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

Authors: MA, YIYI - Boston University; FOLLIS, JACK - St Thomas University; SMITH, CAREN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; TANAKA, TOSHIKO - National Institute On Aging (NIA, NIH); MANICHAIKL, ARI - University Of Virginia; CHU, AUDREY - Harvard University; SAMIERI, CECILIA - University Of Bordeaux; ZHOU, XIA - University Of Minnesota; GUAN, WEIHUA - University Of Minnesota; WANG, LU - Harvard University; BIGGS, MARY - University Of Washington; CHEN, YII-DER - Cedars-Sinai Medical Center; HERNANDEZ, DENA - National Institute On Aging (NIA, NIH); BORECKI, INGRID - Washington University; CHASMAN, DANIEL - Harvard University; RICH, STEPHEN - University Of Virginia; FERRUCCI, LUIGI - National Institute On Aging (NIA, NIH); IRVIN, MARGUERITE - University Of Alabama; ASLIBEKYAN, STELLA - University Of Alabama; ZHI, DEGUI - University Of Alabama; TIWARI, HEMANT - University Of Alabama; CLAAS, STEVEN - University Of Alabama; SHA, JIM - University Of Alabama; KABAGAMBE, EDMOND - Vanderbilt University; Lai, Chao Qiang; Parnell, Laurence; LEE, YU-CHI - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; AMOUYEL, PHILIPPE - Universite De Lille; LAMBERT, JEAN-CHARLES - Universite De Lille; PSATY, BRUCE - University Of Washington; KING IRENA - University Of Mexico; MOZAFFARIAN, DARIUSH - Tufts University; MCKNIGHT, BARBARA - University Of Washington; BANDINELLI, STEFANIA - Azienda Sanitaria Di Firenze; TSAI, MICHAEL - University Of Minnesota; RIDKER, PAUL - Harvard University; DING, JINGZHONG - Wake Forest School Of Medicine; MSTAT, KURT - Wake Forest School Of Medicine; LIU, YONGMEI - Wake Forest School Of Medicine; SOTOODEHNIA, NONA - University Of Washington; BARBERGER-GATEAU, PASCALE - Institut National De La Sante Et De La Recherche Medicale (INSERM); STEFFEN, LYN - University Of Minnesota; SISCOVICK, DAVID - New York Academy Of Medicine; ABSHER, DEVIN - Hudsonalpha Institute For Biotechnology; ARNETT, DONNA - University Of Alabama; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; LEMAITRE, ROZENN - University Of Washington

Submitted to: The American Journal of Clinical Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/8/2015
Publication Date: 1/20/2016
Citation: Ma, Y., Follis, J., Smith, C.E., Tanaka, T., Manichaikl, A., Chu, A.Y., Samieri, C., Zhou, X., Guan, W., Wang, L., Biggs, M., Chen, Y., Hernandez, D., Borecki, I.B., Chasman, D.I., Rich, S.S., Ferrucci, L., Irvin, M.R., Aslibekyan, S., Zhi, D., Tiwari, H.K., Claas, S.A., Sha, J., Kabagambe, E.K., Lai, C., Parnell, L.D., Lee, Y., Amouyel, P., Lambert, J., Psaty, B.M., King Irena, Mozaffarian, D., Mcknight, B., Bandinelli, S., Tsai, M.Y., Ridker, P.M., Ding, J., Mstat, K.L., Liu, Y., Sotoodehnia, N., Barberger-Gateau, P., Steffen, L.M., Siscovick, D.S., Absher, D.M., Arnett, D.K., Ordovas, J.M., Lemaitre, R.N. 2016. Interaction of methylation-related genetic variants with circulating fatty acids on plasma lipids: a meta-analysis of 7 studies & methylation analysis of 3 studies in the Cohorts for Heart & Aging Research. American Journal of Clinical Nutrition. doi: 10.3945/ajcn.115.112987.

Interpretive Summary: DNA methylation is part of the "non-genetic" mechanisms that regulate the timely expression of our genes. DNA methylation is influenced by environmental factors: among them, diet plays a pivotal role. Genetic variation further modulates the sites in the genome that can be methylated. In this work we aimed to explore whether existing interactions between genetics and diet on blood lipids act through DNA methylation. For this purpose we selected 7 genetic variants on the basis of predicted relations in fatty acids, methylation, and lipids. We conducted a combined analysis (meta-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. We showed that the mean difference in HDL cholesterol associated with higher circulating eicosapentaenoic acid (EPA) depended on certain genotypes, which suggests that individuals with specific sequence variants may benefit from higher circulating EPA. Our findings illustrated possible connections between circulating EPA, genetic variation, DNA methylation, and gene expression. However, we obtained little evidence that ABCA1 methylation acted as a mediator of the genotype-dependent differences in the effect of EPA on plasma HDL cholesterol. The current study did not garner substantial evidence to support the hypothesis that gene-by-fatty acid interactions on plasma lipids are mediated by DNA methylation.

Technical 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 (beta = -0.6 mg/dL, P = 0.015) and higher circulating eicosapentaenoic acid (EPA) (beta = 3.87 mg/dL, P = 5.62 x 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 (beta = 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 (beta = 8.84%, P = 3.51 x 10(18)) and lower circulating EPA (beta = -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 (beta = -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).