Multifactorial Determinants of Childhood Hearing Loss in Rural Alaska

摘要 儿童听力损失是少数几种可预防的慢性疾病之一，具有终身后果， 影响早期语言发展、学业成绩和未来就业。听力损失尤其 常见于阿拉斯加农村的土著儿童，通常与感染有关。然而，对风险因素知之甚少 导致感染相关的听力损失，以及可能的遗传、营养和环境风险因素都有影响。 阿拉斯加原住民儿童的呼吸道疾病，通常会导致复发性耳部感染， CPT 1A北极变种肉毒碱棕榈酰转移酶1A（CPT 1A）中的这种单核苷酸变体 一种脂肪酸代谢所需的基因，是在Yup'ik和Inupiaq中发现的最常见的CPT 1A形式 阿拉斯加原住民CPT 1A北极变异体的两个拷贝与呼吸道疾病风险增加相关 疾病、耳部感染和婴儿死亡率。这些健康影响促使阿拉斯加州开始普及 2016年，基于DNA的新生儿筛查CPT 1A北极变体。除了遗传风险因素外， 反复感染，阿拉斯加原住民的营养影响正在改变，因为西方饮食变得 当传统的维生食品，富含ω-3多不饱和脂肪酸（n-3）， 历史上占主导地位。最后，环境差异在阿拉斯加原住民农村很常见。 社区，包括27%的家庭缺乏自来水，家庭拥挤，室内空气质量差 因为烧木头的炉子这项研究的目的是确定CPT 1A北极之间的联系， 变异和儿童听力损失，并描述环境和营养因素如何 改变听力的这种影响。我们将利用NICHD资助的独特（1 R 01 HD 089951 -01）前瞻性研究， 一项在阿拉斯加北方和西部进行的队列研究，该研究将开始招募阿拉斯加土著孕妇， 2020年，并跟踪儿童到2岁，以评估CPT 1A北极变体的整体健康影响。这 一项拟议的研究将与NICHD队列合作，首次评估听力的潜在危险因素 使用多层次的方法，包括遗传，营养和环境影响的损失。目标1： 将描述CPT 1A北极变异与阿拉斯加土著儿童听力损失之间的关系。 我们假设CPT 1A突变体的两个拷贝会增加感染相关性听力损失的风险。 70%。在目标2中，我们将评估产前和产后接触传统生计的影响。 食物和环境风险因素对阿拉斯加土著儿童听力损失的风险。我们假设 传统食物暴露的减少，用n-3 PUFA生物标志物测量，将与 估计感染相关听力损失的风险增加70%，环境因素将增加 与感染相关的听力损失估计减少60%。这些因素将改变CPT 1A与 和听力损失的风险。我们的研究结果将有助于开发未来的干预措施，以减少儿童听力损失， 阿拉斯加原住民儿童的一个重要的健康差距，导致改善健康和社会经济成果。

ABSTRACT Hearing loss in children is one of only a few preventable chronic conditions that has lifelong consequences, affecting early language development, school achievement, and future employment. Hearing loss is particularly common in rural Alaska Native children, often related to infection. However, little is known about risk factors driving infection-related hearing loss, and likely genetic, nutritional, and environmental risk factors all contribute. Respiratory illness in Alaska Native children, which often leads to recurrent ear infections, has been associated with the “CPT1A arctic variant.” This single nucleotide variant in the carnitine palmitoyltransferase 1A (CPT1A) gene, required for fatty acid metabolism, is the most common form of CPT1A found in the Yup’ik and Inupiaq Alaska Native people. Two copies of the CPT1A arctic variant are associated with increased risk of respiratory illness, ear infections, and infant mortality. These health effects prompted the State of Alaska to begin universal DNA-based newborn screening for the CPT1A arctic variant in 2016. In addition to genetic risk factors for recurrent infection, nutritional influences in Alaska Native people are shifting as Western diets become increasingly common when traditional subsistence foods, rich in omega-3 polyunsaturated fatty acids (n-3 PUFAs), historically predominated. Lastly, environmental disparities are common in rural Alaska Native communities, including lack of running water in 27% of homes, household crowding, and poor indoor air quality due to wood-burning stoves. The objective of this study is to define the link between the CPT1A arctic variant and childhood hearing loss, and to characterize how environmental and nutritional factors modify this effect on hearing. We will leverage a unique NICHD-funded (1R01HD089951-01) prospective cohort study in northern and western Alaska that will begin enrolling expectant Alaska Native mothers in early 2020 and follow children through age two to assess overall health effects of the CPT1A arctic variant. This proposed study will partner with the NICHD cohort to evaluate, for the first time, underlying risk factors for hearing loss using a multilevel approach incorporating genetic, nutritional, and environmental influences. In Aim 1, we will characterize the relationship between the CPT1A arctic variant and hearing loss in Alaska Native children. We hypothesize that two copies of the CPT1A artic variant will increase the risk of infection-related hearing loss by 70%. In Aim 2, we will evaluate the impact of prenatal and postnatal exposure to traditional subsistence foods and environmental risk factors on the risk of hearing loss in Alaska Native children. We hypothesize that decreased exposure to traditional foods, measured with an n-3 PUFA biomarker, will be associated with an estimated 70% increase in risk of infection-related hearing loss, and environmental factors will increase risk of infection-related hearing loss by an estimated 60%. These factors will modify the association between CPT1A and risk of hearing loss. Our results will help to develop future interventions to reduce childhood hearing loss, an important health disparity in Alaska Native children, leading to improved health and socioeconomic outcomes.