Journal Article

LINE-1 global DNA methylation, iron homeostasis genes, sex and age in sudden sensorineural hearing loss (SSNHL)

Singh, Ajay Vikram, Zauli, Giorgio, Aimoni, Claudia, D’Aversa, Elisabetta, Ciorba, Andrea, Bianchini, Chiara, Castiglione, Alessandro, Secchiero, Paola, Gallo, Ines, Silva, Juliana Araujo, Pelucchi, Stefano, Gemmati, Donato, Salvatori, Francesca, Tisato, Veronica

2023

Overview

Background 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. Results 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 ( r 2  = 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 (Δ SLC40A1  = + 8.99 dB HL and Δ HAMP  = − 6.07 dB HL). In multivariate investigations, principal component analysis (PCA) yielded PC1 (PTA, age, LINE-1, HAMP , SLC40A1 ) and PC2 (sex, HFE C282Y , 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). Conclusion 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.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Aging / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Cellular stress response / DNA Methylation / Epidrugs / Epigenetics / Epigenomics / Ferroptosis / Genes / Genetic diversity / Genetics / Genetik / Genotypes / Hearing loss / Hearing Loss, Sensorineural - genetics / Hearing Loss, Sudden - drug therapy / Hearing Loss, Sudden - genetics / Hearing protection / Hepcidin / Homeostasis / Homeostasis - genetics / Homozygotes / Human Genetics / Humans / Inflammation / Iron / Iron - metabolism / Iron - therapeutic use / LINE-1 methylation / Oxidative stress / Pharmacogenetics / Pharmacogenomics / Principal components analysis / Proteomics / SSNHL / Superoxide dismutase / Transferrin - genetics / Transferrin - metabolism / Transferrin - therapeutic use