title: 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.
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.
  
  
  METHODS
  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).
  
  
  CONCLUSIONS
  We obtained little evidence that the gene-by-fatty acid interactions on blood lipids act through DNA methylation.
authors.affiliation: Biomedical Genetics, Department of Medicine, Boston University, Boston, MA; Jean Mayer USDA Human Nutrition Research Center on Aging and yiyima@bu.edu.
authors.forename: Yiyi
authors.identifier: http://orcid.org/0000-0002-3609-8877
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Mathematics, Computer Science and Cooperative Engineering, University of St. Thomas, Houston, TX;
authors.forename: Jack L
authors.initials: JL
authors.lastname: Follis
authors.affiliation: Jean Mayer USDA Human Nutrition Research Center on Aging and.
authors.forename: Caren E
authors.initials: CE
authors.lastname: Smith
authors.affiliation: Translational Gerontology Branch and.
authors.forename: Toshiko
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, VA;
authors.forename: Ani W
authors.initials: AW
authors.lastname: Manichaikul
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, MA;
authors.forename: Audrey Y
authors.initials: AY
authors.lastname: Chu
authors.affiliation: Inserm, U897, University of Bordeaux, Bordeaux, France; University of Bordeaux, ISPED, Bordeaux, France;
authors.forename: Cecilia
authors.initials: C
authors.lastname: Samieri
authors.affiliation: Divisions of Epidemiology and Community Health and.
authors.forename: Xia
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Biostatistics, School of Public Health, and.
authors.forename: Weihua
authors.initials: W
authors.lastname: Guan
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, MA;
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Departments of Biostatistics, Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA;
authors.forename: Mary L
authors.initials: ML
authors.lastname: Biggs
authors.affiliation: Cedars-Sinai Medical Center, Medical Genetics Research Institute, Los Angeles, CA; Los Angeles Biomedical Institute, Harbor-University of California, Los Angeles Medical Center, Torrance, CA;
authors.forename: Yii-Der I
authors.initials: YD
authors.lastname: Chen
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD;
authors.forename: Dena G
authors.initials: DG
authors.lastname: Hernandez
authors.affiliation: Department of Genetics, Washington University School of Medicine, St. Louis, MO;
authors.forename: Ingrid
authors.initials: I
authors.lastname: Borecki
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, MA;
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Chasman
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, VA;
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.affiliation: Translational Gerontology Branch and.
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
authors.affiliation: Departments of Epidemiology and.
authors.forename: Marguerite Ryan
authors.initials: MR
authors.lastname: Irvin
authors.affiliation: Departments of Epidemiology and.
authors.forename: Stella
authors.initials: S
authors.lastname: Aslibekyan
authors.affiliation: Biostatics, University of Alabama at Birmingham, Birmingham, AL;
authors.forename: Degui
authors.initials: D
authors.lastname: Zhi
authors.affiliation: Biostatics, University of Alabama at Birmingham, Birmingham, AL;
authors.forename: Hemant K
authors.initials: HK
authors.lastname: Tiwari
authors.affiliation: Departments of Epidemiology and.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Claas
authors.affiliation: Departments of Epidemiology and.
authors.forename: Jin
authors.initials: J
authors.lastname: Sha
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN;
authors.forename: Edmond K
authors.initials: EK
authors.lastname: Kabagambe
authors.affiliation: Jean Mayer USDA Human Nutrition Research Center on Aging and.
authors.forename: Chao-Qiang
authors.initials: CQ
authors.lastname: Lai
authors.affiliation: Jean Mayer USDA Human Nutrition Research Center on Aging and.
authors.forename: Laurence D
authors.initials: LD
authors.lastname: Parnell
authors.affiliation: Jean Mayer USDA Human Nutrition Research Center on Aging and.
authors.forename: Yu-Chi
authors.initials: YC
authors.lastname: Lee
authors.affiliation: Inserm, UMR1167, Lille, France; University of Lille, Lille, France; Institut Pasteur de Lille, Lille, France; Regional University Hospital of Lille, Lille, France;
authors.forename: Philippe
authors.initials: P
authors.lastname: Amouyel
authors.affiliation: Inserm, UMR1167, Lille, France; University of Lille, Lille, France; Institut Pasteur de Lille, Lille, France;
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Lambert
authors.affiliation: Epidemiology, Health Services, and Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA;
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.affiliation: Department of Internal Medicine, University of New Mexico, Albuquerque, NM;
authors.forename: Irena B
authors.initials: IB
authors.lastname: King
authors.affiliation: Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA;
authors.forename: Dariush
authors.initials: D
authors.lastname: Mozaffarian
authors.affiliation: Departments of Biostatistics, Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA;
authors.forename: Barbara
authors.initials: B
authors.lastname: McKnight
authors.affiliation: Geriatric Unit, Azienda Sanitaria Firenze, Florence, Italy;
authors.forename: Stefania
authors.initials: S
authors.lastname: Bandinelli
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN;
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Tsai
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, MA;
authors.forename: Paul M
authors.initials: PM
authors.lastname: Ridker
authors.affiliation: Departments of Internal Medicine and.
authors.forename: Jingzhong
authors.initials: J
authors.lastname: Ding
authors.affiliation: Epidemiology & Prevention, Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC;
authors.forename: Kurt Lohmant
authors.initials: KL
authors.lastname: Mstat
authors.affiliation: Epidemiology & Prevention, Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC;
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA;
authors.forename: Nona
authors.initials: N
authors.lastname: Sotoodehnia
authors.affiliation: Inserm, U897, University of Bordeaux, Bordeaux, France; University of Bordeaux, ISPED, Bordeaux, France;
authors.forename: Pascale
authors.initials: P
authors.lastname: Barberger-Gateau
authors.affiliation: Divisions of Epidemiology and Community Health and.
authors.forename: Lyn M
authors.initials: LM
authors.lastname: Steffen
authors.affiliation: New York Academy of Medicine, New York, NY;
authors.forename: David S
authors.initials: DS
authors.lastname: Siscovick
authors.affiliation: Hudson Alpha Institute for Biotechnology, Huntsville, AL;
authors.forename: Devin
authors.initials: D
authors.lastname: Absher
authors.affiliation: Departments of Epidemiology and.
authors.forename: Donna K
authors.initials: DK
authors.lastname: Arnett
authors.affiliation: Jean Mayer USDA Human Nutrition Research Center on Aging and Department of Epidemiology and Population Genetics, Cardiovascular Research Center, Madrid, Spain; and IMDEA Food Institute, Madrid, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Ordovás
authors.affiliation: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA;
authors.forename: Rozenn N
authors.initials: RN
authors.lastname: Lemaitre
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics* / Q000378:metabolism; D001057:Apolipoproteins E / Q000097:blood / Q000235:genetics / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood*; D015331:Cohort Studies; D019175:DNA Methylation; D004032:Diet / Q000009:adverse effects; D015118:Eicosapentaenoic Acid / Q000032:analysis / Q000097:blood*; D044127:Epigenesis, Genetic; D005227:Fatty Acids / Q000032:analysis / Q000097:blood; D005786:Gene Expression Regulation; D006801:Humans; D008055:Lipids / Q000097:blood / Q000737:chemistry; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D014280:Triglycerides / Q000097:blood / Q000737:chemistry
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D005227:Fatty Acids; D008055:Lipids; D014280:Triglycerides; D015118:Eicosapentaenoic Acid
keywords: DNA methylation; epidemiology; fatty acids; genetic variants; plasma lipids