MD, 8Department of Epidemiology, Johns Hopkins University Bloomberg. School of Public Health, Baltimore, MD. RATIONALE: To date over 500 papers on ...
243
Modulation of Lung Inflammation by Vessel Dilator, an N-Terminal Natriuretic Peptide, in a Mouse Model of Allergic Asthma X. Wang1, W. Xu1, D. Chen1, X. Kong1, R. F. Lockey2, S. S. Mohapatra1; 1 University of South Florida, Tampa, FL, 2James A. Haley Veterans Hospital, Tampa, FL. RATIONALE: Previous studies show that a novel N-terminal natriuretic peptide, NP73-102 (amino acids 73-102), has significant bronchoprotective and anti-inflammatory effects. These results led to the hypothesis that other N-terminal hormone peptides also possess bronchodilatory and antiinflammatory properties. Therefore, In this study, the activity of vessel dilator [(VD), amino acids 31-67)] was examined in a mouse model of allergic asthma. METHODS: A549 cells were transfected with pVD pr pVAX-1, and the anti-inflammatory effects of VD examined by western blot for ERK1/2 and NFkB. VD effect on NPRA expression was examined using NPRApromoter linked luciferase reporter constructs. Balb/c mice were sensitized and challenged with ovalbumin and administered nanoparticles expressing pVD or pVAX1 (vector control). Differential cell counting in bronchoalveolar lavage fluid and histopathology staining of lung sections was performed 4 days after pVD administration. RESULTS: pVD overexpression significantly (p < 0.001) decreases NPRA in A549 cells. A549 cells transfected with pVD show a significant reduction in the activity of NFkB and ERK1/2 compared to controls. Mice with ovalbumin-induced asthma versus control treated with nanoparticles carrying pVD show a substantial decease in lung inflammation, airway hyperreactivity and number of BAL eosinophils. CONCLUSIONS: These results show that VD peptide significantly attenuates allergic inflammation and airway hyperreactivity, VD may be a novel ew therapeutic agent for asthma. Funding: National Institutes of Health
244
Validation of Previously Reported Genetic Associations for Asthma Using a Genome-Wide Association Approach among a Large Population of African Descent N. M. Rafaels1, R. A. Mathias2, A. V. Grant1, T. Hand1, Y. J. Tsai1, P. S. Gao1, N. Hansel3, G. Diette3, N. F. Adkinson1, M. C. Liu3, H. Watson4, M. Faruque5, G. M. Dunston5, A. F. Scott6, I. Ruczinski7, A. Togias1, T. H. Beaty8, K. C. Barnes1; 1Johns Hopkins Asthma & Allergy Center, Johns Hopkins University School of Medicine, Baltimore, MD, 2Inherted Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD, 3Department of Medicine Pulmonary, Johns Hopkins University School of Medicine, Baltimore, MD, 4University of the West Indies, Cave Hill, BARBADOS, 5College of Medicine, National Human Genome Center at Howard University, Washington, DC, 6Genetic Resources Core Facility, Johns Hopkins University School of Medicine, Baltimore, MD, 7Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, 8Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD. RATIONALE: To date over 500 papers on asthma association studies have been published. In one of the most comprehensive reviews on asthma genetics to date (Genes and Immunity (2006) 7, 95-100) it was noted that 25 genes have been associated with asthma or an associated phenotype which have been replicated in six or more populations, with an additional 54 genes associated in 2-5 populations. However, of those reports, only 13 included substantial numbers of subjects of African ancestry. METHODS: Using the Illumina HumanHap650Y BeadChip, we genotyped 655,352 single nucleotide polymorphisms (SNPs) on 447 African American asthmatics and 459 non-asthmatic controls from BaltimoreWashington DC. Association between SNPs and asthma was determined by the Armitage trend test using PLINK. RESULTS: Of the 79 genes for which previous reports suggest significant associations for asthma, 739 SNPs representing 55 of those genes were present on the HumanHap650Y BeadChip. Of those, 24 genes had at least one SNP that was significantly associated with asthma in the African
American group, including 3 genes at P < 10-3, 5 genes at P < 10-2, and 16 genes at P < 0.05. Of the 25 most replicated genes, the strongest replication was for ACE (P 5 0.000317-0.02). Also, SPINK5, NOS1, and ADAM33 were replicated in the African American group (P 5 0.003, 0.006-0.04, and 0.03, respectively). CONCLUSIONS: Results from this genome-wide association study suggest that several of the most replicated genes for asthma are relevant to disease regardless of ethnicity. Further analyses into the specific genes and fine-mapping, and validation in independent populations are underway. Funding: National Institute of Health
245
Prematurity, Chorioamnionitis and the Development of Recurrent Wheezing: a Prospective Birth Cohort Study R. Kumar1, Y. Yu2, R. Story1, J. Pongracic1, R. Gupta2, C. Pearson3, K. Ortiz3, H. Bauchner3, X. Wang2; 1Division of Allergy and Immunology, Children’s Memorial Hospital, Chicago, IL, 2The Mary Ann and J. Milburn Smith Child Health Research Program, Children’s Memorial Hospital and Children’s Memorial Research Center, Chicago, IL, 3Boston University Medical Center, Boston, MA. RATIONALE: Prematurity (
