Background Systemic lupus erythematous (SLE) shows increased DNA demethylation. An intermediate step to DNA demethylation is the DNA hydroxymethylation, where 5-mC is oxidized into 5-hmC. Hydroxymethylation is not completely understood and it may be related to oxidative stress in SLE patient.
Objectives To analyze the association between the hydroxymethylation and demethylation, with the antioxidant response and SLE pathophysiology.
Methods We analyzed in 142 SLE patients and 34 healthy controls the serum concentration of glutathione (GSH) and glutathione disulphide (GSSG) by UPLC-MS/MS, superoxide dismutase (SOD) and total antioxidant capacity (TAC) by colorimetric methods. 5-mC and 5-hmC levels were measured by colorimetric methods. Complete blood-test was made and clinical data by personal interview was collected. Biostatistical analysis with R (3.3.2.) was performed.
Results There is a correlation between the methylation and hydroxymethylation rate (P<0.001), and both were lower in patients than in controls (P=0.024; P<0.001). GSH and GSSG values were lower in patients (P=0.033 y P=0.003), but GSH/GSSG ratio was not statistically different in both groups. SOD levels were higher in patients (P=0.001), but TAC did not show significant differences. Higher demethylation is associated to lower TAC values in patients and healthy controls (P=0.005; P=0.01). In patients, decreased SOD values are associated with higher demethylation and lower hydroxymethylation rates (P<0.001; P=0.007). SOD and TAC levels are increased in SLE patients with higher demethylation and lower hydroxymethylation (P=0.001; P<0.001). We did not observe any association between 5-mC or 5-hmC levels and GSH, GSSG or GSH/GSSG ratio. Higher demethylation is associated to vascular symptoms (defined by RELESSER study) and lupus anticoagulant (AL) positivity (P=0.041; P=0.015), and lower hydroxymethylation to mucocutaneous damage (defined by RELESSER study) and AL positivity (P=0.015; P=0.009). Lower levels of GSH and GSSG were associated to increased accumulated damage assessed by SLICC (P=0.01; P=0.005), and lower SOD values with longer disease duration (P=0.001).
Conclusions We observed higher demethylation and lower hydroxymethylation in SLE patients than in controls, related to increased SOD activity. Moreover higher demethylation leads to lower TAC levels. These epigenetic disorders are related to antioxidant response disruptions in SLE patients, probably because of the chronic inflammatory condition. Our results suggest that epigenetic processes are involved in SLE physiopathology.
Acknowledgements Financial support by GVA (GV15/83) is acknowledged.
Disclosure of Interest None declared