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Introduction: Dietary sodium-to-potassium ratio (Na/K ratio) has been associated with elevated blood pressure and increased risk of hypertension in both observational and clinical research. However, the underlying molecular mechanisms are still not clear, and there is no previous study examining the effect of dietary Na/K ratio on DNA methylation. Hypothesis: We tested the hypothesis that dietary Na/K ratio would be involved in epigenetic regulation. Methods: An epigenome-wide association study was conducted using Illumina 450K Bead-Chip on leukocyte DNA in 284 African American adolescents. Linear regression was performed to identify differentially methylated CpG sites associated with dietary Na/K ratio (log transformed) while adjusted for age, sex, energy intake, body mass index and further adjusted for dietary folate intake. A FDR<0.1 was considered significant. Results: After adjusting for age, sex, energy intake and body mass index, dietary Na/K ratio was significantly associated with increased methylation level of cg03778155 (FDR = 0.063), which is located in the gene body region of R-Spondin 3 (RSPO3). The association remained significant after further adjustment of dietary folate intake (FDR = 0.019), which is a key methyl donor. Conclusions: Our study shows that locus-specific DNA methylation level at RSPO3 gene is associated with dietary Na/K ratio, suggesting that dietary Na/K intake ratio may be involved in epigenetic regulation. Given that RSPO3 can activate the Wnt/beta-catenin signaling pathway, and is associated with endothelial cell proliferation, blood urea nitrogen and BP, further studies are warranted to replicate our findings. [ABSTRACT FROM AUTHOR]