Genetic variants modify the effect of age on APOE methylation in the Genetics of Lipid Lowering Drugs and Diet Network study

Authors: MA, YI YI - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; SMITH, CAREN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; Lai, Chao Qiang; IRVIN, MARGUERITE - University Of Alabama; Parnell, Laurence; PHAM, LUCIA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; ASLIBEKYAN, STELLA - University Of Alabama; CLAAS, STEVEN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; TSAI, MICHAEL - University Of Minnesota; BORECKI, INGRID - Washington University; KABAGAMBE, EDMOND - Vanderbilt University; BERCIANO, SILVIA - Imdea Institute; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; ABSHER, DEVIN - Hudsonalpha Institute For Biotechnology

Submitted to: Aging Cell
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/3/2014
Publication Date: 12/5/2014
Citation: Ma, Y., Smith, C.E., Lai, C., Irvin, M.R., Parnell, L.D., Pham, L., Aslibekyan, S., Claas, S.A., Tsai, M.Y., Borecki, I.B., Kabagambe, E.K., Berciano, S., Ordovas, J.M., Absher, D.M. 2014. Genetic variants modify the effect of age on APOE methylation in the Genetics of Lipid Lowering Drugs and Diet Network study. Aging Cell. 14:49-59.

Interpretive Summary: The world population is living longer and this has resulted in a dramatic increase of age related diseases. Genetics play an important role in the aging process and longevity of individuals. One of the genes implicated in this process is the apolipoprotein E (APOE) gene. Variants of APOE have been associated with longevity, Alzheimer’s, macular degeneration and cardiovascular diseases. However, despite extensive research, it is still unclear why different forms of the APOE gene can have such dramatic impact on the aging process. Mounting evidence suggests that a type of gene modification called DNA methylation may be one of the causes. So we tested this theory on about one thousand individuals. Our results show that DNA methylation at the APOE was linked with aging. Moreover, our findings in these individuals were corroborated by carrying these analyses on a public dataset from the Encyclopedia of DNA Elements (ENCODE) consortium.

Technical 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 y) in the Genetics of Lipid Lowering Drugs and Diet Network study (GOLDN) study and from Encyclopedia of DNA Elements (ENCODE) consortium, 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. Methylation at most CpG sites was negatively correlated with gene expression (minimum r = 0.66 with P = 0.004). APOE methylation was significantly associated with age (minimum P = 2.06E 08) and plasma total cholesterol (minimum P = 0.005). Finally, APOE methylation patterns differed across APOE epsilon variants (minimum P = 7.44E 05) and the promoter variant rs405509 (minimum P = 0.03), 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.