Abstract 11956: Blood DNA Methylation Predicts Differential Metabolic Outcomes Induced by Different Types of Weight-Loss Intervention: Findings From an Epigenome-Wide Association Study

Abstract

Background Previous epigenetic studies in obesity interventions have focused on the intervention-associated DNA methylation (DNAm) changes, yet whether the DNAm before intervention could be used as a predictor of prognosis has not been investigated. Here we hypothesize that baseline DNAm can predict differential metabolic outcomes, i.e., changes in fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c), induced by different weight-loss interventions. Methods The analyses included 75 individuals with obesity in the HeadsUp Study, a longitudinal study assessing the effectiveness of different weight-loss interventions, from the non-surgical intensive medical intervention (IMI), adjustable gastric band (BAND) and Roux-en-Y gastric bypass (RYGB) groups (n = 25 per group). Genome-wide DNAm was determined using baseline blood samples, while changes in FPG and HbA1c were measured at 1-year follow-up. Epigenome-wide association studies were performed on 455,983 CpGs to identify DNAm predictors of differential metabolic outcomes, adjusting for age, sex, BMI, FPG/HbA1c at baseline, weight loss and batch effect. Results DNAm levels at 3,216 and 117 CpG loci significantly predicted differential changes in FPG and HbA1c, respectively, when comparing RYGB vs. IMI groups, but not in other group comparisons (RYGB vs. BAND or BAND vs. IMI, with the exception of 6 CpGs identified for HbA1c changes when comparing RYGB vs. BAND), after FDR correction for multiple testing. Of these, altered DNAm at 79 CpGs significantly predicted changes in both FPG and HbA1c (RYGB vs. IMI). These CpGs were annotated to 68 genes, among which the most significant ones were SNX18, LNPK, CCDC178, ADAM7 and ZNF23 . These genes are mostly involved in adaptive thermogenesis, temperature homeostasis and regulation of cell population proliferation. Conclusions To our knowledge, this is the first study demonstrating that baseline blood DNAm predicts differential metabolic outcomes induced by different types of weight-loss interventions, independent of weight loss. Such results help explain, at least partly, the favorable metabolic outcomes of RYGB over other types of weight-loss intervention (e.g., BAND, IMI), and are likely to lead to precision strategies for obesity treatment.