Investigation of base excision repair gene variants in late-onset Alzheimer’s disease

• Published in: PloS one Vol. 14; no. 8; p. e0221362
• Main Authors: Ertuzun, Tugce, Semerci, Asli, Cakir, Mehmet Emin, Ekmekcioglu, Aysegul, Gok, Mehmet Oguz, Soltys, Daniela T., de Souza-Pinto, Nadja C., Sezerman, Ugur, Muftuoglu, Meltem
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 15.08.2019; Public Library of Science (PLoS)
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Apolipoprotein E; Apolipoproteins; Apolipoproteins E - genetics; Apolipoproteins E - metabolism; Apoptosis; Autopsy; Base excision repair; Biology and Life Sciences; Biotechnology; Blood; Brain; Cerebellum; Cognitive ability; Cortex (temporal); Damage accumulation; Dementia; Deoxyribonucleic acid; Development and progression; DNA; DNA damage; DNA glycosylase; DNA Glycosylases - genetics; DNA Glycosylases - metabolism; DNA methylation; DNA Polymerase beta - genetics; DNA Polymerase beta - metabolism; DNA Repair; DNA sequencing; Endonuclease; Endonuclease VIII; Epistasis; Etiology; Etiology (Medicine); Female; Gene expression; Gene sequencing; Genes; Genetic aspects; Genetic diversity; Genetic research; Genetic variance; Genetic variation; Genotype & phenotype; Health aspects; Health risk assessment; Humans; Male; Medical schools; Medicine and Health Sciences; Molecular biology; Neurosciences; Next-generation sequencing; Nucleases; Pathogenesis; Peripheral blood; Polymorphism; Polymorphism, Genetic; Post-transcription; Proteins; Pyrimidines; Regulatory genes; Repair; Research and analysis methods; Risk analysis; Risk Factors; Structure; Systematic review; Temporal lobe; Transcription (Genetics); Transcription factors; Uracil; Uracil-DNA Glycosidase - genetics; Uracil-DNA Glycosidase - metabolism; Turkey; Brazil; Istanbul Turkey
• DOI: 10.1371/journal.pone.0221362
• ISSN: 1932-6203

Base excision repair (BER) defects and concomitant oxidative DNA damage accumulation play a role in the etiology and progression of late-onset Alzheimer's disease (LOAD). However, it is not known whether genetic variant(s) of specific BER genes contribute to reduced BER activity in LOAD patients and whether they are associated with risk, development and/or progression of LOAD. Therefore, we performed targeted next generation sequencing for three BER genes, uracil glycosylase (UNG), endonuclease VIII-like DNA glycosylase 1 (NEIL1) and polymerase β (POLβ) including promoter, exonic and intronic regions in peripheral blood samples and postmortem brain tissues (temporal cortex, TC and cerebellum, CE) from LOAD patients, high-pathology control and cognitively normal age-matched controls. In addition, the known LOAD risk factor, APOE was included in this study to test whether any BER gene variants associate with APOE variants, particularly APOE ε4. We show that UNG carry five significant variants (rs1610925, rs2268406, rs80001089, rs1018782 and rs1018783) in blood samples of Turkish LOAD patients compared to age-matched controls and one of them (UNG rs80001089) is also significant in TC from Brazilian LOAD patients (p<0.05). The significant variants present only in CE and TC from LOAD are UNG rs2569987 and POLβ rs1012381950, respectively. There is also significant epistatic relationship (p = 0.0410) between UNG rs80001089 and NEIL1 rs7182283 in TC from LOAD subjects. Our results suggest that significant BER gene variants may be associated with the risk of LOAD in non-APOE ε4 carriers. On the other hand, there are no significant UNG, NEIL1 and POLβ variants that could affect their protein level and function, suggesting that there may be other factors such as post-transcriptional or-translational modifications responsible for the reduced activities and protein levels of these genes in LOAD pathogenesis. Further studies with increased sample size are needed to confirm the relationship between BER variants and LOAD risk.