title: Oral contraceptives modify the effect of GATA3 polymorphisms on the risk of asthma at the age of 18 years via DNA methylation.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis, Memphis, TN, USA.
authors.forename: Kranthi
authors.initials: K
authors.lastname: Guthikonda
authors.affiliation: Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis, Memphis, TN, USA.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis, Memphis, TN, USA.
authors.forename: Vikki G
authors.initials: VG
authors.lastname: Nolan
authors.affiliation: Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis, Memphis, TN, USA.
authors.forename: Nelís
authors.initials: N
authors.lastname: Soto-Ramírez
authors.affiliation: Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA.
authors.forename: Ali H
authors.initials: AH
authors.lastname: Ziyab
authors.affiliation: Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, MI, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Ewart
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, and NIHR Respiratory Biomedical Research Unit, University of Southampton, Southampton, UK ; The David Hide Asthma and Allergy Research Centre, Isle of Wight, UK.
authors.forename: Hasan S
authors.initials: HS
authors.lastname: Arshad
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, and NIHR Respiratory Biomedical Research Unit, University of Southampton, Southampton, UK ; The David Hide Asthma and Allergy Research Centre, Isle of Wight, UK.
authors.forename: Veeresh
authors.initials: V
authors.lastname: Patil
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, and NIHR Respiratory Biomedical Research Unit, University of Southampton, Southampton, UK ; Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: John W
authors.initials: JW
authors.lastname: Holloway
authors.affiliation: Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Gabrielle A
authors.initials: GA
authors.lastname: Lockett
authors.affiliation: Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis, Memphis, TN, USA.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Karmaus
keywords: CpG; DNA methylation; GATA3 gene; adolescence; age at menarche; asthma; epigenetics; genetic variants; oral contraceptives; puberty; single nucleotide polymorphism