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

描述（由申请人提供）：肥胖增加儿童和成人哮喘诊断的风险。随着肥胖的增加，更好地了解这种联系可能对公众健康至关重要。这项提案的目标是1)解决肥胖相关哮喘的重要病因学问题，2)让Lang博士在儿科哮喘临床试验和药物遗传学领域发展专业知识。这位候选人在哈佛大学公共卫生学院与斯蒂芬妮·肖尔博士一起工作期间，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。Lang博士目前在佛罗里达州杰克逊维尔的Nemours儿童诊所（NCC）担任儿科肺病专家。2009年春天，他开始学习获得公共卫生硕士学位所需的核心课程。职业发展奖将允许Lang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将为临床和转化研究提供良好的培训环境，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。朗博士感兴趣的是确定肥胖人群患哮喘风险的增加是否源于两种疾病共有的基因起源。我们建议从三个过去的ALA-ACRC哮喘试验以及三个匹配的非哮喘患者队列中询问三个高质量的基因型-表型现有数据集，以寻找与肥胖相关的合理候选基因多态性。与肥胖相关的遗传多态性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型和表型数据库（dbGaP）中评估公开的基因型/表型样本的复制。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脂肪酸已被证明：减少对哮喘很重要的炎症，并以一种不一致的方式改善哮喘的结果，在之前的小型研究中-结果与药物遗传影响一致。有证据表明，omega-3脂肪酸反应表现出与ALOX5基因型相关的药理学反应。朗博士的初步数据表明，肥胖者携带这种ALOX5基因变体的风险更大，因此肥胖的哮喘患者可能对鱼油更敏感。我们将确定（在子目标中）鱼油是否存在与ALOX5基因型相关的反应效应。这将是欧米伽-3脂肪酸治疗哮喘的最大临床试验，也是首次应用药物遗传学/营养遗传学分析。该提案的设计方式是：1)极具成本效益（因为我们使用与ALA-ACRC有关联的现有DNA样本，并且因为完成拟议的教育和研究的所有费用都不是由该奖项提供的，将由Nemours基金会承担），2)为PI提供遗传学，药物基因组学和临床试验专业知识，以成为一名成功的转化科学家。

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.