Open AccessGenetic variants modify the effect of age on APOE methylation in the G enetics of L ipid L owering D rugs and D iet N etwork study
Author(s) -
Ma Yiyi,
Smith Caren E.,
Lai ChaoQiang,
Irvin Marguerite R.,
Parnell Laurence D.,
Lee YuChi,
Pham Lucia,
Aslibekyan Stella,
Claas Steven A.,
Tsai Michael Y.,
Borecki Ingrid B.,
Kabagambe Edmond K.,
Berciano Silvia,
Ordovás José M.,
Absher Devin M.,
Arnett Donna K.
Publication year - 2015
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12293
Subject(s) - methylation , dna methylation , biology , cpg site , apolipoprotein e , genetics , promoter , gene , microbiology and biotechnology , gene expression , medicine , disease
Summary 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.