A Population-Based Study of Plasma Metabolomic Profiles of Persistent Tinnitus Identifies Candidate Biomarkers

Abstract

Tinnitus, the perception of sound without the corresponding external stimulus, currently affects 15% of the US population. There is a critical need to unravel the heterogeneous etiologies underlying tinnitus and identify tailored treatment targets. Metabolomic studies have elucidated biological pathways underlying several neurodegenerative disorders and could identify metabolic perturbations that influence tinnitus development. We conducted the first large-scale metabolomic study to identify novel tinnitus biomarkers. We cross-sectionally evaluated plasma metabolite profiles and persistent tinnitus among 6477 women (488 with daily tinnitus ≥5 minutes and 5989 controls). A broad array of 466 metabolites was measured using liquid-chromatography mass spectrometry. Logistic regression was used to estimate odds ratios (OR, per 1 SD increase in metabolite values) and 95% confidence intervals (CI) for each individual metabolite while Metabolite Set Enrichment Analysis (MSEA) was used to identify metabolite classes enriched for associations with tinnitus; all models were adjusted for multiple comparisons. Compared with controls, homocitrulline (OR(95%CI)=1.32(1.16-1.50), C38:6 phosphatidylethanolamine (PE; 1.24(1.12-1.38)), C52:6 triglyceride (TAG; 1.22(1.10-1.36)), C36:4 PE (1.22(1.1-1.35)), C40:6 PE (1.22(1.09-1.35)), and C56:7 TAG (1.21(1.09-1.34)) were positively associated, whereas alpha-keto-beta-methylvalerate (0.68(0.56-0.82)) and levulinate (0.60(0.46-0.79)) were inversely associated with tinnitus (adjusted-p<0.05). Among metabolite classes, TAGs, PEs, and diglycerides (DAGs) were positively associated, while phosphatidylcholine (PC) plasmalogens, lysophosphatidylcholines (LPC), and cholesteryl esters were inversely associated with tinnitus (false discovery rate <0.05). This study identified novel plasma metabolites and metabolite classes that were significantly associated with persistent tinnitus. These findings extend our current understanding of tinnitus and could inform investigations of therapeutic targets for this challenging disorder.

Current and Emerging Therapies for Chronic Subjective Tinnitus

“…In recent years, several candidate genes for tinnitus have been identified, as well as plasma metabolomic biomarkers of persistent tinnitus, which may open up exciting new avenues for diagnostics, gene-based therapeutics, and alterative therapy development [65,176]. A recent (2022) metabolomic study that compared the blood plasma levels of 466 metabolites between women with persistent tinnitus (n = 488) and controls without tinnitus (n = 5989) identified several novel biomarkers positively or inversely associated with chronic tinnitus [177]. Compounds such as triglycerides and diglycerides were positively associated with tinnitus, while other cholesterol metabolites such as cholesteryl esters and lysophosphatidylcholines were inversely associated with tinnitus.…”