Obesity and Asthma: Genetics and Nutrigenetic Response to Omega-3 Fatty Acids

描述(由申请人提供)：肥胖增加了儿童和成人哮喘诊断的风险。随着肥胖症的增加，更好地理解这种联系对公众健康可能变得至关重要。这项建议的目标是：1)解决与肥胖相关的哮喘的重要病因学问题；2)使朗博士能够在儿童哮喘临床试验和药物遗传学领域发展专业知识。这位候选人在与哈佛大学公共卫生学院的斯蒂芬妮·肖尔博士合作期间，对肥胖和哮喘之间的联系产生了兴趣。他现在有兴趣将这一基础科学经验转化为儿童哮喘、药物遗传学和营养遗传学领域。朗博士目前在佛罗里达州杰克逊维尔的内穆尔儿童诊所(NCC)担任儿科肺病专家。2009年春，他开始攻读公共卫生硕士学位所需的核心课程。职业发展奖将允许朗博士完成他的公共卫生硕士学位，特别强调流行病学、统计遗传学、药物遗传学和营养学。NCC将为临床和转化性研究提供一个极好的培训环境，因为它有专门的生物医学研究部，药物基因组学中心(由他的导师利马博士指导)，以及它与美国肺脏协会-哮喘临床研究中心网络的密切联系。朗博士感兴趣的是，肥胖者患哮喘的风险增加是否源于这两种疾病的共同基因起源。我们建议询问来自过去3个ALA-ACRC哮喘试验的3个高质量的基因型-表型现有数据集，以及3个匹配的非哮喘患者队列，以寻找与肥胖相关的可信的候选基因多态。与肥胖相关的基因多态将进一步评估与哮喘的相关性，然后在国家生物技术信息中心维护的基因和表型数据库(DBGaP)上评估可公开获得的基因/表型样本之间的复制。在目标2中，我们将确定鱼油衍生的二十碳五烯酸(EPA)和二十二碳六烯酸(DHA)对肥胖哮喘患者哮喘控制的影响。这些omega-3脂肪酸已经被证明：在以前的较小规模的研究中，以一种不一致的方式减少对哮喘重要的炎症和改善哮喘结果--结果与药物遗传影响一致。有证据表明，omega-3脂肪酸的反应表现出与ALOX5基因相关的药物遗传反应。朗博士的初步数据表明，肥胖个体拥有相同的ALOX5变异的风险更大，因此肥胖哮喘患者可能对鱼油更敏感。我们将确定(在子目标中)是否存在与鱼油ALOX5基因相关的反应效应。这将是欧米茄-3脂肪酸治疗哮喘的最大规模的临床试验，也是第一次应用药物遗传学/营养遗传学分析。这项建议的设计方式是：1)非常具有成本效益(因为我们使用了我们与ALA-ACRC合作的现有DNA样本，并且由于完成建议的教育和研究的所有费用将由内穆斯基金会承担)，以及2)为PI配备遗传、药物基因组和临床试验专业知识，以成为一名成功的翻译科学家。 此外，该项目的结果可能会增加对个性化哮喘护理的追求，并指导未来对肥胖相关哮喘病因的调查。这个项目，通过我们ALA-ACRC的合作，可能会很好地过渡到一个大型的多中心哮喘试验。

DESCRIPTION (provided by applicant): Obesity increases the risk for asthma diagnosis in children and adults. With obesity on the rise, a better understanding of this association may become critically important to public health. The goals of this proposal are to 1) address important etiologic questions in obesity-related asthma and, 2) allow Dr. Lang to develop expertise in the fields of pediatric asthma clinical trials and pharmacogenetics. The candidate became interested in the link between obesity and asthma during his work with Dr. Stephanie Shore at the Harvard School of Public Health. He is now interested in translating this basic science experience into the fields of pediatric asthma, pharmacogenetics and nutrigenetics. Dr. Lang is currently working as a pediatric pulmonologist at the Nemours Children's Clinic (NCC) in Jacksonville, Florida. In the spring of 2009, he started the core coursework needed to earn a Master's degree in Public Health. A Career Development Award would allow Dr. Lang to finish his MPH with special emphasis on Epidemiology, Statistical Genetics, Pharmacogenetics and Nutrition. NCC will furnish an excellent training environment for clinical and translational research due to its dedicated Biomedical Research Department, the Center for Pharmacogenomics (directed by his mentor, Dr. Lima), and its close affiliation with the American Lung Association - Asthma Clinical Research Centers Network. Dr. Lang is interested in determining if the increased risk of asthma among the obese stems from a genetic origin shared by both conditions. We propose to interrogate three high quality genotype-phenotype extant datasets from 3 past ALA-ACRC asthma trials as well as 3 matched cohorts of non-asthmatics for plausible candidate gene polymorphisms that associate with obesity. Genetic polymorphisms associating with obesity will be further evaluated for association with asthma, and then assessed for replication among publically available genotype/phenotype samples on the database of Genotypes and Phenotypes (dbGaP) maintained by National Center for Biotechnology Information. In aim #2, we will determine the impact of fish oil-derived Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA) on asthma control among obese asthmatics. These omega-3 fatty acids have been shown to: reduce inflammation important to asthma and improve asthma outcomes in an inconsistent manner across previous smaller studies - results that are consistent with a pharmacogenetic influence. There exists evidence that omega-3 fatty acid response displays a pharmacogenetic response related to ALOX5 genotype. Dr. Lang's preliminary data suggests that obese individuals are at greater risk for possessing this same ALOX5 variant and thus obese asthmatics may be more responsive to fish oil. We will determine (in a sub-aim) if there exists an ALOX5 genotype-related response effect with fish oil. This will be the largest clinical trial of omega-3 fatty acid for the treatment of asthma, and the first applying pharmacogenetic/nutrigenetic analysis. This proposal is designed in a fashion to: 1) be extremely cost-effective (since we utilize extant DNA samples from our affiliation with the ALA-ACRC, and since all costs associated with completing the proposed education and research that are not supplied through the award will to be borne by the Nemours Foundation), and 2) equip the PI with the genetic, pharmacogenomic, and clinical trials expertise to become an successful translational scientist. Furthermore, the results of this project may add to the pursuit of personalized asthma care and direct future investigation into the etiology of obesity-related asthma. This project, through our ALA-ACRC affiliation, may be well positioned to transition into a large multicenter asthma trial.