Background: Many epigenetic loci have been associated with plasma triglyceride (TG) levels, but epigenetic connections between those loci and dietary exposures are largely unknown. This study aimed to characterize the epigenetic links between diet, lifestyle, and TG.Methods: We first conducted an epigenome-wide association study (EWAS) for TG in the Framingham Heart Study Offspring population (FHS, n = 2,264). We then examined relationships between dietary and lifestyle-related variables, collected four times in 13 years, and differential DNA methylation sites (DMSs) associated with the last TG measures. Third, we conducted a mediation analysis to evaluate the causal relationships between diet-related variables and TG. Finally, we replicated three steps to validate identified DMSs associated with alcohol and carbohydrate intake in the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) study (n = 993).Results: In the FHS, the EWAS revealed 28 TG-associated DMSs at 19 gene regions. We identified 102 unique associations between these DMSs and one or more dietary and lifestyle-related variables. Alcohol and carbohydrate intake showed the most significant and consistent associations with 11 TG-associated DMSs. Mediation analyses demonstrated that alcohol and carbohydrate intake independently affect TG via DMSs as mediators. Higher alcohol intake was associated with lower methylation at seven DMSs and higher TG. In contrast, increased carbohydrate intake was associated with higher DNA methylation at two DMSs (CPT1A and SLC7A11) and lower TG. Validation in the GOLDN further supports the findings.Conclusion: Our findings imply that TG-associated DMSs reflect dietary intakes, particularly alcoholic drinks, which could affect the current cardiometabolic risk via epigenetic changes. This study illustrates a new method to map epigenetic signatures of environmental factors for disease risk. Identification of epigenetic markers of dietary intake can provide insight into an individual’s risk of cardiovascular disease and support the application of precision nutrition.Clinical Trial Registration:www.ClinicalTrials.gov, the Framingham Heart Study (FHS), NCT00005121; the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN), NCT01023750.

Type 2 Diabetes (T2D) is a multi‐factorial disease, caused by a complex interaction of environmental and genetic factors. Dietary fats represent an important environmental factor. Our previous research has demonstrated that the ‘nod like receptor pyrin domain containing‐3’ (NLRP3) inflammasome plays a critical role in obesity associated insulin resistance (IR) and has a specific sensitivity to saturated fatty acids (SFA) (*Finucane et al, 2014). We investigated genetic variants related to NLRP3 and potential interactions with SFA, which may modulate T2D risk. Using METAL software, a cross‐sectional meta‐analyses of 6 Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (n=19,005), tested interactions (linear regression effects) between dietary saturated fats and candidate NLRP3 related SNP's, to determine if these interactions could modulate three glycemic traits, fasting insulin, fasting glucose and Homeostasis Model Assessment of IR (HOMA‐IR). NLRP3 variant rs12143966 interacted with SFA intake (β ± SE = 0.0068 ± 0.002, p= 0.001), suggesting that each 1% increase SFA intake, in the presence of the minor A allele (MAF 0.38), increased fasting insulin by 0.0068 units. Olfactory Receptor Family 2, Subfamily B member 11 ( OR2B11 ) variant rs4925663, minor allele T (MAF 0.4), also interacted with SFA (β ± SE = −0.0068 ± 0.002, p= 0.0001), suggesting a 0.0068 uIU/ml reduction in fasting insulin with each additional 1% SFA intake. Both SNP's are located on Chromosome 1 q44. In Silico functional analysis describes OR2B11 variant rs4925663 as a non‐synonymous missense SNP with highly significant eQTL hits with NLRP3 expression in whole blood and liver tissue. Two inflammatory SNPs show a novel interaction with dietary SFA to modulate fasting insulin. Altering SFA intake may modulate T2D risk depending on the genotype of inflammasome related variants. Support or Funding Information Science Foundation Ireland Principal Investigator Programme awarded to Prof Helen Roche (11/PI/1119)