title: Genetic variants modify the effect of age on APOE methylation in the Genetics of Lipid Lowering Drugs and Diet Network study.
abstract: Although apolipoprotein E (APOE) variants are associated with age-related diseases, the underlying mechanism is unknown and DNA methylation may be a potential one. With methylation data, measured by the Infinium Human Methylation 450 array, from 993 participants (age ranging from 18 to 87 years) in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study, and from Encyclopedia of DNA Elements (ENCODE) consortium, combined with published methylation datasets, we described the methylation pattern of 13 CpG sites within APOE locus, their correlations with gene expression across cell types, and their relationships with age, plasma lipids, and sequence variants. Based on methylation levels and the genetic regions, we categorized the 13 APOE CpG sites into three groups: Group 1 showed hypermethylation (> 50%) and were located in the promoter region, Group 2 exhibited hypomethylation (< 50%) and were located in the first two exons and introns, and Group 3 showed hypermethylation (> 50%) and were located in the exon 4. APOE methylation was negatively correlated with gene expression (minimum r = -0.66, P = 0.004). APOE methylation was significantly associated with age (minimum P = 2.06E-08) and plasma total cholesterol (minimum P = 3.53E-03). Finally, APOE methylation patterns differed across APOE ε variants (minimum P = 3.51E-05) and the promoter variant rs405509 (minimum P = 0.01), which further showed a significant interaction with age (P = 0.03). These findings suggest that methylation may be a potential mechanistic explanation for APOE functions related to aging and call for further molecular mechanistic studies.
authors.affiliation: Nutrition and Genomics Laboratory, Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.
authors.forename: Yiyi
authors.initials: Y
authors.lastname: Ma
authors.forename: Caren E
authors.initials: CE
authors.lastname: Smith
authors.forename: Chao-Qiang
authors.initials: CQ
authors.lastname: Lai
authors.forename: Marguerite R
authors.initials: MR
authors.lastname: Irvin
authors.forename: Laurence D
authors.initials: LD
authors.lastname: Parnell
authors.forename: Yu-Chi
authors.initials: YC
authors.lastname: Lee
authors.forename: Lucia
authors.initials: L
authors.lastname: Pham
authors.forename: Stella
authors.initials: S
authors.lastname: Aslibekyan
authors.forename: Steven A
authors.initials: SA
authors.lastname: Claas
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Tsai
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Borecki
authors.forename: Edmond K
authors.initials: EK
authors.lastname: Kabagambe
authors.forename: Silvia
authors.initials: S
authors.lastname: Berciano
authors.forename: José M
authors.initials: JM
authors.lastname: Ordovás
authors.forename: Devin M
authors.initials: DM
authors.lastname: Absher
authors.forename: Donna K
authors.initials: DK
authors.lastname: Arnett
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D001057:Apolipoproteins E / Q000097:blood / Q000235:genetics*; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics*; D004032:Diet; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D014644:Genetic Variation; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008055:Lipids / Q000097:blood; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D055815:Young Adult
chemical_list: D001057:Apolipoproteins E; D000960:Hypolipidemic Agents; D008055:Lipids
keywords: DNA methylation; age; apolipoprotein E; epidemiology; interaction; variants