Abstract P141: T2D-DNA Methylation Score and Changes in Glycemic Traits in Response to Weight-Loss Dietary Interventions: The MACRO Trial

Introduction: Epigenome-wide association studies (EWAS) have identified several CpGs associated with type 2 diabetes (T2D). A previous study has shown that a DNA methylation score provided more comprehensive information related to T2D risk than individual CpGs. However, whether such T2D-DNA methylation score is associated with changes in glycemic traits in response to weight loss dietary interventions remains unknown. Hypothesis: We hypothesized that a T2D-related DNA methylation score was associated with changes in glycemic traits in response to weight-loss dietary interventions; and may modify the effect of the interventions. Method: The current study included 147 participants from the MACRO trial, who were randomly assigned to a low-fat diet or a low-carbohydrate diet. A weighted DNA methylation score was created by 5 CpGs (cg19693031 at TXNIP , cg11024682 at SREBF1 , cg02650017 at PHOSPHO1 , cg18181703 and SOCS3 , and cg06500161 at ABCG1 ) from a previous EWAS at baseline. One-year changes in glycemic traits were calculated. Results: We found that a higher DNA methylation score was significantly associated with greater reductions in glucose (β: -3.20, SE: 1.08, p=0.003), insulin (β: -2.29, SE: 0.86, p=0.009), and homeostasis model assessments of insulin resistance (HOMA-IR, β: -0.86, SE: 0.30, p=0.005). The DNA methylation score was more strongly associated with changes in glycemic traits than any individual CpG sites ( Figure ). In addition, DNA methylation score significantly interacted with dietary interventions (low-fat vs. low-carbohydrate). The beneficial associations appeared to be stronger among participants with the low-carbohydrate diet (p-interaction=0.009 for glucose, 0.003 for insulin, and 0.004 for HOMA-IR). Conclusions: Our data indicate that a higher DNA methylation score was significantly associated with greater reductions in glycemic traits in response to weight-loss dietary interventions; such beneficial associations were stronger among those who consumed a low-carbohydrate diet.