The Genetics of Metabolic Dysfunction in Sleep Apnea

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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.