Abstract 12: Whole Blood DNA Methylation Signatures of a Mediterranean-style Dietary Pattern

Introduction: Mediterranean-style dietary patterns (MSDPs) have been associated with lower risk of cardiometabolic diseases, but the underlying biological mechanisms are poorly understood. To date, little is known in humans of the relationship between MSDPs and epigenetics. We hypothesized that adherence to a MSDP is associated with DNA methylation, an important epigenetic modification. Methods: We conducted a cross-sectional study of 3,563 Framingham Heart Study participants (median age 59 years, 55% women). We excluded participants with heavy alcohol use. Whole-blood derived DNA methylation of 480,000 cytosine-phosphate-guanine dinucleotides (CpGs) was assessed using the Illumina HumanMethylation450 BeadChip. A MSDP score was created based on nine dietary components, including fruits, vegetables, legumes, nuts, whole grains, fish, red meat, alcohol, and ratio of monounsaturated fatty acids to saturated fatty acids. Food intake was assessed by a validated food frequency questionnaire. Our study sample was randomly split into separate discovery/replication groups (n=1,788 and n=1,775) by pedigrees. We tested the association of CpG methylation with the MSDP score using linear mixed model, adjusted for sex, age, and energy intake (as well as family structure, imputed leukocyte composition, and technical variables). CpGs identified in discovery at FDR<0.05 were taken forward for replication. We then tested the significance (Bonferroni corrected α 0.05) of the identified CpGs after additional adjustment for smoking, physical activity, and BMI in whole study sample. Results: One CpG, cg05575921 in the AHRR gene, was associated with MSDP score in the discovery sample ( P =3.3x10 -10 ) and replicated in the replication sample ( P =3.6x10 -5 ). In whole study sample, higher MSDP score was associated with greater methylation of cg05575921 after adjustment for sex, age, energy intake, smoking, physical activity, and BMI ( P =4.5x10 -3 ). Higher fruit and whole grain intake was also associated with higher methylation level of cg05575921 ( P =3.8x10 -7 and 5.1x10 -8 , respectively) and legume intake was associated with higher methylation level of cg17333223 (annotated to the NSA2 gene, P =1.3x10 -7 ). In contrast, fruit intake was associated with lower methylation of cg07035242 (annotated to the UBIAD1 gene, P =2.0x10 -7 ). These patterns persisted in the replication and in whole study sample. Conclusions: These data demonstrate a unique whole blood DNA methylation signature of a MSDP score and some of its individual components. The differentially methylated genes may represent therapeutic targets for prevention or treatment of cardiometabolic diseases. Future work is needed to explore the underlying mechanisms.