Biothiols and oxidative stress markers and polymorphisms of<i>TOMM40</i>and<i>APOC1</i>genes in Alzheimer’s disease patients

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, <i>e.g.,</i> in <i>APOE</i> cluster, <i>TOMM40</i> or <i>APOC1</i> is known to facilitate the dementia onset under oxidative stress. The aim of the study was to analyze rs1052452, rs2075650 <i>TOMM40</i> polymorphisms, rs4420638 <i>APOC1</i>, 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 <i>TOMM40</i> genotype was determined by HRM and capillary electrophoresis, while <i>APOC1</i> 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 <i>vs.</i> UC, p<0.001 <i>vs.</i> RC), while GSH (p<0.01 <i>vs.</i> UC), 8-oxo2dG (p<0.01 <i>vs.</i> UC, p<0.001 <i>vs.</i> 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 <i>APOE</i> 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 <i>APOC1</i> and <i>TOMM40</i> 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.