Interaction of methylation-related genetic variants with circulating fatty acids on plasma lipids: a meta-analysis of 7 studies and methylation analysis of 3 studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium

Am J Clin Nutr. 2016 Feb;103(2):567-78. doi: 10.3945/ajcn.115.112987. Epub 2016 Jan 20.

Abstract

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 = -0.6 mg/dL, P = 0.015) and higher circulating eicosapentaenoic acid (EPA) (β = 3.87 mg/dL, P = 5.62 × 10(21)). 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 × 10(18)) and lower circulating EPA (β = -1.46%, 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 = -2.83%, P = 0.007). Higher ABCA1 cg14019050 methylation was correlated with lower ABCA1 expression (r = -0.61, P = 0.009) in the ENCODE consortium and lower plasma HDL cholesterol in the GOLDN study (r = -0.12, 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.

Keywords: DNA methylation; epidemiology; fatty acids; genetic variants; plasma lipids.

Publication types

  • Meta-Analysis
  • Research Support, American Recovery and Reinvestment Act
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1 / genetics*
  • ATP Binding Cassette Transporter 1 / metabolism
  • Apolipoproteins E / blood
  • Apolipoproteins E / genetics
  • Apolipoproteins E / metabolism
  • Cholesterol, HDL / blood*
  • Cohort Studies
  • DNA Methylation*
  • Diet / adverse effects
  • Eicosapentaenoic Acid / analysis
  • Eicosapentaenoic Acid / blood*
  • Epigenesis, Genetic*
  • Fatty Acids / analysis
  • Fatty Acids / blood
  • Gene Expression Regulation*
  • Humans
  • Lipids / blood
  • Lipids / chemistry
  • Polymorphism, Single Nucleotide*
  • Promoter Regions, Genetic
  • Triglycerides / blood
  • Triglycerides / chemistry

Substances

  • ABCA1 protein, human
  • ATP Binding Cassette Transporter 1
  • Apolipoproteins E
  • Cholesterol, HDL
  • Fatty Acids
  • Lipids
  • Triglycerides
  • Eicosapentaenoic Acid