Sudden sensorineural hearing loss (SSNHL) is an abrupt loss of hearing, still idiopathic in most of cases. Several mechanisms have been proposed including genetic and epigenetic interrelationships also considering iron homeostasis genes, ferroptosis and cellular stressors such as iron excess and dysfunctional mitochondrial superoxide dismutase activity. We investigated 206 SSNHL patients and 420 healthy controls for the following genetic variants in the iron pathway: SLC40A1 − 8CG (ferroportin; FPN1), HAMP − 582AG (hepcidin; HEPC), HFE C282Y and H63D (homeostatic iron regulator), TF P570S (transferrin) and SOD2 A16V in the mitochondrial superoxide dismutase-2 gene. Among patients, SLC40A1 − 8GG homozygotes were overrepresented (8.25% vs 2.62%; P = 0.0015) as well SOD2 16VV genotype (32.0% vs 24.3%; P = 0.037) accounting for increased SSNHL risk (OR = 3.34; 1.54–7.29 and OR = 1.47; 1.02–2.12, respectively). Moreover, LINE-1 methylation was inversely related (r2 = 0.042; P = 0.001) with hearing loss score assessed as pure tone average (PTA, dB HL), and the trend was maintained after SLC40A1 − 8CG and HAMP − 582AG genotype stratification (ΔSLC40A1 = + 8.99 dB HL and ΔHAMP = − 6.07 dB HL). In multivariate investigations, principal component analysis (PCA) yielded PC1 (PTA, age, LINE-1, HAMP, SLC40A1) and PC2 (sex, HFEC282Y, SOD2, HAMP) among the five generated PCs, and logistic regression analysis ascribed to PC1 an inverse association with moderate/severe/profound HL (OR = 0.60; 0.42–0.86; P = 0.0006) and with severe/profound HL (OR = 0.52; 0.35–0.76; P = 0.001). Recognizing genetic and epigenetic biomarkers and their mutual interactions in SSNHL is of great value and can help pharmacy science to design by pharmacogenomic data classical or advanced molecules, such as epidrugs, to target new pathways for a better prognosis and treatment of SSNHL.

中文翻译：

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突发感音神经性听力损失 (SSNHL) 中的 LINE-1 整体 DNA 甲基化、铁稳态基因、性别和年龄


突发性感音神经性听力损失（SSNHL）是一种突然的听力损失，在大多数情况下仍然是特发性的。已经提出了几种机制，包括遗传和表观遗传的相互关系，还考虑了铁稳态基因、铁死亡和细胞应激源，例如铁过量和功能失调的线粒体超氧化物歧化酶活性。我们调查了 206 名 SSNHL 患者和 420 名健康对照者，了解铁途径中的以下遗传变异：SLC40A1 - 8CG（铁转运蛋白；FPN1）、HAMP - 582AG（铁调素；HEPC）、HFE C282Y 和 H63D（稳态铁调节剂）、TF P570S（转铁蛋白）和线粒体超氧化物歧化酶 2 基因中的 S​​OD2 A16V。在患者中，SLC40A1 − 8GG 纯合子比例过高（8.25% vs 2.62%；P = 0.0015）以及 SOD2 16VV 基因型（32.0% vs 24.3%；P = 0.037），导致 SSNHL 风险增加（OR = 3.34；1.54–7.2） 9 和OR = 1.47；分别为 1.02–2.12）。此外，LINE-1甲基化与纯音平均听力损失评分（PTA，dB HL）呈负相关（r2 = 0.042；P = 0.001），并且在SLC40A1 - 8CG和HAMP - 582AG基因型分层后仍保持这种趋势（ ΔSLC40A1 = + 8.99 dB HL 和 ΔHAMP = − 6.07 dB HL）。在多变量调查中，主成分分析 (PCA) 在五个生成的 PC 中生成了 PC1（PTA、年龄、LINE-1、HAMP、SLC40A1）和 PC2（性别、HFEC282Y、SOD2、HAMP），逻辑回归分析将 PC1 和与中度/重度/深度 HL (OR = 0.60; 0.42–0.86; P = 0.0006) 和重度/深度 HL (OR = 0.52; 0.35–0.76; P = 0.001) 呈负相关。 认识 SSNHL 中的遗传和表观遗传生物标志物及其相互作用具有重要价值，可以帮助药学科学通过药物基因组数据设计经典或先进的分子（例如表药物），以针对 SSNHL 更好的预后和治疗的新途径。