Association Between DNA Methylation of <i>MTHFR</i> and Diabetic Kidney Disease

<b>Objective:</b> The objective of this study is to explore the association between <i>MTHFR</i> DNA methylation and diabetic kidney disease (DKD). <b>Methods:</b> This study involved 120 healthy people, 200 diabetes mellitus (DM) patients, and 200 DKD patients who visited China-Japan Friendship Hospital from 2022 to 2023. We selected four CpG islands for the detection of <i>MTHFR</i> DNA methylation: three located in the promoter region and one in Exon 2. The methylation rate of the <i>MTHFR</i> gene was measured using an enzyme digestion method combined with quantitative PCR. Clinical and biochemical characteristics between the two groups were also collected. <b>Results:</b> The methylation rate of the three CpG islands in the promoter region showed no significant differences between the DM and DKD patients. However, a significant difference in the CpG island methylation rate of the <i>MTHFR</i> gene Exon 2 was observed (25.14% vs. 21.94%, <i>p</i> < 0.001). Logistic regression analysis indicated that the methylation rate of <i>MTHFR</i> Exon2 is negatively associated with the occurrence and progression of DKD (OR = 0.947, 95% CI [0.919, 0.977], <i>p</i> = 0.001), with adjustments for gender, age, BMI, smoking, drinking, CHO, and TG. Significant differences were observed in the methylation ratios in different HCY groups (24.51% vs. 21.99%, <i>p</i> = 0.031). Linear regression showed <i>MTHFR</i> Exon 2 methylation negatively correlated with homocysteine (HCY) levels (<i>p</i> = 0.007). <b>Conclusion:</b> Methylation of the <i>MTHFR</i> gene Exon 2 is a protective factor for DKD and may contribute to its onset and progression through its influence on HCY levels. These findings highlight the potential of <i>MTHFR</i> methylation as a biomarker for DKD.