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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #340720

Research Project: Genomics, Nutrition, and Health

Location: Jean Mayer Human Nutrition Research Center On Aging

Title: 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

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

Submitted to: 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).