Background: DNA methylation is influenced by diet and single nucleotide polymorphisms (SNPs), and methylation modulates gene expression. Objective: We aimed to explore whether the gene-by-diet interactions on blood lipids act through DNA methylation. Design: We selected 7 SNPs on the basis of predicted relations in fatty acids, methylation, and lipids.We conducted a meta-analysis and a methylation and mediation analysis with the use of data from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium and the ENCODE (Encyclopedia of DNA Elements) consortium. Results: On the basis of the meta-analysis of 7 cohorts in the CHARGE consortium, higher plasma HDL cholesterol was associated with fewer C alleles at ATP-binding cassette subfamily A member 1 (ABCA1) rs2246293 (β = 20.6 mg/dL, P = 0.015) and higher circulating eicosapentaenoic acid (EPA) (β = 3.87 mg/dL, P = 5.62 1021). The difference in HDL cholesterol associated with higher circulating EPA was dependent on genotypes at rs2246293, and it was greater for each additional C allele (β = 1.69 mg/dL, P = 0.006). In the GOLDN (Genetics of Lipid Lowering Drugs and Diet Network) study, higher ABCA1 promoter cg14019050 methylation was associated with more C alleles at rs2246293 (β = 8.84%, P = 3.51 1018) and lower circulating EPA (β = 21.46%, P = 0.009), and the mean difference in methylation of cg14019050 that was associated with higher EPA was smaller with each additional C allele of rs2246293 (β = 22.83%, P = 0.007). Higher ABCA1 cg14019050 methylation was correlated with lower ABCA1 expression (r = 20.61, P = 0.009) in the ENCODE consortium and lower plasma HDL cholesterol in the GOLDN study (r = 20.12, P = 0.0002). An additional mediation analysis was meta-analyzed across the GOLDN study, Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis. Compared with the model without the adjustment of cg14019050 methylation, the model with such adjustment provided smaller estimates of the mean plasma HDL cholesterol concentration in association with both the rs2246293 C allele and EPA and a smaller difference by rs2246293 genotypes in the EPA-associated HDL cholesterol. However, the differences between 2 nested models were NS (P > 0.05). Conclusion: We obtained little evidence that the gene-by-fatty acid interactions on blood lipids act through DNA methylation.
Bibliographical noteFunding Information:
Supported by the NIH through the American Recovery and Reinvestment Act of 2009 (5RC2HL102419; to the " Building on GWAS for NHLBI-diseases: the U.S. CHARGE Consortium" ). The methylation analysis in the Genetics of Lipid Lowering Drugs and Diet Network was funded by the National Heart, Lung, and Blood Institute (NHLBI) (grants U01HL072524-04 and 5R01HL1043135-04) and by the National Institute of Neurological Disorders and Stroke (grant T32NS054584). Methylation in the Cardiovascular Health Study was funded by the NHLBI (grants HL092111, HL111089, and HL116747) and by the Laughlin Family, Alpha Phi Foundation, and Locke Charitable Foundation. The methylation analysis the in Multi-Ethnic Study of Atherosclerosis was supported by the NHLBI (grant 1R01HL101250-01; to Wake Forest University Health Sciences). Study-specific sources of support and acknowledgments are listed in Supplemental Methods.
- DNA methylation
- Fatty acids
- Genetic variants
- Plasma lipids