c-4ba3-8c43-99ba061c1ba7
Soto-Ramírez, Nelís
3526295b-e2ec-4cf3-bc74-088d10943f45
Ziyab, Ali H.
12905e44-3fd1-47c2-98e5-35320e89815b
Ewart, Susan
28667421-3cf7-43d7-b1c3-ca27564938f7
Arshad, Hasan S.
917e246d-2e60-472f-8d30-94b01ef28958
Patil, Veeresh
b898b9a7-db31-4c1c-b0f0-4165b3e4d29c
Holloway, John W.
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Lockett, Gabrielle A.
4d92a28c-f54c-431b-81f6-e82ad9057d7a
Karmaus, Wilfried
281d0e53-6b5d-4d38-9732-3981b07cd853

Guthikonda, Kranthi, Zhang, Hongmei, Nolan, Vikki G., Soto-Ramírez, Nelís, Ziyab, Ali H., Ewart, Susan, Arshad, Hasan S., Patil, Veeresh, Holloway, John W., Lockett, Gabrielle A. and Karmaus, Wilfried (2014) Oral contraceptives modify the effect of GATA3 polymorphisms on the risk of asthma at the age of 18 years via DNA methylation. Clinical Epigenetics, 6 (1), 17. (doi:10.1186/1868-7083-6-17). (PMID:25250096)

Record type: Article

Abstract

Background: The prevalence of asthma in girls increases after puberty. Previous studies have detected associations between sex hormones and asthma, as well as between sex hormones and T helper 2 (Th2) asthma-typical immune responses. Therefore, we hypothesized that exogenous or endogenous sex hormone exposure (represented by oral contraceptive pill (OCP) use and early menarche, respectively) are associated with DNA methylation (DNA-M) of the Th2 transcription factor gene, GATA3, in turn affecting the risk of asthma in girls, possibly in interaction with genetic variants.

Blood samples were collected from 245 female participants aged 18 years randomly selected for methylation analysis from the Isle of Wight birth cohort, UK. Information on use of OCPs, age at menarche, and concurrent asthma were assessed by questionnaire. Genome-wide DNA-M was determined using the Illumina Infinium HumanMethylation450 beadchip. In a first stage, we tested the interaction between sex hormone exposure and genetic variants on DNA-M of specific cytosine-phosphate-guanine (CpG) sites. In a second stage, we determined whether these CpG sites interact with genetic variants in GATA3 to explain the risk of asthma.

Results: Interactions between OCP use and seven single nucleotide polymorphisms (SNPs) of GATA3 were analyzed for 14 CpG sites (stage 1). The interaction between OCP use and SNP rs1269486 was found to be associated with the methylation level of cg17124583 (P?=?0.002, false discovery rate (FDR) adjusted P?=?0.04). DNA-M of this same CpG site was also influenced by the interaction between age at menarche and rs1269486 (P?=?0.0017). In stage 2, we found that cg17124583 modified the association of SNP rs422628 with asthma risk at the age of 18 years (P?=?0.006, FDR adjusted P?=?0.04). Subjects with genotype AG showed an increase in average risk ratio (RR) from 0.31 (95% CI: 0.10 to 0.8) to 11.65 (95% CI: 1.71 to 79.5) when methylation level increased from 0.02 to 0.12, relative to genotype AA.

Conclusion: A two-stage model consisting of genetic variants in the GATA3 gene, OCP use, age at menarche, and DNA-M may explain how sex hormones in women can increase the asthma prevalence after puberty.

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Published date: 19 September 2014
Organisations: Human Development & Health, Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 369417
URI: https://eprints.soton.ac.uk/id/eprint/369417
ISSN: 1868-7075
PURE UUID: 330b6cb4-9389-4cdb-b719-e64d0735b6ac
ORCID for John W. Holloway: ORCID iD orcid.org/0000-0001-9998-0464

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Date deposited: 01 Oct 2014 12:40
Last modified: 06 Jun 2018 12:59

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