Genome-wide investigation of DNA methylation in congenital adrenal hyperplasia

Background: Patients with congenital adrenal hyperplasia (CAH) are at risk of long-term cognitive and metabolic sequelae. This study investigates genome-wide DNA methylation in patients with CAH to determine whether there is evidence for epigenomic reprogramming as well as any relationship to patient outcome. Methods: We analysed CD4+ T cell DNA from 28 patients with CAH (mean age=18.5 ±6.5 years [y]) and 37 population controls (mean age=17.0 ±6.1 y) with the Infinium-HumanMethylation450 BeadChip array to measure genome-wide locus-specific DNA methylation levels. Effects of CAH, phenotype and CYP21A2 genotype on methylation were investigated as well as the association between differentially methylated CpGs, metabolic profiles (glucose homeostasis and blood lipid profile) and cognitive outcome. In addition, we report data on a small cohort of 11 patients (mean age=19.1, ±6.0 y) with CAH who were treated prenatally with dexamethasone (DEX). Results: We identified two CpGs to be associated with patient phenotype: cg18486102 (located in the FAIM2 gene; rho=0.58, adjusted p=0.027) and cg02404636 (located in the SFI1 gene; rho=0.58, adjusted p=0.038). cg02404636 was also associated with genotype (rho=0.59, adjusted p=0.024). We did not observe any effect of DEX on DNA methylation in individuals with CAH. No significant association was found between FAIM2 methylation and cognitive or metabolic outcome. However, SFI1 TSS methylation was associated with fasting plasma HDL cholesterol levels (p=0.035). Conclusion: In conclusion, higher methylation levels in CpG sites covering FAIM2 and SFI1 were associated with disease severity. Hypermethylation in these genes may have implications for long-term cognitive and metabolic outcome in patients with CAH.