Noise-Induced Hearing Loss: Threshold, exposure and genetic susceptibility

描述(由申请人提供)：这项R21翻译研究补助金PAR 06-095申请的短期目标是建立一个基础，用于识别表现出噪声性听力损失(NIHL)遗传易感性的人，其标题为“噪声性听力损失：阈值、暴露和遗传敏感性”。这项申请是由一个由三名研究人员组成的团队提出的：PI是苏珊·L·菲利普斯，听力学博士(CCC-A)，她与Co-PI的文森特·C·亨里奇，遗传学博士，斯科特·J·里希特，统计学博士，以及桑德拉·T·梅斯，音乐教育博士和认证听力保护专家一起工作。众所周知，声暴露过多会导致噪声性听力损失。然而，即使在没有经历过不寻常水平的声学暴露的受试者中，NIHL也有相当大的变异性，因此，我们对谁是和不是最有可能患NIHL的知识存在着严重的差距。该项目将通过确定与NIHL遗传易感性相关的关键变量来填补知识空白。到目前为止，我们研究中确定的关键变量包括听力学特征(单侧或双侧、凹口深度和凹口频率)、报告的当前和过去的声暴露以及测量的声暴露(强度和持续时间)。其具体目的是：1)比较在先前研究中发现与NIHL相关的几个基因座位上的双侧、单侧或无缺口变异的受试者的粗略患病率和调整后的患病率。基于Phillips等人提出的标准。(在出版中)，工作假设将是，在有双侧切迹的个体中，患NIHL的易感等位基因的频率将高于那些有单侧切迹或没有切迹的个体。2)检查是否存在显著的基因-环境交互作用。工作假设是，目前暴露于NIHL并携带易感等位基因的个体将表现出最大的NIHL进展。我们将在一项涉及1,000名年龄在18-25岁之间的学生的研究中直接和间接测量阈值和暴露水平，使我们能够避免其他NIHL基因关联研究中存在的混淆。这些因素包括与年龄有关的听力损失和可能导致听力损失的疾病因素，可能导致听力损失的额外化学暴露，以及与工业人口相关的极端暴露和暴露时间。以前的研究发现，有必要对这些混淆进行统计校正，并承认这些校正使数据的解释复杂化(Konings等人，2009年)。将从三组学生的口腔细胞中收集并提取DNA：有双侧切迹的学生，有单侧切迹的学生，以及没有切迹的对照组学生。该项目与公众健康的相关性反映在我们的长期目标中，即利用对NIHL的机械性理解来开发个性化的NIHL预防计划，使用标准的临床听力学测试作为遗传易感性的指标。在早期识别高危个人和暴露情况的能力，或许可以通过制定NIHL风险概况，使卫生保健提供者、音乐教育工作者、工业和军事听力保护者以及其他人能够针对高危个人采取预防措施。预防措施包括教育、使用听力保护装置、修改暴露部位的声音衰减以及监测暴露强度和持续时间。 公共卫生相关性：NIHL在12-19岁的儿童中是一个日益严重的健康问题，发现在12-19岁的儿童中有15.5%(Niskar等人，2001年)，28%的大学生听个人听力设备(Mostafour等人，1998年)，以及44%的大学音乐学院的学生音乐家(Phillips等人，正在出版中)。R21翻译研究助学金PAR 06-095的这项申请的短期目标是建立一个基础，用于识别对噪声性听力损失表现出遗传易感性的人，其标题为“噪声导致的听力损失：阈值、暴露和遗传易感性”。该项目与公共健康的相关性反映在长期目标中，该目标是利用对噪音导致的听力损失的机械性理解来开发一项个性化的预防计划，使用标准的临床听力学测试作为遗传易感性的指标。

DESCRIPTION (provided by applicant): The short-term goal of this R21 Translational Research Grant PAR 06-095 application, entitled "Noise-induced hearing loss: threshold, exposure, and genetic susceptibility," is to establish a basis for identifying people showing a genetic susceptibility to noise-induced hearing loss (NIHL). The application is proposed by a team of three researchers: The PI is Susan L. Phillips, Ph.D. in audiology (CCC-A), who is working with Co-PI's Vincent C. Henrich, Ph.D. in genetics, Scott J. Richter, Ph.D. in statistics and Sandra T. Mace, Ph.D. in music education and certified Hearing Conservation Specialist. It is known that acoustic overexposure can cause noise-induced hearing loss. Nevertheless, there is considerable variability in NIHL even among subjects who have not experienced unusual levels of acoustic exposure, and, thus, there is a critical gap in our knowledge about who is and is not most at risk for NIHL. This project will fill the gap in knowledge by identifying the critical variables associated with a genetic predisposition to NIHL. Critical variables identified in our study so far include the audiological profile (unilateral or bilateral, depth of notch and frequency of notch), reported current and past acoustic exposure and measured acoustic exposure (intensity and duration). The Specific Aims are: 1) Compare the crude and adjusted prevalence among subjects with bilateral, unilateral, or no notches of variants at several gene loci found in previous research to be associated with NIHL. Based on criteria laid out in Phillips et al. (in press), the working hypothesis will be that the frequency of predisposing alleles for NIHL will be higher among individuals with bilateral notches than in those with unilateral or no notches. 2) Examine whether there are significant gene-environment interactions present. The working hypothesis will be that the individuals with the highest current exposure and carrying predisposing alleles to NIHL will show the greatest progression of NIHL. We will make direct and indirect measurements of thresholds and exposure levels in a study involving 1,000 students between the ages of 18-25 years, allowing us to avoid the confounds present in other genetic association studies of NIHL. These include age-related hearing loss and disease factors that can contribute to hearing loss, additional chemical exposures that can contribute to hearing loss, and the extreme exposures and exposure durations associated with industrial populations. Previous studies have found it necessary to apply statistical corrections for these confounds and the corrections were acknowledged to have complicated the interpretation of the data (Konings et al., 2009). Buccal cells will be collected and DNA extracted from students in three groups: those with bilateral notches, with unilateral notches, and a control group of students with no notches. The project's relevance to public health is reflected in our long-term goal, which is to use a mechanistic understanding of NIHL to develop a personalized NIHL prevention program using standard clinical audiological tests as indicators of genetic susceptibility. The ability to identify at-risk individuals and exposure situations at an early age, perhaps through the development of a NIHL Risk Profile, will allow health care providers, music educators, industrial and military hearing conservationists, and others to target preventive measures to at-risk individuals. Preventive measures include education, the use of hearing protection devices, sound attenuation modifications to exposure sites and monitoring of exposure intensities and durations. PUBLIC HEALTH RELEVANCE: NIHL is a growing health concern among children, found in 15.5% aged 12-19 (Niskar et al., 2001), in 28% of college students who listen to personal listening devices (Mostafpour et al., 1998), and 44% of student musicians in a university School of Music (Phillips et al., in press). The short-term goal of this application for an R21 Translational Research Grant PAR 06-095, entitled "Noise-induced hearing loss: threshold, exposure, and genetic susceptibility," is to establish a basis for identifying people showing a genetic susceptibility to noise-induced hearing loss. The relevance of the project to public health is reflected in the long-term goal, which is to use a mechanistic understanding of noise-induced hearing loss to develop a personalized prevention program using standard clinical audiological tests as indicators of genetic susceptibility.