DNA Methylation of Lipid-Related Genes Affects Blood Lipid Levels

Abstract

Background Epigenetic mechanisms might be involved in the regulation of interindividual lipid level variability and thus may contribute to the cardiovascular risk profile. The aim of this study was to investigate the association between genome-wide DNA methylation and blood lipid levels high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and total cholesterol. Observed DNA methylation changes were also further analyzed to examine their relationship with previous hospitalized myocardial infarction. Methods and Results Genome-wide DNA methylation patterns were determined in whole blood samples of 1776 subjects of the Cooperative Health Research in the Region of Augsburg F4 cohort using the Infinium HumanMethylation450 BeadChip (Illumina). Ten novel lipid-related CpG sites annotated to various genes including ABCG1, MIR33B/SREBF1, and TNIP1 were identified. CpG cg06500161, located in ABCG1, was associated in opposite directions with both high-density lipoprotein cholesterol (β coefficient=−0.049; P=8.26E-17) and triglyceride levels (β=0.070; P=1.21E-27). Eight associations were confirmed by replication in the Cooperative Health Research in the Region of Augsburg F3 study (n=499) and in the Invecchiare in Chianti, Aging in the Chianti Area study (n=472). Associations between triglyceride levels and SREBF1 and ABCG1 were also found in adipose tissue of the Multiple Tissue Human Expression Resource cohort (n=634). Expression analysis revealed an association between ABCG1 methylation and lipid levels that might be partly mediated by ABCG1 expression. DNA methylation of ABCG1 might also play a role in previous hospitalized myocardial infarction (odds ratio, 1.15; 95% confidence interval=1.06–1.25). Conclusions Epigenetic modifications of the newly identified loci might regulate disturbed blood lipid levels and thus contribute to the development of complex lipid-related diseases.

Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach

“…DHCR24 (24-dehydrocholesterol reductase) catalyzes the reduction of sterol intermediates during cholesterol synthesis. Differential methylation of SREBF1, CPT1A, ABCG1, and DHCR24 has been reported in previous EWASs of adiposity, glycemic traits, and lipids [29][30][31][71][72][73][74][75][76]. We add to the published literature and provide evidence that differential methylation at the ABCG1 locus is likely a downstream effect of BMI.…”

Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT/EDIC type 1 diabetes cohort

“…This finding was further validated in WB by pyrosequencing and ampliconseq. Interestingly, association of TXNIP hypo-me at the same CpG3 with type 2 diabetes and related traits (including fasting glucose, HbA1C, and insulin resistance) (57-60), serum metabolites related to diabetes (61), and high blood triglycerides (62) in WB DNA from various cohorts was recently reported. Because Txnip was associated with lipids in a mouse model (63), we reanalyzed methylation differences in cases vs. controls at CpG3 after adding triglycerides at the EDIC Study baseline as a covariate.…”

The multifaceted interplay between lipids and epigenetics

“…A second EWAS in CD4 þ T cells (n ¼ 663) observed associations between LDL and VLDL levels and CpGs in CPT1A [32], which was later replicated in blood (n ¼ 526) [33]. The most recent EWAS in whole blood (n ¼ 1776) observed associations between DNA methylation and triglycerides for CpGs mapping to the genes CPT1A, ABCG1, SREBF1 and SCD, between DNA methylation and HDL-C for a CpG in ABCG1, and between DNA methylation and LDL-C for a CpG in TNIP1 [34]. Several associations were subsequently replicated in adipose tissue (n ¼ 634) and skin (n ¼ 395), indicating that associations are not necessarily tissue specific [34].…”

“…The most recent EWAS in whole blood (n ¼ 1776) observed associations between DNA methylation and triglycerides for CpGs mapping to the genes CPT1A, ABCG1, SREBF1 and SCD, between DNA methylation and HDL-C for a CpG in ABCG1, and between DNA methylation and LDL-C for a CpG in TNIP1 [34]. Several associations were subsequently replicated in adipose tissue (n ¼ 634) and skin (n ¼ 395), indicating that associations are not necessarily tissue specific [34]. Most of these genes (including ABCG1 which was also identified as differentially expressed after oxLDL exposure in the in-vitro study previously discussed [23 && ]) have an important function in lipid metabolism, supporting a regulatory role of epigenetic mechanisms.…”