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。随着肥胖症的增加，更好地了解这种联系可能对公共卫生至关重要。该提案的目标是：1）解决肥胖相关哮喘的重要病因学问题，2）使Lang博士能够发展儿科哮喘临床试验和药物遗传学领域的专业知识。这位候选人在哈佛公共卫生学院与斯蒂芬妮海岸博士合作期间，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科哮喘，药物遗传学和营养遗传学领域。朗博士目前在佛罗里达杰克逊维尔的内穆尔儿童诊所（NCC）担任儿科肺病学家。在2009年春天，他开始了获得公共卫生硕士学位所需的核心课程。一个职业发展奖将允许朗博士完成他的硕士学位，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，这是由于其专门的生物医学研究部门，药物基因组学中心（由他的导师利马博士指导）及其与美国肺脏协会-哮喘临床研究中心网络的密切联系。Lang博士有兴趣确定肥胖者患哮喘的风险增加是否源于这两种疾病的遗传起源。我们建议从过去3个ALA-ACRC哮喘试验以及3个匹配的非哮喘患者队列中询问3个高质量的基因型-表型现存数据集，以寻找与肥胖相关的合理候选基因多态性。将进一步评价与肥胖相关的遗传多态性与哮喘的相关性，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）上评估药物可获得的基因型/表型样本中的复制情况。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ω-3脂肪酸已被证明：减少炎症对哮喘的重要性，并改善哮喘的结果，在以前的小型研究中不一致-结果与药物遗传学影响一致。有证据表明，ω-3脂肪酸应答显示出与ALOX 5基因型相关的药物遗传学应答。Lang博士的初步数据表明，肥胖个体拥有相同的ALOX 5变体的风险更大，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）是否存在与鱼油相关的ALOX 5基因型反应效应。这将是最大的omega-3脂肪酸治疗哮喘的临床试验，也是第一次应用药物遗传学/营养遗传学分析。本提案旨在：（1）成本效益高（因为我们使用我们与ALA-ACRC合作的现存DNA样本，并且因为与完成未通过该奖项提供的拟议教育和研究相关的所有费用将由Nemours基金会承担），以及2）为PI配备遗传，药物基因组学，和临床试验专业知识，成为一个成功的转化科学家。 此外，该项目的结果可能有助于追求个性化的哮喘护理，并指导未来对肥胖相关哮喘病因的调查。这个项目，通过我们的ALA-ACRC联盟，可以很好地过渡到一个大的多中心哮喘试验。

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.