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

Aging Cell

Yiyi Ma²  Caren E. Smith²  Chao-Qiang Lai²  Marguerite R. Irvin⁶  Laurence D. Parnell²  Yu-Chi Lee²  Lucia Pham²  Stella Aslibekyan⁶  Steven A. Claas⁶  Michael Y. Tsai¹  Ingrid B. Borecki⁴  Edmond K. Kabagambe⁵  Silvia Berciano³  José M. Ordovás²  Devin M. Absher⁷ 

[1] Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA;Nutrition and Genomics Laboratory, Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA;Instituto Madrileño de Estudios Avanzados en Alimentación (IMDEA-FOOD), Madrid, Spain;Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA;Department of Medicine, Vanderbilt University, Nashville, TN, USA;Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA;Hudson Alpha Institute for Biotechnology, Huntsville, AL, USA

关键词: apolipoprotein E;    age;    DNA methylation;    variants;    epidemiology;    interaction;   

DOI  :  10.1111/acel.12293

来源: Wiley

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

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