SLC30A8 Promoter Hypomethylation is Associated with Impaired Renal Function in Type 2 Diabetes: A Cross-Sectional Study

Background: Diabetic kidney disease (DKD) remains a major challenge in type 2 diabetes (T2DM) management. The solute carrier family 30 member 8 (SLC30A8) gene is a known T2DM susceptibility locus. However,the relationship between SLC30A8 promoter methylation and renal function in DKD remains unclear. This study aimed to investigate this association. Methods: In this cross-sectional study, 351 hospitalized patients with T2DM (181 with DKD, 170 without) were enrolled. Peripheral blood DNA methylation at six CpG sites in the SLC30A8 promoter was quantified by pyrosequencing. Multivariate linear/logistic regression, smooth curve fitting, and subgroup analyses were used to evaluate the independent association between SLC30A8 methylation and estimated glomerular filtration rate (eGFR). Results: SLC30A8 methylation was significantly lower in the DKD group (73.6% ± 6.4%) than in the T2DM-only group (88.7% ± 7.1%, P < 0.001), and progressively decreased across categories of declining eGFR and increasing albuminuria (all P for trend < 0.05). In a multivariate linear regression model adjusted for age, sex, BMI, systolic blood pressure, UACR, uric acid, lipids, fasting glucose, and diabetes duration, each 1% increase in methylation was independently associated with a 2.336 mL/min/1.73 m 2 higher eGFR (95% CI: 1.780– 2.891, P < 0.001). A nonlinear threshold was identified at 70.9% methylation. Below this, the association with eGFR was nonsignificant; above it, each 1% increase correlated with a 4.471 mL/min/1.73 m 2 increase in eGFR (95% CI: 3.961– 4.981, P < 0.001). This stable association was consistent across all clinical subgroups (P for interaction > 0.05). Conclusion: SLC30A8 promoter hypomethylation is independently associated with impaired renal function in T2DM, exhibiting a dose-response relationship where lower methylation levels correlated with more severe kidney damage, and a distinct threshold effect at approximately 70.9% methylation, below which the association with eGFR was significantly stronger. These exploratory findings suggest that SLC30A8 promoter methylation may represent a promising epigenetic biomarker for DKD risk stratification, warranting further validation in prospective studies. Keywords: type 2 diabetes mellitus, diabetic kidney disease, DNA methylation, SLC30A8, estimated glomerular filtration rate, epigenetics, biomarker