Published ahead of print on February 28, 2008, doi:10.1164/rccm.200711-1644OC Am. J. Respir. Crit. Care Med., Volume 177, Number 11, June 2008, 1194-1200 A more recent version of this article appeared on June 1, 2008
Submitted on November 6, 2007 ORMDL3 Gene is Associated with Asthma in Three Ethnically Diverse PopulationsJoshua Galanter1*,1 Lung Biology Center, Department of Medicine and the Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA, 2 Veterans Caribbean Health Care System, San Juan, Puerto Rico, 3 Centro de Neumologia Pediatrica, San Juan, Puerto Rico, 4 Instituto Nacional de Enfermedades Respiratorias (INER), Mexico City, Mexico, 5 The James A. Watson Wellness Center, Oakland, CA, USA, 6 Children's Hospital Oakland Research Institute (CHORI), Oakland, CA, USA, 7 Bay Area Pediatrics, Oakland, CA, USA, 8 Division of Allergy-Immunology, Northwestern University, Chicago, IL, USA, 9 Lung Biology Center, Department of Medicine and the Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA; Department of Biopharmaceutical Sciences, University of California, San Francisco, San Francisco, CA, USA * To whom correspondence should be addressed. E-mail: joshua.galanter{at}ucsf.edu.
Rationale: Independent replication of genetic associations in complex diseases, particularly in wholegenome association studies is critical to confirm the association. Objectives: A recent whole-genome association study dentified ORMDL3 as a promising candidate gene for asthma in Caucasian populations. Here, we attempted to confirm the role of ORMDL3 genetic variants in asthma in three ethnically diverse populations: Mexican, Puerto Rican and African American. Methods: We used family based analyses to test for association between seven candidate SNPs in and around the ORMDL3 gene and asthma and related phenotypes in 701 Puerto Rican and Mexican parentchild trios. We also valuated these seven SNPs and an additional ORMDL3 SNP in 264 African American asthmatic subjects and 176 healthy controls. Measurements and Main Results: We found significant associations between two SNPs within ORMDL3 (rs4378650 and rs12603332) and asthma in Mexicans and African Americans (p = 0.028 and 0.001 for rs4378650 and p = 0.021 and 0.001 for rs12603332, respectively), and a trend towards association in Puerto Ricans (p = 0.076 and 0.080 for SNPs rs4378650 and rs12603332, respectively). These associations became stronger in Mexican and Puerto Rican asthmatics with IgE levels > 100 IU/ml. We did not find any association between ORMDL3 SNPs and baseline lung function or response to the bronchodilator albuterol. Conclusions: Our results confirm that the ORMDL3 locus is a risk factor for asthma in ethnically diverse populations. However, inconsistent SNP-level results suggest that further studies will be needed to determine the mechanism by which ORMDL3 predisposes to asthma. Key words: Asthma, Genetics, ORMDL3, single-nucleotide polymorphism, Latinos
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