Association of Vascular Endothelial Growth Factor (VEGF) Polymorphisms with Childhood Asthma and Airway-Remodeling Phenotypes. S. Sharma¹, B. Raby¹, A. Murphy¹, M. Soto-Quiros², L. Avila², B. Klanderman¹, J. Sylvia¹, A. Patel¹, J. Celedon¹, S. Weiss¹ 1) Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; 2) Division of Pediatric Pulmonology, Hospital Nacional de Niņos, San Jose, Costa Rica.

   Rationale: Asthma is a chronic inflammatory disease associated with airway remodeling and subsequent long-term decline in lung function. Expression of VEGF, an angiogenic factor implicated in airway remodeling, correlates with the severity of airflow obstruction. We hypothesized that VEGF gene polymorphisms are associated with asthma and airway-remodeling phenotypes. Methods: We genotyped 17 VEGF single nucleotide polymorphisms (SNPs) in 471 white (non-Hispanic) trios participating in the Childhood Asthma Management Program (CAMP). Family-based association tests were performed using PBAT under additive and dominant genetic models. We assessed asthma and three pulmonary function phenotypes: post bronchodilator FEV1, FVC, and FEV1/FVC ratio (FF). Haplotype block analysis was performed in FBAT. Repeated measures analysis of FF was conducted with FBAT-PC. We tested for evidence of replication in 439 asthmatic children and their parents from the Central Valley of Costa Rica. Results: In CAMP, one SNP was associated with asthma (p=0.01), and three others with FVC and FF (p=0.01-0.03). Most notably, rs4711750 was associated with FF in CAMP (p=0.01) and Costa Rica (p=0.02). In the Costa Rican trios, one SNP was associated with asthma (p=0.01) and two others were associated with FEV1 and FF (p=0.006-0.02). Haplotype block analysis confirmed the association with FF in both cohorts. Repeated-measures analysis also demonstrated an association between rs4711750 and FF over time. Conclusions: VEGF polymorphisms are associated with childhood asthma and airway remodeling phenotypes in two ethnically distinct populations. Our analysis suggests that variants in VEGF influence airway remodeling, which is a critical long-term outcome of asthma. Funding: Grants HL65899, HLO7427, HL04370, HL66289, and HL74193 from the National Institutes of Health.