Department of Molecular and Cell Biology, Faculty of Basic Sciences, University of Mazandaran, Babolsar, 47416-95447, Iran.
Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.
Environ Sci Pollut Res Int. 2020 Dec;27(34):42600-42610. doi: 10.1007/s11356-020-10144-0. Epub 2020 Jul 25.
Antioxidant enzymes such as glutathione S-transferases (GSTs) and cytochromes P450 (CYPs) are involved in the metabolism and detoxification of cytotoxic compounds, as well as the elimination of reactive oxygen species (ROS). Therefore, alterations in the structure of these enzymes could result in prolonged production of ROS with subsequent risk of development of disorders such as presbycusis. This study aimed to investigate the association between CYP1A1 (rs4646903, rs1048943) and GSTs (GSTM1-deletion, GSTT1-deletion, GSTP1-rs1695) with presbycusis risk in an Iranian population which was followed by an in silico approach. In a case-control study, 280 subjects including 140 cases with presbycusis and 140 healthy controls were enrolled. Genotypes of single-nucleotide polymorphisms (SNPs) were detected by PCR-RFLP method and the genotype of the above mentioned deletions was determined by touchdown PCR. Some bioinformatics tools were employed to evaluate the impact of SNPs on the gene function. SNP analysis revealed that there are significant associations between rs1048943 (AG vs. AA: OR = 2.46, 95%CI = 1.30-4.65, p = 0.006; GG + AG vs. AA: OR = 2.53, 95%CI = 1.36-4.69, p = 0.003; G vs. A: OR = 2.36, 95%CI = 1.33-4.17, p = 0.003) and rs4646903 (C vs. T: OR = 1.45, 95%CI = 1.02-2.06, p = 0.040) variations and increased risk of presbycusis. However, there was no significant association between rs1695 and presbycusis risk. Also, significant associations were observed between GSTM1 (OR = 4.28, 95%CI = 1.18-15.52, p = 0.027) and GSTT1 (OR = 1.64, 95%CI = 1.02-2.65, p = 0.041) deletions and elevated risk of presbycusis. Moreover, the combination analysis revealed a significant association between GSTM1+/GSTT1- genotype and presbycusis susceptibility (OR = 1.63, 95%CI = 1.00-2.67, p = 0.049). In silico analysis revealed that the rs1048943 SNP could influence significantly on the RNA structure of CYP1A1 (distance: 0.1454; p value: 0.1799). Based on our findings, the rs4646903, rs1048943 SNPs as well as GSTM1 and GSTT1 deletions could be considered as genetic risk factors for the development and progression of presbycusis.
抗氧化酶，如谷胱甘肽 S-转移酶（GSTs）和细胞色素 P450（CYPs），参与细胞毒性化合物的代谢和解毒，以及活性氧物种（ROS）的清除。因此，这些酶结构的改变可能导致 ROS 的产生延长，随后可能会发展为 presbycusis 等疾病。本研究旨在调查 CYP1A1（rs4646903，rs1048943）和 GSTs（GSTM1 缺失，GSTT1 缺失，GSTP1-rs1695）与伊朗人群 presbycusis 风险之间的关联，随后进行了一项基于计算机的方法。在病例对照研究中，纳入了 280 名受试者，包括 140 名 presbycusis 患者和 140 名健康对照者。采用 PCR-RFLP 方法检测单核苷酸多态性（SNP）的基因型，采用降落 PCR 法检测上述缺失的基因型。使用了一些生物信息学工具来评估 SNP 对基因功能的影响。SNP 分析显示，rs1048943（AG 与 AA：OR = 2.46，95%CI = 1.30-4.65，p = 0.006；GG + AG 与 AA：OR = 2.53，95%CI = 1.36-4.69，p = 0.003；G 与 A：OR = 2.36，95%CI = 1.33-4.17，p = 0.003）和 rs4646903（C 与 T：OR = 1.45，95%CI = 1.02-2.06，p = 0.040）变异与 presbycusis 风险增加相关。然而，rs1695 与 presbycusis 风险之间没有显著关联。此外，GSTM1（OR = 4.28，95%CI = 1.18-15.52，p = 0.027）和 GSTT1（OR = 1.64，95%CI = 1.02-2.65，p = 0.041）缺失与 presbycusis 风险增加也存在显著关联。此外，组合分析显示 GSTM1+/GSTT1-基因型与 presbycusis 易感性之间存在显著关联（OR = 1.63，95%CI = 1.00-2.67，p = 0.049）。基于计算机的分析显示，rs1048943 SNP 可能会显著影响 CYP1A1 的 RNA 结构（距离：0.1454；p 值：0.1799）。根据我们的发现，rs4646903、rs1048943 SNP 以及 GSTM1 和 GSTT1 缺失可被视为 presbycusis 发生和进展的遗传风险因素。
