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

Risa Mitsumori; Kazuya Sakaguchi; Daichi Shigemizu; Taiki Mori; Shintaro Akiyama; Kouichi Ozaki; Shumpei Niida; Nobuyoshi Shimoda

doi:10.1371/journal.pone.0239196

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

PLoS One. 2020 Sep 29;15(9):e0239196. doi: 10.1371/journal.pone.0239196. eCollection 2020.

Authors

Risa Mitsumori¹, Kazuya Sakaguchi², Daichi Shigemizu¹, Taiki Mori¹, Shintaro Akiyama¹, Kouichi Ozaki¹, Shumpei Niida¹, Nobuyoshi Shimoda²

Affiliations

¹ Medical Genome Center, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan.
² Department of Regenerative Medicine, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Alzheimer Disease / diagnosis
Alzheimer Disease / genetics*
Biomarkers / blood
Clusterin* / blood
Clusterin* / genetics
CpG Islands*
DNA Methylation*
Female
Genetic Association Studies
Genetic Predisposition to Disease
Humans
Japan
Male
Middle Aged
Monomeric Clathrin Assembly Proteins* / blood
Monomeric Clathrin Assembly Proteins* / genetics
Receptors, Complement 3b* / blood
Receptors, Complement 3b* / genetics

Substances

Biomarkers
CLU protein, human
CR1 protein, human
Clusterin
Monomeric Clathrin Assembly Proteins
PICALM protein, human
Receptors, Complement 3b

Grants and funding

This work was supported by The Research Funding for Longevity Sciences (21-16 and 29-20 to NS and 29-45 to KO) from National Center for Geriatrics and Gerontology and by the Japanese Ministry of Health, Labor, and Welfare (KO). K.S. (Kazuya Sakaguchi) is affiliated with Axcelead Drug Discovery Partners, Inc., Fujisawa, Kanagawa, Japan. The funder provided support in the form of salaries for K.S., but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of the author are articulated in the ‘author contributions’ section.