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

肥胖和哮喘：Omega-3 脂肪酸的遗传学和营养遗传学反应

• 批准号: 8667495
• 负责人: Jason E. Lang
• 金额: $ 15.93万
• 依托单位: NEMOURS CHILDREN'S CLINIC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8667495
• 关键词: Address; Adult; American Lung Association; Anti-Inflammatory Agents; Anti-inflammatory; Asthma; Award; Basic Science; Biomedical Research; Biotechnology; Candidate Disease Gene; Caring; Case-Control Studies; Child; Childhood; Childhood Asthma; Clinic; Clinical; Clinical Research; Clinical Trials; DNA; Data; Data Set; Databases; Diagnosis; Disease susceptibility; Docosahexaenoic Acids; Education; Effectiveness; Eicosapentaenoic Acid; Environment; Epidemiology; Etiology; Fish Oils; Florida; Foundations; Future; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genomics; Genotype; Goals; Individual; Inflammation; Investigation; K-Series Research Career Programs; Lead; Leukotrienes; Link; Logistic Regressions; Master' s Degree; Medicine; Mentors; Modeling; Nutrient; Obesity; Oils; Omega-3 Fatty Acids; Outcome; Oxidants; Oxidative Stress; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Phenotype; Positioning Attribute; Predisposition; Process; Proteins; Public Health; Public Health Schools; Pulmonary Function Test/Forced Expiratory Volume 1; Race; Randomized; Research; Risk; Sampling; Scientist; Soybean Oil; Supplementation; Susceptibility Gene; Symptoms; Testing; Training; Translating; Translational Research; Variant; Work; Zileuton; asthmatic patient; cohort; cost; cost effective; database of Genotypes and Phenotypes; design; dietary supplements; experience; genetic variant; improved; interest; montelukast; novel; nutrition; nutrition related genetics; obesity in children; promoter; response; risk variant; soy; stem; theories; young adult

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.

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。随着肥胖的增长，对这种关联的更好理解可能对公共卫生至关重要。该提案的目标是1）解决与肥胖有关的哮喘中的重要病因问题，以及2）允许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。候选人在哈佛公共卫生学院与斯蒂芬妮·海尔（Stephanie Shore）的工作期间对肥胖与哮喘之间的联系感兴趣。现在，他有兴趣将这种基础科学经验转化为儿科哮喘，药物遗传学和营养学领域。 Lang博士目前正在佛罗里达州杰克逊维尔的Nemours儿童诊所（NCC）担任小儿肺科医生。在2009年春季，他开始了获得公共卫生硕士学位所需的核心课程。职业发展奖将使Lang博士特别强调流行病学，统计遗传学，药物遗传学和营养。 NCC将为其专门的生物医学研究部，药物基因组学中心（由他的导师Lima博士指导）以及与美国肺肺部临床研究中心网络的密切相关性，为临床和转化研究提供了出色的培训环境。 Lang博士有兴趣确定肥胖的哮喘风险是否来自两种情况共同的遗传起源。我们建议从过去的3项ALA-ACRC哮喘试验中询问三种高质量的基因型 - 表型现有数据集，以及3种与肥胖相关的合理候选基因多态性的非偶然候选基因多态性的匹配。将进一步评估与肥胖相关的遗传多态性，以与哮喘关联，然后在基因型和表型数据库（DBGAP）（由国家生物技术中心维持的基因型和表型（DBGAP））上评估复制。在AIM＃2中，我们将确定鱼油衍生的二十碳烯酸（EPA）和Docosahexaenoic酸（DHA）对肥胖哮喘患者哮喘控制的影响。这些omega -3脂肪酸已显示出：减少对哮喘重要的炎症，并在先前较小的研究中以不一致的方式改善哮喘结局 - 与药物遗传学影响一致的结果。有证据表明，omega-3脂肪酸反应显示与Alox5基因型有关的药物遗传学反应。 Lang博士的初步数据表明，肥胖个体具有具有相同ALOX5变体的更大风险，因此肥胖的哮喘患者可能对鱼油的反应更快。我们将确定（在子-IAM中）是否存在与鱼油有关的ALOX5基因型相关的响应效应。这将是Omega-3脂肪酸的最大临床试验，用于治疗哮喘，也是首次应用药物遗传学/营养分析的临床试验。 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. 此外，该项目的结果可能会增加对个性化哮喘护理的追求，并将未来对与肥胖有关的哮喘的病因进行研究。通过我们的ALA-ACRC隶属关系，该项目可以很好地定位为大型多中心哮喘试验。

项目成果

Nutrigenetic response to omega-3 fatty acids in obese asthmatics (NOOA): rationale and methods.

• DOI: 10.1016/j.cct.2012.12.009
• 发表时间: 2013-03
• 期刊: Contemporary clinical trials
• 影响因子: 2.2
• 作者: Lang JE;Mougey EB;Allayee H;Blake KV;Lockey R;Gong Y;Hossain J;Killen K;Lima JJ;Nemours Network for Asthma Research
• 通讯作者: Nemours Network for Asthma Research