Aims: To see if methylation is genotype dependent in IL13 and to assess the effect of the interaction between IL13 SNPs and DNA methylation on FEV1/FVC and BHR.
Methods: Subjects from the 1989 Isle of Wight birth cohort (n=1456) were followed up at 1, 2, 4, 10 and 18 years. At 18 years 839/1313 had spirometry, 585/1313 had bronchial challenge. Illumina Human450K methylation arrays were used to assess DNA methylation (DNA-M) levels at >484,000 CpG sites in 245 female participants. DNA-M in three IL13 promoter region CpG sites; cg13566430, cg14523284 and cg06584121 were explored among genotypes of three IL13 SNP`s that have been shown to be associated with asthma related lung function measurements. Outcomes are FEV1/FVC from spirometry and DRS (Dose Response Curve): gradient of the linear regression line for FEV1 drop from baseline with each successive incremental dose of methacholine administered. Kruskall-Wallis tests were used to assess genotype dependent methylation and linear regression and linear mixed models were used to investigate interactions between SNPs and DNA-M.
Results: Methylation levels were significantly different (p<0.001) for cg13566430 across the genotypes of all three SNPs. An interaction effect for rs1800925*cg13566430 was seen for both FEV1/FVC (p=0.013) and DRS (p= 0.036). For DRS; interactions of rs20541 with cg13566430 (p=0.030) and cg0658412 (p=0.036), rs2243204*cg13566430 (p=0.005), rs2243204*cg0658412 (p=0.012) and rs2243204*cg14523284 (p=0.017) were significant.
Conclusions: Genotype-dependent DNA methylation was seen at cg13566430. Interaction between genotype and DNA methylation was significantly associated with obstructive (FEV1/FVC) and reactive (DRS) aspects of asthma in adolescent females. DNA methylation is likely to modify the effect size of the impact of genetic variants that play a role in the development of complex traits like asthma.