Patients with congenital adrenal hyperplasia (CAH) are at risk of long-term cognitive and metabolic sequelae with some of the effects being attributed to the chronic glucocorticoid treatment that they receive. Our pilot study investigates genome-wide DNA methylation in patients with CAH to determine whether there is preliminary evidence for epigenomic reprogramming as well as any relationship to patient outcome. Here, 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 and glucose homeostasis, blood lipid profile, and cognitive functions. 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) in addition to postnatal glucocorticoid treatment.

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). Higher levels of serum C-peptide was also observed in patients with CAH (p = 0.044). Additionally, levels of C-peptide and HbA1c were positively correlated with patient phenotype (p = 0.044 and p = 0.034) and genotype (p = 0.044 and p = 0.033), respectively. 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).

In conclusion, in this pilot study, 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, although the data must be interpreted with caution due to the small sample size. Additional studies in larger cohorts are therefore warranted.

先天性肾上腺皮质增生（CAH）患者有长期认知和代谢后遗症的风险，其中一些影响归因于他们接受的慢性糖皮质激素治疗。我们的初步研究调查了CAH患者的全基因组DNA甲基化，以确定是否存在表观基因组重编程的初步证据以及与患者预后的关系。在这里，我们使用Infinium-HumanMethylation450 BeadChip阵列分析了28位CAH患者（平均年龄= 18.5±6.5岁[y]）和37位人群对照（平均年龄= 17.0±6.1年）的CD4 + T细胞DNA，以测量基因组-广泛的基因座特异性DNA甲基化水平。CAH，表型和CYP21A2的影响研究了甲基化的基因型以及差异甲基化的CpGs与葡萄糖稳态，血脂谱和认知功能之间的关系。此外，我们报告了一组11例CAH患者的数据，这些患者除产后接受糖皮质激素治疗外，还接受了地塞米松（DEX）的产前治疗，平均年龄为19.1±6.0 y。

我们确定了两个与患者表型相关的CpG：cg18486102（位于FAIM2基因中； rho = 0.58，调整后的p  = 0.027）和cg02404636（位于SFI1基因中； rho = 0.58，调整后的p  = 0.038）。cg02404636也与基因型相关（rho = 0.59，调整后的p  = 0.024）。在CAH患者中也观察到较高水平的血清C肽（p  = 0.044）。此外，C肽和HbA1c的水平与患者的表型（p  = 0.044和p  = 0.034）和基因型（p  = 0.044和p = 0.033）。FAIM2甲基化与认知或代谢结果之间未发现显着关联。然而，SFI1 TSS甲基化与空腹血浆HDL胆固醇水平相关（p  = 0.035）。

总之，在该初步研究中，覆盖FAIM2和SFI1的CpG位点的甲基化水平较高与疾病的严重程度有关。这些基因中的高甲基化可能对CAH患者的长期认知和代谢结果产生影响，尽管由于样本量小，必须谨慎解释数据。因此，有必要在较大的队列中进行其他研究。