Identification and validation of seven new loci showing differential DNA methylation related to serum lipid profile: an epigenome-wide approach. The REGICOR study.

Abstract

Lipid traits (total, low-densityand high-density lipoproteincholesterol, and triglycerides) are risk factors for cardiovascular disease. DNA methylation is an inherited but also modifiable epigenetic mark that has been related tocardiovascular risk factors. Our aim was to identify loci showing differential DNA methylation related to serum lipid levels. Blood DNA methylation was assessed using the Illumina HumanMethylation450 BeadChip. Atwo-stage epigenome-wide association study was performed, with a discovery sample intheREGICOR study (n=645)and validation in the Framingham Offspring Study (n=2,542).FourteenCpG sites located in 9 genes (SREBF1, SREBF2, PHOSPHO1, SYNGAP1, ABCG1, CPT1A, MYLIP, TXNIP andSLC7A11) and 2 intergenic regions showeddifferential methylation in association with lipid traits. Six of these genes and 1 intergenic region were new discoveries showing differential methylation relatedto total cholesterol (SREBF2), HDL-cholesterol (PHOSPHO1, SYNGAP1 and an intergenic region in chromosome 2) and triglycerides (MYLIP, TXNIP andSLC7A11).These CpGs explained0.7%, 9.5% and18.9% of the variability of total cholesterol, HDL cholesterol and triglycerides in the Framingham Offspring Study, respectively. The expression of the genesSREBF2and SREBF1was inversely associated with methylation of their corresponding CpGs(p-value=0.0042 and 0.0045, respectively) in participants of the GOLDN study(n=98). In turn, SREBF1expression wasdirectly associated with HDL cholesterol(p-value=0.0429). Genetic variants in SREBF1, PHOSPHO1, ABCG1and CPT1Awerealso associated with lipid profile. Further research is warranted to functionally validatethesenew loci and assess the causality ofnew and established associationsbetween these differentially methylated lociand lipid metabolism.