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

抽象的。年龄相关性听力损失是一种常见的疾病，定义为听力损失 随着年龄的增长。在美国，65岁至74岁之间的人口中约有33% 在75岁以后，大约50%的人有听力 有问题。与年龄相关的听力损失有很多原因，包括年龄引起的听力变化 内耳和中耳的变化，以及从耳朵开始的神经通路的复杂变化 对大脑的影响。流行病学研究，如听力损失流行病学研究和 1999-2004年国家健康和营养检查调查显示，主要风险 与年龄相关的听力损失的因素是噪音暴露和吸烟。非常有限的信息是 关于年龄相关性听力损失的分子通路以及吸烟如何 行为增加了它的风险。我们之前的研究结果表明，基因变异可能在 缓解吸烟对年龄相关性听力损失的影响减少吸烟所致的损害 在涉及听觉功能的大脑区域。在目前的提案中，我们将在全基因组范围内应用 确定与年龄相关性听力损失有关的其他机制的方法 通过吸烟行为。具体地说，我们将进行全基因组范围的年龄关联研究- 500,000多名受试者中的相关听力损失(150,000名尼古丁接触者，350,000名受试者 尼古丁--未接触)。我们将使用来自队列的遗传和表型信息 英国生物库，护士健康研究I和II，健康专业人员后续研究，以及 国家生物技术信息中心基因型别和表型数据库 对接触尼古丁的个体进行一项全基因组听力损失的关联研究。一个 关于大脑结构和活动的后续研究将使用磁力进行 来自英国生物库的共振成像数据。此外，我们将进行一个多变量 孟德尔随机化研究哪些代谢改变和/或脑结构 变化在吸烟和听力损失之间的因果关系中起中介作用。这样做的目的是 分析是为了验证因果关系和相互作用中涉及的调解过程 吸烟行为和听力损失之间的关系。预期中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 更好地了解它的遗传学可以让我们开发出更有效的预防措施 可提高不断增长的老年人生活质量的策略和治疗方法 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.