Hypomethylation of the Interferon γ Gene as a Potential Risk Factor for Essential Hypertension: A Case-Control Study.

Essential hypertension (EH) is a multifactorial disease. Interferon-γ (IFN-γ) plays an important role in the onset of EH through cytokine-mediated systemic inflammatory responses. We aimed to determine whether the methylation status of the IFN-γ gene (IFNG) promoter is involved in the pathogenesis of EH. Six copies of CpG dinucleotides are distributed between 3,203 bp and 3,121 bp upstream from the transcription initiation site of IFNG, termed CpG1 to CpG6 in the 5'-to-3' direction. We recruited 96 patients with EH and 96 sex- and age-matched healthy subjects as controls. Using bisulfate pyrosequencing datasets, we analyzed the methylation status of the six CpG sites and thus found that CpG5 was consistently methylated in all of the 96 EH patients and 96 control subjects. Among the remaining five CpG sites, there was no significant difference in the methylation levels of CpG4 and CpG6 between the two groups. By contrast, CpG1 (P = 0.003) and CpG3 (P = 5.87 × 10-7) were highly methylated among the EH subjects compared with the controls, whereas CpG2 (P = 1.24 × 10-12) was significantly less methylated in among EH subjects. The methylation levels of CpG2 were still lower after adjustment with logistic regression (adjusted P = 0.032). The CpG2 methylation level was an effective marker of EH (area under curve = 0.384; P = 1.40 × 10-15). The present study shows that hypomethylation of the IFNG promoter is significantly related to the risk of EH, providing new insights into the pathogenesis of EH.

Preliminary analysis of the association between methylation of the ACE2 promoter and essential hypertension.

The aim of the present study was to investigate whether methylation of the angiotensin I converting enzyme 2 (ACE2) promoter increases the risk of essential hypertension (EH). A total of 96 patients with EH were recruited and 96 sex­ and age­matched healthy controls. Methylation of 5 CpG dinucleotides in the ACE2 promoter was quantified using bisulfite pyrosequencing. Logistic regression and multiple linear regression were used to adjust for confounding factors and the generalized multifactor dimensionality reduction (GMDR) method was applied to investigate high­order interactions. Methylation of CpG4 (adjusted P=0.020) and CpG5 (adjusted P=0.036) was significantly higher in patients with EH, with frequency 97.56±5.65% and 12.75±4.15% in EH individuals and 95.73±9.11% and 11.47±3.67% in healthy controls. GMDR detected significant interaction among the 5 CpG sites (odds ratio=7.33, adjusted P=0.01). Furthermore, receiver operating characteristic curves identified that CpG5 methylation was a significant predictor of EH. Notably, CpG2 methylation was significantly higher in males than in females (adjusted P=0.018). Conversely, CpG5 methylation was significantly lower in males (adjusted P=0.032). These results indicated that aberrant methylation of the ACE2 promoter may be associated with EH risk. In addition, sex may significantly influence ACE2 methylation.