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TREM locus methylation in Alzheimer’s disease
Author(s) -
Weber Grace E.,
Khrestian Maria,
Shao Yvonne,
Tuason Elizabeth D.,
Rao Stephen M.,
Pillai Jagan A.,
Leverenz James B.,
Bekris Lynn M.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.043874
Subject(s) - dna methylation , trem2 , methylation , biology , cpg site , differentially methylated regions , locus (genetics) , promoter , gene , genetics , epigenetics , neuroinflammation , biomarker , gene expression , immunology , receptor , inflammation , myeloid cells
Background Alzheimer’s disease (AD) is a devastating neurodegenerative disorder, and currently lacks a blood‐based biomarker of neuroinflammation. The triggering receptor expressed on myeloid cells 2 ( TREM2 ) R47H genetic variant is associated with increased risk for AD. TREM2 mRNA has been described as elevated in AD leukocytes, and associated with a decrease in TREM2 DNA methylation. In contrast, TREM2 hypermethylation has been described as associated with increased expression in the brain, suggesting differences in DNA methylation of TREM2 according to the tissue microenvironment. DNA methylation can dynamically regulate clusters of genes according to the needs of the cellular microenvironment. The TREM2 gene is part of a complex cluster genes that also includes other TREM and TREM‐like ( TREML ) genes. Understanding its DNA methylation signature is important to decipher any change in its regulatory state in AD. We hypothesized that TREM locus genes are differentially methylated in whole blood among AD patients compared to cognitively normal controls. Method Participants included age‐matched cognitively normal controls (HC), mild cognitive impairment related to AD (MCI‐AD) and AD dementia (confirmed by CSF AD biomarkers). Peripheral blood was collected for DNA extraction. Methylation of peripheral blood DNA was measured using Illumina 450k methylation chip. Percent methylation of CpG sites across the TREM locus were grouped into regions based on genomic context. Hierarchical clustering was used to evaluate relationships between genomic regions. Result Genomic regions across the TREM locus exhibited differential methylation where in general promoters are hypomethylated while other non‐promoter regions are hypermethylated. Although levels of methylation were similar between groups, regions within the TREM locus correlated differently between the groups. Conclusions Taken together, the results suggest that differential methylation exists at the TREM locus that is genomic region and AD specific. We anticipate that future studies will contribute to a better understanding of TREM2 and its role as a biomarker to aid in earlier diagnosis and interventions of AD.