Abstract P619: DNA Methylation at SREBF1 and Long-Term Changes in Body Composition: The POUNDS Lost Trial

Introduction: A previous epigenome-wide association study has causally linked DNA methylation (DNAm) at the SREBF1 gene (cg11024682) with obesity and lipids. However, little is known about whether DNAm at SREBF1 is associated with long-term changes in body adiposity and composition. Hypothesis: We hypothesized that participants with different DNAm at SRBF1 might respond differently to dietary weight-loss interventions on changes in body adiposity and composition. Methods: The current study included 314 individuals with overweight or obese, who participated in POUNDS Lost: a 2-year randomized dietary weight-loss trial. The blood DNAm level was profiled by methylC-capture sequencing at baseline. Regional DNAm at SREBF1 was calculated as the average methylation level over CpGs within ±250 bp of cg11024682. Body composition, including total fat mass (FM), percentage of FM (FM%), total fat-free mass (FFM), percentage of FFM (FFM%), and percentage of trunk fat (TF%) were measured by dual-energy X-ray absorptiometry (DEXA) at baseline, 6 months, and 2 years. Results: Lower regional DNAm at SREBF1 was significantly associated with changes in body composition across 2 years ( Table ). At 6 months, per SD lower regional DNAm at SREBF1 was significantly associated with greater reductions in FM (β [SE] -0.23 [0.07], p=0.002), FM% (-0.30 [0.09], p<0.001), and TF% (-0.44 [0.13], p<0.001), and greater increases in FFM (0.18 [0.08], p=0.028) and FFM% (0.30 [0.09], p<0.001), regardless of dietary intervention groups and independent of concurrent weight loss. Such association remained at 2 years: FM (β [SE] -0.21 [0.10], p=0.045), FM% (-0.32 [0.11], p=0.004), TF% (-0.36 [0.16], p=0.026), FFM (0.22 [0.12], p=0.07) and FFM% (0.32 [0.11], p=0.004). Conclusions: Overweight and obese individuals with a lower regional DNAm at SREBF1 achieved greater improvement in body composition across the 2-year intervention, independent of concurrent weight loss, suggesting DNAm at SREBF1 is predictive of individuals’ response to treatment.