Galanter Joshua, Choudhry Shweta, Eng Celeste, Nazario Sylvette, Rodríguez-Santana José R, Casal Jesús, Torres-Palacios Alfonso, Salas Jorge, Chapela Rocio, Watson H Geoffrey, Meade Kelley, LeNoir Michael, Rodríguez-Cintrón William, Avila Pedro C, Burchard Esteban González
Lung Biology Center, Department of Medicine, Institute for Human Genetics, University of California, San Francisco, California 94143-2911, USA.
Am J Respir Crit Care Med. 2008 Jun 1;177(11):1194-200. doi: 10.1164/rccm.200711-1644OC. Epub 2008 Feb 28.
Independent replication of genetic associations in complex diseases, particularly in whole-genome association studies, is critical to confirm the association.
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.
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.
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.
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.
在复杂疾病中，尤其是在全基因组关联研究中，基因关联的独立复制对于确认关联至关重要。
一项全基因组关联研究确定ORMDL3是白种人群中哮喘的一个有前景的候选基因。在此，我们试图在三个不同种族的人群（墨西哥人、波多黎各人及非裔美国人）中确认ORMDL3基因变异在哮喘中的作用。
我们采用基于家系的分析方法，检测ORMDL3基因及其周围的七个候选单核苷酸多态性（SNP）与701名波多黎各人和墨西哥人的亲子三联体中的哮喘及相关表型之间的关联。我们还在264名患有哮喘的非裔美国人受试者和176名健康对照受试者中评估了这七个SNP以及另外一个ORMDL3 SNP。
我们发现ORMDL3基因内的两个SNP（rs4378650和rs12603332）与墨西哥人和非裔美国人的哮喘之间存在显著关联（rs4378650的P值分别为0.028和0.001，rs12603332的P值分别为0.021和0.001），在波多黎各人中存在关联趋势（rs4378650和rs12603332的P值分别为0.076和0.080）。在哮喘患者中，这些关联在墨西哥人和波多黎各人中，当IgE水平大于100 IU/ml时变得更强。我们未发现ORMDL3 SNP与基线肺功能或对支气管扩张剂沙丁胺醇的反应之间存在任何关联。
我们的结果证实，在不同种族人群中，ORMDL3基因座是哮喘的一个危险因素。然而，SNP水平结果不一致表明，需要进一步研究以确定ORMDL3导致哮喘的机制。
