title: The interplay of DNA methylation over time with Th2 pathway genetic variants on asthma risk and temporal asthma transition.
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.
authors.affiliation: Division of Epidemiology, Biostatistics and Environmental Health, School of Public Health, University of Memphis, 236A Robison Hall, Memphis, TN 38152, USA.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, 800 Sumter Street, Columbia, SC 29208, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Tong
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Road, Southampton SO17 1BJ, UK ; Human Development and Health, Faculty of Medicine, University of Southampton, University Road, Southampton SO17 1BJ, UK.
authors.forename: John W
authors.initials: JW
authors.lastname: Holloway
authors.affiliation: Human Development and Health, Faculty of Medicine, University of Southampton, University Road, Southampton SO17 1BJ, UK.
authors.forename: Faisal I
authors.initials: FI
authors.lastname: Rezwan
authors.affiliation: Human Development and Health, Faculty of Medicine, University of Southampton, University Road, Southampton SO17 1BJ, UK.
authors.forename: Gabrielle A
authors.initials: GA
authors.lastname: Lockett
authors.affiliation: The David Hide Asthma and Allergy Research Centre, St Mary's, Hospital, Parkhurst Road, Newport, Isle of Wight PO30 5TG, UK.
authors.forename: Veeresh
authors.initials: V
authors.lastname: Patil
authors.affiliation: Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, 800 Sumter Street, Columbia, SC 29208, USA.
authors.forename: Meredith
authors.initials: M
authors.lastname: Ray
authors.affiliation: Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, 800 Sumter Street, Columbia, SC 29208, USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Everson
authors.affiliation: Division of Epidemiology, Biostatistics and Environmental Health, School of Public Health, University of Memphis, 236A Robison Hall, Memphis, TN 38152, USA.
authors.forename: Nelís
authors.initials: N
authors.lastname: Soto-Ramírez
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Road, Southampton SO17 1BJ, UK ; The David Hide Asthma and Allergy Research Centre, St Mary's, Hospital, Parkhurst Road, Newport, Isle of Wight PO30 5TG, UK.
authors.forename: S Hasan
authors.initials: SH
authors.lastname: Arshad
authors.affiliation: Department of Large Animal Clinical Sciences, Michigan State University, 3700 East Gull Lake Drive, East Lansing, MI 48824, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Ewart
authors.affiliation: Division of Epidemiology, Biostatistics and Environmental Health, School of Public Health, University of Memphis, 236A Robison Hall, Memphis, TN 38152, USA.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Karmaus
keywords: Asthma risk; Asthma transition; DNA methylation and SNP interaction; Th2 pathway
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