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

Introduction: Late-onset Alzheimer disease (LOAD) is the most common dementia worldwide. APOE-e4 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.