Background: Epigenome-wide association studies identified DNA methylation (DNAm) at several CpG sites of the carnitine palmitoyltransferase-1A (CPT1A) gene to be associated with triglycerides (TG) . However, little is known about whether the pre-treatment DNAm level at CPT1A is associated with changes in TG in response to weight-loss diet interventions.
Methods: We included 673 white participants with overweight or obesity, who were randomly assigned to 1 of 4 diets varying in macronutrients components. Blood DNAm levels were profiled by a high-resolution methyl-capture sequencing at baseline. We defined the regional DNAm at CPT1A as the average methylation level over CpGs within 500 bp of the 3 TG-related DNAm sites (cg00574958, cg09737197, and cg17058475) , which were closely located. Two-year changes in TG were calculated. Linear regression models were used to examine the associations between baseline DNAm at CPT1A and 2-year changes in TG.
Results: Higher regional DNAm level at CPT1A was associated with lower TG at baseline (β=-2.21, SE=1.01, p=0.029) . We found that dietary fat intake significantly modified the association between baseline DNAm at CPT1A and 2-year changes in TG, independent of concurrent weight-loss (p-int=0.018) . In the low-fat diet group, a higher regional DNAm level was associated with a greater reduction in TG at 2 years, after adjustment for age, sex, baseline body mass index, use of lipid-lowering medication, baseline TG level, and concurrent weight-loss (p=0.01) , whereas no such association was observed in the high-fat diet group (p=0.64) . A similar interaction pattern was also found between dietary fat and baseline DNAm at CPT1A on 2-year changes of TG in very-low-density lipoprotein without apolipoprotein C-III (p-int=0.01) .
Conclusion: Our data indicate that participants with a higher regional DNAm level at CPT1A benefited more in long-term improvement in TG when assigned a low-fat weight-loss diet.
X.Li: None. X.Shao: None. Q.Xue: None. E.Grundberg: None. G.Bray: None. F.Sacks: None. L.Qi: None.
The study was supported by grants from the National Heart, Lung, and Blood Institute (HL071981, HL034594, HL126024) , the National Institute of Diabetes and Digestive and Kidney Diseases (DK115679, DK091718, DK100383) , the Fogarty International Center (TW010790) , and Tulane Research Centers of Excellence Awards. Xiang Li was the recipient of the American Heart Association Predoctoral Fellowship Award (19PRE34380036) .