Differential Methylation Levels in CpGs of the BIN1 Gene in Individuals With Alzheimer Disease

Abstract

Introduction: Late-onset Alzheimer disease (LOAD) is the most common dementia worldwide. APOE-ɛ4 and BIN1 (Bridging Integrator 1) have been implicated in the pathogenesis of this disease, but, although DNA methylation of dinucleotide CpGs in the BIN1 gene influences alterations, it has not been studied in Hispanics. Objective: The objective of this study was to evaluate the BIN1 3′ intergenic region DNA methylation patterns in a Colombian sample of LOAD patients. Methods: A case-control study was conducted in 50 individuals with LOAD and 50 age-sex matched controls to determine associations of LOAD with DNA methylation. DNA was isolated from peripheral blood, and methylation levels of 8 CpGs were estimated by bisulfite conversion followed by Sanger sequencing with direct PCR analysis. Logistic regression models adjusted by age, sex, and APOE were used to calculate risk associations between methylation levels and LOAD. Results: Overall, participants with LOAD had significantly lower methylation levels on CpG26 (0.86±0.11 vs. 0.95±0.05; P>0.001), CpG44 (0.84±0.09 vs. 0.94±0.06; P=0.001), and CpG87 (0.64±0.12 vs. 0.82±0.10; P>0.001). Adjusted regression models showed that decreased methylation levels of these CpGs remained as risk factors for LOAD (P<0.05). Conclusions: Hypomethylation of CpGs in BIN1 might play an important role in the expression of BIN1 and may be a biomarker for identifying individuals at high risk of developing LOAD.

Epigenome‐wide analyses identify DNA methylation signatures of dementia risk

“…In contrast, several studies have identified altered methylation of BIN1 in AD patients or in association with AD neuropathological hallmarks 7,47 , 48 . These findings are of particular interest, as altered BIN1 brain expression has been reported in AD 49–51 and DNA methylation has been suggested to regulate BIN1 ’s expression 52 .…”

Epigenome-wide analyses identify DNA methylation signatures of dementia risk

“…In contrast, several studies have identified altered methylation of BIN1 in AD patients or in association with AD neuropathological hallmarks [7, 45, 46]. These findings are of particular interest as altered BIN1 brain expression has been reported in AD [47-49] and DNA methylation has been suggested to regulate BIN1 ’s expression [50].…”

Recent Evidence in Epigenomics and Proteomics Biomarkers for Early and Minimally Invasive Diagnosis of Alzheimer’s and Parkinson’s Diseases

“…Previous studies have pointed out the relevant role of GPCRs in the pathogenesis of AD [ 107 ]. A significant hypomethylation of BIN1 in a specific assay for late-onset AD (LOAD) was also detected (LOAD (50), HC (50)) [ 89 ]. BIN1 had functions relevant to several aspects of AD pathogenesis [ 108 ], and was identified as the second major genetic risk factor for LOAD after APOE-ɛ4 by the AlzGene database [ 109 ].…”