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ORMDL3 Gene Is Associated with Asthma in Three Ethnically Diverse Populations

¹ Lung Biology Center, Department of Medicine and the Institute for Human Genetics, University of California, San Francisco, San Francisco, California; ² Veterans Caribbean Health Care System and ³ Centro de Neumología Pediátrica, CSP, San Juan, Puerto Rico; ⁴ Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico; ⁵ James A. Watson Wellness Center, ⁶ Children's Hospital Oakland Research Institute, and ⁷ Bay Area Pediatrics, Oakland, California; ⁸ Division of Allergy-Immunology, Northwestern University, Chicago, Illinois; and ⁹ Department of Biopharmaceutical Sciences, University of California, San Francisco, San Francisco, California

Correspondence and requests for reprints should be addressed to Joshua Mark Galanter, M.D., UCSF/Lung Biology Center, Box 2911, Rock Hall, 1550 4th Street, University of California, San Francisco, San Francisco, CA 94143-2911. E-mail: joshua.galanter{at}ucsf.edu

Rationale: Independent replication of genetic associations in complex diseases, particularly in whole-genome association studies, is critical to confirm the association.

Objectives: A whole-genome association study identified ORMDL3 as a promising candidate gene for asthma in white 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 single-nucleotide polymorphisms (SNPs) in and around the ORMDL3 gene and asthma and related phenotypes in 701 Puerto Rican and Mexican parent–child trios. We also evaluated these seven SNPs and an additional ORMDL3 SNP in 264 African American subjects with asthma and 176 healthy control subjects.

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 toward association in Puerto Ricans (P = 0.076 and 0.080 for SNPs rs4378650 and rs12603332, respectively). These associations became stronger among Mexican and Puerto Rican subjects with asthma with IgE levels greater than 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 • Latinos • African Americans

AT A GLANCE COMMENTARY Scientific Knowledge on This Subject A whole-genome association study identified the gene ORMDL3 as a promising candidate for asthma in white populations. This association has not yet been independently replicated in nonwhite populations. What This Study Adds to the Field This study confirms the association between ORMDL3 and asthma. The association in three genetically diverse populations provides strong support for its role in asthma susceptibility.

 

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