The Genetics of Metabolic Dysfunction in Sleep Apnea

描述（由申请人提供）： 候选人：候选人计划作为一名独立的临床研究者，专注于阻塞性睡眠呼吸暂停（OSA）及其并发症的遗传流行病学。在分子遗传实验室方法和统计遗传分析方法的高级课程将继续进行。研究方面的实际培训将通过完成一项密切指导的研究方案来进行。 环境：哈佛大学是一个独特的适合这个奖项的环境。睡眠障碍和钱宁实验室分别在睡眠生理学和呼吸遗传流行病学方面拥有丰富的专业知识。Case Western提供睡眠呼吸暂停遗传流行病学方面的专业知识。 研究：阻塞性睡眠呼吸暂停综合征是一种发病率很高的常见病。最近的数据表明，OSA可能是代谢紊乱的一个独立的危险因素，包括胰岛素和瘦素抵抗。这些疾病之间的相互关系是复杂的，因为肥胖是所有三种疾病的主要危险因素。大量文献表明，每种疾病都有大量的家族成分，这意味着重要的遗传机制。然而，迄今为止，在睡眠呼吸暂停人群中胰岛素和瘦素抵抗的遗传学尚未被探索。我们推测，有遗传多态性，影响个体与OSA发展胰岛素和瘦素抵抗的易感性，以及对OSA治疗的反应。为了验证这一假设，我们将首先在OSA患病率高的家族人群中进行胰岛素和瘦素抵抗的全基因组连锁分析，以发现调节这些疾病易感性的候选区域。将进行精细定位以缩小感兴趣区域，从该区域中将鉴定候选基因。将对基于连锁结果选择的位置候选基因进行基因分型，沿着生物学候选基因，并进行连锁不平衡研究，以检测与疾病的相关性。这些相关性研究将在从临床试验中招募的独立OSA人群中重复进行，以确保结果的普遍性。

DESCRIPTION (provided by applicant): Candidate: The candidate plans a career as an independent clinical investigator focusing on the genetic epidemiology of obstructive sleep apnea (OSA) and its complications. Advanced coursework in both molecular genetic laboratory methods and statistical genetic analytic methods will be pursued. Practical training in research will occur through the completion of a closely mentored research protocol. Environment: Harvard University is a uniquely suited environment for this award. The Sleep Disorders and Channing Laboratories have extensive expertise in sleep physiology and respiratory genetic epidemiology respectively. Case Western provides specific expertise in sleep apnea genetic epidemiology. Research: OSA is a common disease with substantial morbidity. Recent data suggest OSA may be an independent risk factor for metabolic derangements including resistance to insulin and leptin. The inter-relationships between these disorders are complex since obesity is a major risk factor for all three disorders. Substantial literature exists that each disorder has a substantial familial component implying important genetic mechanisms. To date, however, the genetics of insulin and leptin resistance in a sleep apneic population has not been explored. We hypothesize that there are genetic polymorphisms which influence the susceptibility of individuals with OSA to develop insulin and leptin resistance as well as the response to OSA therapy. To test this hypothesis, we will first perform genome wide linkage analyses of insulin and leptin resistance in a population of families with a high prevalence of OSA to discover candidate regions regulating susceptibility to these disorders. Fine mapping will be performed to narrow regions of interest from which candidate genes will be identified. Genotyping of positional candidate genes selected based on the linkage results along with biological candidate genes will be undertaken and linkage disequilibrium studies performed to test for association with the disorder. These association studies will be repeated in an independent OSA population recruited from a clinical trial to ensure generalizability of findings.