Abstract
Alzheimer’s disease (AD) is a progressive disease, with frequently observed improper biothiols turnover, homocysteine (Hcy) and glutathione (GSH). GSH protects cells from oxidative stress and may be determined by 8-oxo-2’-deoxyguanosine (8-oxo2dG) level and its repair enzyme 8-oxoguanine DNA glycosylase (OGG1). The presence of unfavorable alleles, e.g., in APOE cluster, TOMM40 or APOC1 is known to facilitate the dementia onset under oxidative stress.The aim of the study was to analyze rs1052452, rs2075650 TOMM40 polymorphisms, rs4420638 APOC1, and their correlation with Hcy, GSH, 8-oxo2dG, OGG1 levels in plasma of AD patients and controls.We recruited 230 individuals: 88 AD, 80 controls without (UC), 62 controls with (RC) positive family history of AD. The TOMM40 genotype was determined by HRM and capillary electrophoresis, while APOC1 by HRM. The concentrations of OGG1, 8-oxo2dG were determined by ELISA, whereas Hcy, GSH by HPLC/EC.We showed that over 60% of AD patients had increased Hcy levels (p<0.01 vs. UC, p<0.001 vs. RC), while GSH (p<0.01 vs. UC), 8-oxo2dG (p<0.01 vs. UC, p<0.001 vs. RC) were reduced. Minor variants: rs10524523-L, rs4420638-G, rs2075650-G were significantly overrepresented in AD. For rs4420638-G, rs2075650-G variants, the association remained significant in APOE E4 non-carriers. The misbalance of analyzed biothiols, and 8-oxo2dG, OGG1 were more pronounced in carriers of major variants: rs10524523-S/VL, rs4420638-A, rs2075650-A.We showed, for the first time, that APOC1 and TOMM40 rs2075650 polymorphisms may be independent risk factors of developing AD, whose major variants are accompanied by disruption of biothiols metabolism and inefficient removal of DNA oxidation.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disease and a major cause of dementia in adults over 60 years of age, affecting cognitive functions of nearly 24 million patients worldwide [1].The AD occurs in two forms: familial and sporadic AD [2]
For the first time, that APOC1 and TOMM40 rs2075650 polymorphisms may be independent risk factors of developing AD, whose major variants are accompanied by disruption of biothiols metabolism and inefficient removal of DNA oxidation
The elevated plasma Hcy we observed in 60.9% AD patients as compared to 34.2% of Unrelated controls (UC) and 32.3% of Related controls (RC) (OR=3.00, 95% CI: 1.53-5.86, p
Summary
The AD occurs in two forms: familial and sporadic AD [2]. The latter is typical for aging population, and is caused by both, genetic (70%) [3] and environmental (30%) [4] factors. The pathomechanism of AD is explained in multiple pathways, including dysregulation of the interaction network between the production, clearance, and aggregation of amyloid β (Aβ), a central player in an Aβ cascade hypothesis. This phenomenon may occur more often in individuals with rare variants in genes associated with metabolism of Aβ and cholesterol turnover, located on chromosome 19, in APOE gene cluster. The APOE gene polymorphisms have been extensively studied, and the emerging research focuses on other genes in the immediate vicinity of the APOE gene, i.e., TOMM40 and APOC1, APOC2, APOC4 [5,6,7]
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