الفهرس 
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Abstract
Background and aim of the work:End-stage renal disease (ESRD) is one of the
main causes of morbidity and mortality worldwide. It is a state of chronic inflammation. DNA methylation is a major epigenetic modification that has the potential to silence gene expression. Interferon-gamma (IFN-γ) and suppressor of cytokine signaling (SOCS) are essential modulators of inflammation. Methylenetetrahydrofolate reductase (MTHFR) gene inactivation is recognized as a predisposing factor of hyperhomocysteinemiain renal patients. The current study aims to determine the methylation status within the IFN-γ, SOCS1, SOCS3 and MTHFR promoter region in DNA isolated from peripheral blood of ESRD patients and controls and the correlation of this methylation status with the clinical and biochemical characteristics of ESRD patients.
Subjects and method:Ninety-six ESRD patients and96 healthy ethnically, age and gender matched controlswere included within the study. Serum creatinine, urea, total cholesterol (TC), high density lipoprotein-cholesterol (HDL-C) and triglycerides (TG) levels were determined spectrophotometrically. Serum low density lipoprotein-cholesterol (LDL- C) level was calculated according to Friedewald formula. Estimated glomerular filtration rate (eGFR) was assessed using the Modification of Diet in Renal Disease Study equation. The promoter methylation of the studied genes was assessed using methylation specific polymerasechain reaction (MSP).
Results:Significant increase in both serum creatinine and serum urea levelswas found in ESRD patients compared to normal control group, while eGFR was significantly decreased in ESRD patients in comparison to normal control subjects. Serum TG and VLDL-Clevel were significantly increased in ESRD patients compared to controls. However, serum HDL-C level was significantly lower in the patient group comparing to the normal subjects. On the other hand, no significant differences in serum TC and serum LDL-C levels were detected between the two groups. Most samples in both ESRD patients and controls were positive for IFN-γ promoter methylation. Full unmethylation was observed only in the ESRD group (7.3%), and statistical difference was observed among groups (P=0.02). IFN-γ unmethylation was associated with a decrease in eGFRand an increase in both serum creatinine and TC levels. For SOCS1 promoter methylation, partial and full methylation were observed only in ESRD patients (5.2% and 2.1%, respectively); however, no methylation was detected in controls (P=0.014). No significant associations were found with any of the studied parameters with SOCS1 promoter methylationin ESRD patients.SOCS3 promoter methylation was not detected in either the patient or control group. The frequency of MTHFR methylation was significantly higher in ESRD patients than in controls (P = 0.003). MTHFR methylation was associated with a decrease in eGFR, serum HDL-C level and an increase in both serum TC and LDL-C levels.
Conclusion:The data shows that the methylation profile within IFN-γ, SOCS1 and MTHFR promoter regions play an important role in ESRD. An association of IFN-γ unmethylationwith a decrease in eGFRand an increase in both serum creatinine and TC levelswas present. MTHFR methylation was associated with a decrease in eGFR, serum HDL-C level and an increase in both serum TC and LDL-C levels.The present study highlights the role of epigenetics in disease progression.
Keywords: End stage renal disease; Epigenetics; Interferon gamma; Suppressor of cytokine signaling; Methylenetetrahydrofolate reductase.