BackgroundAlterations in DNA methylation (DNAm) have been reported to be a mechanism by which bariatric surgeries resulted in considerable metabolic improvements. Previous studies have mostly focused on change in DNAm following weight-loss interventions, yet whether DNAm prior to intervention can explain the variability in glycemic outcomes has not been investigated. Here, we aim to examine whether baseline DNAm is differentially associated with glycemic outcomes induced by different types of weight-loss interventions.MethodsParticipants were 75 adults with severe obesity who underwent non-surgical intensive medical intervention (IMI), adjustable gastric band (BAND) or Roux-en-Y gastric bypass (RYGB) (n= 25 each). Changes in fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) were measured at 1-year after intervention. DNAm was quantified by Illumina 450 K arrays in baseline peripheral blood DNA. Epigenome-wide association studies were performed to identify CpG probes that modify the effects of different weight-loss interventions on glycemic outcomes, i.e., changes in FPG and HbA1c, by including an interaction term between types of intervention and DNAm. Models were adjusted for weight loss and baseline clinical factors.ResultsBaseline DNAm levels at 3216 and 117 CpGs were differentially associated with changes in FPG and HbA1c, respectively, when comparing RYGB versus IMI. Of these, 79 CpGs were significant for both FPG and HbA1c. The identified genes are enriched in adaptive thermogenesis, temperature homeostasis and regulation of cell population proliferation. Additionally, DNAm at 6 CpGs was differentially associated with changes in HbA1c when comparing RYGB versus BAND.ConclusionsBaseline DNAm is differentially associated with glycemic outcomes in response to different types of weight-loss interventions, independent of weight loss and other clinical factors. Such findings provided initial evidence that baseline DNAm levels may serve as potential biomarkers predictive of differential glycemic outcomes in response to different types of weight-loss interventions.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13148-023-01522-9.