Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, People's Republic of China.
Environ Sci Pollut Res Int. 2021 Aug;28(30):40782-40792. doi: 10.1007/s11356-021-13649-4. Epub 2021 Mar 26.
The purposes of the current study were to investigate the association of a few of single nucleotide polymorphisms (SNPs) within the AKT2 gene and noise-induced hearing loss (NIHL) susceptibility and explore the potential mechanism underlying NIHL. Three SNPs (rs2304186, rs41275750, and rs76524493) were genotyped in a Chinese population which consists of 690 NIHL patients and 650 normal hearing controls. Bioinformatic analysis was conducted to predict the potential miRNA-binding site of SNPs. Plasmid construction, cell transfection, and dual-luciferase reporter assay were performed to investigate the potential molecular mechanism of SNPs involving in NIHL. The results revealed that rs2304186 GT genotype (OR = 1.41; 95% CI = 1.09-1.83) and TT genotype (OR = 1.51; 95% CI = 1.08-2.10) imparted increased risk of NIHL, and the increased risk could also be found in a dominant model (OR = 1.44; 95% CI = 1.12-1.84). The stratification analysis showed that rs2304186 GT/TT conferred a higher risk for NIHL, especially in subgroups of male, age (35-45 and > 45 years), noise exposure time (> 16 years), and noise exposure level (≤ 85 and ≥ 92 dB), when GG genotype as a reference. Furthermore, the haplotype TCCTACT (rs2304186-rs41275750-rs76524493) was found to be significantly associated with a high risk of NIHL (OR = 1.19; 95% CI = 1.02-1.40). Functional experiments showed that rs2304186 G allele combined with hsa-miR-625-5p mimics could significantly decrease the luciferase activity compared with T allele, indicating that rs2304186 altered the binding affinity of hsa-miR-625-5p to SNP rs2304186 mutation region, thus directly targeting AKT2 gene. In conclusion, our study provides evidence for the first time that SNP rs2304186 of AKT2 3'UTR might affect NIHL susceptibility by altering the binding affinity of has-miR-625-5p to mutation region in an allele-specific manner and it may act as a potential biomarker of NIHL susceptibility.
本研究旨在探讨 AKT2 基因中几个单核苷酸多态性（SNPs）与噪声性听力损失（NIHL）易感性的关系，并探讨 NIHL 潜在的发病机制。我们在中国人群中检测了 690 名 NIHL 患者和 650 名正常听力对照者的 3 个 SNPs（rs2304186、rs41275750 和 rs76524493）的基因型。进行生物信息学分析以预测 SNPs 的潜在 miRNA 结合位点。构建质粒、细胞转染和双荧光素酶报告基因检测，以研究 SNPs 参与 NIHL 的潜在分子机制。结果表明，rs2304186 GT 基因型（OR = 1.41；95%CI = 1.09-1.83）和 TT 基因型（OR = 1.51；95%CI = 1.08-2.10）增加了 NIHL 的发病风险，且这种增加的风险也可以在显性模型中发现（OR = 1.44；95%CI = 1.12-1.84）。分层分析显示，以 GG 基因型为参照，rs2304186 GT/TT 基因型对 NIHL 的风险更高，尤其是在男性亚组、年龄（35-45 岁和>45 岁）、噪声暴露时间（>16 年）和噪声暴露水平（≤85 和≥92dB）。此外，发现 haplotype TCCTACT（rs2304186-rs41275750-rs76524493）与 NIHL 的高风险显著相关（OR = 1.19；95%CI = 1.02-1.40）。功能实验表明，与 T 等位基因相比，rs2304186 G 等位基因与 hsa-miR-625-5p 模拟物的组合可显著降低荧光素酶活性，表明 rs2304186 改变了 hsa-miR-625-5p 与 SNP rs2304186 突变区域的结合亲和力，从而直接靶向 AKT2 基因。总之，本研究首次提供证据表明，AKT2 3'UTR 的 SNP rs2304186 可能通过等位基因特异性改变 hsa-miR-625-5p 与突变区域的结合亲和力来影响 NIHL 的易感性，并且可能作为 NIHL 易感性的潜在生物标志物。
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