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.

Public Health Relevance

The mechanism by which obesity increases the rate of asthma is unknown. This project will explore two prominent theories: 1) genetics (investigating 'risk-genes'that may lead to both conditions) and 2) obesity related inflammation that promotes asthma. This project will determine the effectiveness of an anti-inflammatory nutrient in obese asthmatics and assess if a person's genes alter the response to treatment (personalized medicine). This project may improve our ability to treat asthma and our understanding of the link between obesity and asthma - both results would have immense positive impact on public health.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZHL1-CSR-R (F1))
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Tigno, Xenia
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Nemours Children's Clinic
United States
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Lang, Jason E; Hossain, Jobayer; Holbrook, Janet T et al. (2016) Gastro-oesophageal reflux and worse asthma control in obese children: a case of symptom misattribution? Thorax 71:238-46
Lang, Jason E; Holbrook, Janet T; Lima, John J et al. (2015) Reply: worsening asthma control in children taking lansoprazole: possible mechanisms. Ann Am Thorac Soc 12:1110-1
Lang, Jason E; Holbrook, Janet T; Mougey, Edward B et al. (2015) Lansoprazole Is Associated with Worsening Asthma Control in Children with the CYP2C19 Poor Metabolizer Phenotype. Ann Am Thorac Soc 12:878-85
Lang, Jason E (2014) Obesity and asthma in children: current and future therapeutic options. Paediatr Drugs 16:179-88
Lang, Jason E; Mougey, Edward B; Allayee, Hooman et al. (2013) Nutrigenetic response to omega-3 fatty acids in obese asthmatics (NOOA): rationale and methods. Contemp Clin Trials 34:326-35
Lang, Jason E; Holbrook, Janet T; Wise, Robert A et al. (2013) Obesity in children with poorly controlled asthma: Sex differences. Pediatr Pulmonol 48:847-56
Lang, Jason E; Dozor, Allen J; Holbrook, Janet T et al. (2013) Biologic mechanisms of environmental tobacco smoke in children with poorly controlled asthma: results from a multicenter clinical trial. J Allergy Clin Immunol Pract 1:172-80
Mougey, E; Lang, J E; Allayee, H et al. (2013) ALOX5 polymorphism associates with increased leukotriene production and reduced lung function and asthma control in children with poorly controlled asthma. Clin Exp Allergy 43:512-20