Lower DNA methylation levels in CpG island shores of CR1, CLU, and PICALM in the blood of Japanese Alzheimer's disease patients.

Risa Mitsumori,Nobuyoshi Shimoda,Daichi Shigemizu,Kouichi Ozaki,Shumpei Niida,Shintaro Akiyama,Taiki Mori,Kazuya Sakaguchi,Stephen D Ginsberg

doi:10.1371/journal.pone.0239196

Risa Mitsumori, Nobuyoshi Shimoda + Show 7 more

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https://doi.org/10.1371/journal.pone.0239196

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Journal: PloS one	Publication Date: Sep 29, 2020
Citations: 23	License type: CC BY 4.0

Affiliation: National Center for Geriatrics and Gerontology

Abstract

The aim of the present study was to (1) investigate the relationship between late-onset Alzheimer's disease (AD) and DNA methylation levels in six of the top seven AD-associated genes identified through a meta-analysis of recent genome wide association studies, APOE, BIN1, PICALM, CR1, CLU, and ABCA7, in blood, and (2) examine its applicability to the diagnosis of AD. We examined methylation differences at CpG island shores in the six genes using Sanger sequencing, and one of two groups of 48 AD patients and 48 elderly controls was used for a test or replication analysis. We found that methylation levels in three out of the six genes, CR1, CLU, and PICALM, were significantly lower in AD subjects. The combination of CLU methylation levels and the APOE genotype classified AD patients with AUC = 0.84 and 0.80 in the test and replication analyses, respectively. Our study implicates methylation differences at the CpG island shores of AD-associated genes in the onset of AD and suggests their diagnostic value.

Highlights

Moderate concordance rates for Alzheimer’s disease (AD) among genetically identical twins suggest the possible involvement of epigenetics in the etiology of AD [1, 2]
To clarify how specific the methylation changes detected are in dementia, we examined the methylation levels of APOE and CLU in blood samples of control, AD, dementia with Lewy bodies (DLB), vascular dementia (VaD), and frontotemporal dementia (FTD)
Sanger sequencing of more than twenty thousand clones from 96 blood samples quantified the methylation levels of the CpG island shores of six of the top seven ADassociated genes in the latest meta-analysis [31]. It was low-throughput, we detected decreases in DNA methylation in three out of the six genes, CLU, CR1, and PICALM, whereas no significant DNA methylation changes were observed in APOE, BIN1, and ABCA7

Summary

Introduction

Moderate concordance rates for Alzheimer’s disease (AD) among genetically identical twins suggest the possible involvement of epigenetics in the etiology of AD [1, 2]. DNA methylation and chromatin modifications are of great interest in AD because they have been reported to change with aging [3, 4], which is the main cause of the disease, and their unintended changes affect gene expression [5]. As DNA methylation differences in genomes between AD patients and cognitive normal elderly individuals are expected to reveal AD-susceptible genes, and provide biomarkers for clinical purposes, they have been extensively examined in blood and the brain using candidate genes and genome-wide approaches [6,7,8,9,10]. Sanger or pyrosequencing and DNA methylation arrays have generally been employed for region-specific and genome-wide analyses, respectively.

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