A Multi-omics Investigation of Incident Persistent Tinnitus

摘要 超过5000万美国人患有耳鸣。持续性耳鸣可引起相当大的痛苦和 残疾、睡眠、认知、心理健康和日常功能受损，以及因以下原因造成的经济负担 残疾、生产力损失和医疗成本都很高。然而，人们对这些沉淀物知之甚少。 导致持续性耳鸣的途径和治疗选择有限。我们的长期目标是确定 治疗目标和预防策略，以减轻耳鸣负担，提高生活质量。我们的整体 目的是(I)确定耳鸣发生的新的代谢学和多组学危险因素 在两个大型纵向女性队列中(N&>26,000)；和(2)收集与耳鸣有关的个人水平数据 在另外两个正在进行的更年轻和更多样化的男性和女性队列中(N&GT；70,000)。我们的中央 假设特定的血浆代谢物与发生耳鸣的风险有关，而遗传性 变种会影响环境暴露如何促进耳鸣的发展。理由是 确定耳鸣的危险因素将为改善耳鸣管理提供强有力的科学框架， 将数据收集扩大到包括年轻人将创建一个全面的资源，将 使遗传和环境因素的研究成为可能，并将对推动未来的耳鸣起到无可估量的作用 研究。研究目标将在三个具体目标中实现：1)确定血浆代谢风险 发生持续性耳鸣的因素；2)评估基因组学和基因-环境相互作用的风险 发生持续性耳鸣的因素；以及3)在两个正在进行的年轻队列中收集耳鸣信息 个人。我们将利用来自四个纵向队列研究的丰富资产和来自两个大型 耳鸣全基因组关联研究(GWAS)。在目标1中，我们将使用Logistic回归来识别小说 发生耳鸣的代谢危险因素。在目标2a中，我们将进行GWAS并执行Meta- 根据英国生物库发表的耳鸣GWAS结果进行分析。在目标2b中，我们将评估基因如何 负责咖啡因和止痛剂代谢的酶的变化调节 摄入咖啡因或使用止痛药与耳鸣风险。在目标3中，我们将利用定期管理的 在两个特征良好的年轻队列中进行问卷调查，以收集详细的耳鸣信息。这是一项创新 建议将组学与流行病学数据相结合，以确定耳鸣的新风险因素，改善 了解耳鸣的病因，揭示代谢途径和未来功能的候选基因 后续行动。这项拟议的研究意义重大，因为识别风险因素和组学前兆可能 在治疗更有可能有效的时候，及早进行神经保护干预。作为早期阶段 调查员，这个项目将为我未来的R01提案提供必要的初步数据，以延长 这些对耳鸣的大规模多组学研究，确定了其他新的风险因素，并发现了新的 治疗目标在女性和男性的一生中，并将我的事业推进到下一个阶段。

ABSTRACT Over 50 million Americans experience tinnitus. Persistent tinnitus can cause considerable suffering and disability, impairing sleep, cognition, mental health and daily function, and the economic burden due to disability, lost productivity and healthcare costs is substantial. However, little is known about the precipitants and pathways that lead to persistent tinnitus and treatment options are limited. Our long-term goal is to identify treatment targets and preventative strategies to reduce tinnitus burden and improve quality of life. Our overall objectives are to (i) identify novel metabolomic and multi-omic risk factors for the development of tinnitus among two large longitudinal cohorts of women (N>26,000); and (ii) collect tinnitus-related individual level data in two additional ongoing cohorts of younger and more diverse men and women (N>70,000). Our central hypotheses are that specific plasma metabolites are associated with risk of developing tinnitus and that genetic variants influence how environmental exposures contribute to the development of tinnitus. The rationale is that identifying risk factors for tinnitus will provide a strong scientific framework for improving tinnitus management, and expanding data collection to include younger individuals will create a comprehensive resource that will enable studies of genetic and environmental factors and will be invaluable in advancing future tinnitus research. The study objectives will be addressed in three specific aims: 1) Identify plasma metabolomic risk factors for developing persistent tinnitus; 2) Evaluate genomics and gene-environment interactions as risk factors for developing persistent tinnitus; and 3) Collect tinnitus information in two ongoing cohorts of younger individuals. We will leverage rich assets from four longitudinal cohort studies and findings from two large tinnitus genome-wide association studies (GWAS). In Aim 1, we will use logistic regression to identify novel metabolomic risk factors for developing tinnitus. In Aim 2a, we will conduct a GWAS and perform a meta- analysis with published tinnitus GWAS results from the UK Biobank. In Aim 2b, we will assess how genetic variations in enzymes responsible for caffeine and analgesic metabolism modulate associations between caffeine intake or analgesic use and tinnitus risk. In Aim 3, we will leverage regularly administered questionnaires in 2 well-characterized younger cohorts to collect detailed tinnitus information. This innovative proposal integrates omics with epidemiological data to identify new risk factors for tinnitus, improve understanding of tinnitus etiology and reveal metabolic pathways and candidate genes for future functional follow-up. The proposed research is significant because identifying risk factors and omics precursors may enable earlier neuroprotective interventions when treatments are more likely to be effective. As an early-stage investigator, this project will provide me with necessary preliminary data for a future R01 proposal to extend these large-scale multi-omics investigations of tinnitus, identify additional novel risk factors, and uncover new treatment targets in women and men across the lifespan, and advance my career to the next stage.