A Multi-omics Investigation of Incident Persistent Tinnitus

摘要 超过5000万美国人经历耳鸣。持续性耳鸣会引起相当大的痛苦， 残疾，损害睡眠，认知，心理健康和日常功能，以及由于 残疾、生产力损失和医疗保健费用是巨大的。然而，人们对沉淀物知之甚少， 并且导致持续性耳鸣的途径和治疗选择是有限的。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）确定耳鸣发展的新的代谢组学和多组学危险因素 在两个大型纵向队列的妇女（N> 26，000）;和（ii）收集耳鸣相关的个人水平的数据 在另外两个正在进行的年轻和更多样化的男性和女性队列中（N> 70，000）。我们的中央 有假说认为，特定的血浆代谢物与发生耳鸣的风险有关， 耳鸣的症状有哪些？耳鸣的症状有哪些基本原理是 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， 扩大数据收集范围，包括年轻人，将创造一个全面的资源， 使遗传和环境因素的研究，并将在推进未来耳鸣的宝贵 research.研究目的将在三个具体目标中解决：1）确定血浆代谢组学风险 发展持续性耳鸣的因素; 2）评估基因组学和基因-环境相互作用作为风险 发展持续性耳鸣的因素;和3）收集耳鸣信息在两个正在进行的队列的年轻人 个体我们将利用四项纵向队列研究的丰富资产和两项大型研究的发现， 耳鸣全基因组关联研究（GWAS）。在目标1中，我们将使用逻辑回归来识别新的 耳鸣的危害有哪些？在目标2a中，我们将进行GWAS并执行元- 分析来自英国生物库的已发表耳鸣GWAS结果。在目标2b中，我们将评估基因如何 负责咖啡因和镇痛剂代谢的酶的变化调节了 咖啡因摄入或止痛剂使用和耳鸣风险。在目标3中，我们将利用定期管理的 在2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。这一创新 提案将组学与流行病学数据相结合，以识别耳鸣的新危险因素，改善耳鸣 了解耳鸣的病因，揭示代谢途径和候选基因，为未来的功能 随访这项拟议中的研究意义重大，因为识别风险因素和组学前体可能 当治疗更可能有效时，能够更早地进行神经保护干预。作为早期阶段 调查员，这个项目将为我提供必要的初步数据，为未来的R01建议，以扩大 这些大规模的耳鸣多组学研究，确定额外的新的危险因素，并揭示新的 治疗目标在女性和男性的整个生命周期，并推动我的职业生涯到下一个阶段。

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.