Abstract P251: Epigenome-Wide Study of Erythrocyte Fatty Acids in the Genetics of Lipid Lowering Drugs and Diet Network

Abstract

Introduction: Dietary fatty acids have a role in many physiological mechanisms that influence cardiovascular health. An emerging body of evidence suggests that dietary fats may interact with genetic variants in regulating tissue levels of fatty acids, thus impacting disease risk. Epigenetic changes such as DNA methylation are a promising mechanism underlying such interactions. However, no studies to date have investigated the relationship between DNA methylation and tissue fatty acids at the genome-wide level. Methods: We have performed the first epigenome-wide association study (EWAS) of erythrocyte concentrations of polyunsaturated, monounsaturated, saturated, and trans fatty acids in 958 participants of the Genetics of Diet and Lipid Lowering Drugs Network (GOLDN). We assayed the methylation status of approximately 450,000 CpG sites in CD4+ T-cells. To investigate the associations between methylation of each CpG site and red blood cell fatty acids, we fit linear mixed models adjusted for age, sex, cell purity, and family structure. Results: The strongest association was observed between the methylation status of a CpG site in PDE4D, previously linked to systemic inflammation and stroke, and red blood cell trans fatty acids (P=4x10-7). In the analysis of polyunsaturated fatty acids, we found inverse associations with the methylation status of two CpG sites in BRSK2 (P=9x10-6 and P=1x10-5 respectively), as well as with a CpG site located in a “gene desert” on chromosome 14 proximally to VRK1 (P=5x10-7). BRSK2 encodes a kinase previously shown to control epigenetic programs that determine T-cell function. The top hits for monounsaturated and saturated fatty acids were located in ATL2 (P=1x10-6) and FGD2 (P=1x10-5), respectively. Conclusions: We present preliminary evidence of cross-sectional association between the methylation status of several biologically relevant genomic regions and erythrocyte concentrations of polyunsaturated, trans, monounsaturated, and saturated fatty acids. Upon successful validation, these findings further current understanding of gene-fatty acid interactions in human health and disease.