Genome-wide Investigation of the Interplay Between Age-Related Hearing Loss and Smoking Behaviors

摘要。听力损失是一种常见的听力障碍， 随着年龄的增长。在美国，大约33%的65岁至74岁的人口 75岁以后，大约50%的人口有听力， 问题与年龄相关的听力损失有很多原因，包括年龄引起的听力损失。 以及沿着从耳神经通路的复杂变化 到大脑。流行病学研究，如听力损失流行病学研究和 1999-2004年全国健康和营养检查调查显示， 与年龄有关的听力损失的因素是噪音暴露和吸烟。信息非常有限， 关于与年龄相关的听力损失的分子途径以及吸烟如何影响听力损失， 行为会增加风险。我们先前的研究结果表明，遗传变异可以在 减轻吸烟对年龄相关性听力损失的影响 大脑中与听觉功能有关的区域。在当前的提案中，我们将应用全基因组 确定与年龄相关的听力损失引起的其他机制的方法 吸烟行为。具体来说，我们将进行一项年龄的全基因组关联研究- 超过500，000名受试者（> 150，000名尼古丁暴露者，> 350，000名 尼古丁-未暴露）。我们将使用来自队列的遗传和表型信息， 英国生物银行，护士健康研究I和II，卫生专业人员随访研究，以及 国家生物技术信息中心基因型和表型数据库， 对暴露于尼古丁的个体进行听力损失的全基因组关联研究。一 将使用磁共振成像技术对脑结构和活动进行随访研究。 来自英国生物银行的共振成像数据。此外，我们将进行多变量 孟德尔随机化研究哪些代谢组学改变和/或脑结构 这些变化介导了吸烟和听力损失之间的因果关系。这个目标 分析是为了验证因果效应和中介过程中所涉及的相互作用 吸烟行为和听力损失之间的联系预期的发现将提供新的见解 关于吸烟行为导致年龄相关性听力损失的分子机制， 更好地了解其遗传学可以使我们开发更有效的预防措施， 策略和治疗方法，可以提高日益增长的老年人的生活质量 人口

ABSTRACT. Age-related hearing loss is a common disorder defined as the loss of the hearing with aging. In the United States, approximately 33% of the population between ages of 65 and 74 are subjected to hearing loss, and after 75 years of age, about 50% of the population have hearing problems. There are many causes of age-related hearing loss, including age-induced changes in the in the inner and middle ear and also complex changes along the nerve pathways from the ear to the brain. Epidemiological studies, such as The Epidemiology of Hearing Loss Study and National Health and Nutrition Examination Survey 1999-2004, have shown that the major risk factors for age-related hearing loss are noise exposure and smoking. Very limited information is available regarding the molecular pathways involved in age-related hearing loss and how smoking behaviors increase its risk. Our previous results suggest that genetic variation can play a role in moderating the effect of smoking on age-related hearing loss reducing smoking-induced damage in brain regions involved in auditory function. In the current proposal, we will apply genome-wide approaches to identify additional mechanisms involved in the age-related hearing loss induced by smoking behaviors. Specifically, we will conduct a genome-wide association study of age- related hearing loss in more than 500,000 subjects (>150,000 nicotine-exposed, >350,000 nicotine-unexposed). We will use the genetic and phenotypic information from cohorts from the UK Biobank, the Nurses' Health Studies I and II, the Health Professionals Follow-Up Study, and the National Center for Biotechnology Information the database of Genotypes and Phenotypes to conduct a genome-wide association study of hearing loss in individuals exposed to nicotine. A follow-up study will be performed with respect brain structure and activity using magnetic resonance imaging data from the UK Biobank. Additionally, we will conduct a multivariable Mendelian Randomization to investigate which metabolomic alterations and/or brain-structure changes mediate the causal relationship between smoking and hearing loss. The goal of this analysis is to verify the causal effect and the mediation processes involved in the interplay between smoking behaviors and hearing loss. The expected findings will provide novel insights regarding the molecular mechanisms by which smoking behaviors cause age-related hearing loss A better understanding of its genetics could permit us to develop more effective preventive strategies and therapeutic approaches that can improve the quality of life of the growing elderly population.