PURPOSE OF THE STUDY.
Genetic variations at the 17q21 locus, as well as human rhinovirus (HRV) and respiratory syncytial virus (RSV) wheezing illness, are associated with the development of asthma. This retrospective study aimed to determine the effects of these 2 factors independently and together on the risk of asthma.
Data were compiled from the Childhood Origins of Asthma (COAST) and the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) birth cohorts as well as a group of adult volunteers. For the COAST study, 289 newborns had at least 1 parent with respiratory allergies, a history of physician-diagnosed asthma, or both and 200 were evaluated for asthma beginning at age 6 years. For COPSAC, 297 of 411 children born to mothers with a history of physician-diagnosed asthma and who had complete follow-up from the first 3 years of life and information on asthma status by age 7 years were included. Finally, 100 unrelated adult volunteers were recruited to examine the effects of HRV stimulation on gene expression patterns in peripheral blood mononuclear cells (PBMCs) along the 17q21 genes.
Five asthma-associated 17q21 single-nucleotide polymorphisms (SNPs) were genotyped in the COAST cohort. Each SNP was evaluated for an association with the development of asthma, as well as HRV or RSV wheezing illness, by using a logistic regression model or a linear regression model. The authors also evaluated for interactions between the specific 17q21 genotypes and HRV or RSV wheezing illness as it pertains to the development of asthma. Last, this study examined genotype-specific expression of 17q21 genes in unstimulated and HRV-stimulated PBMCs by using the blood samples obtained from each adult volunteer.
The 17q21 variants identified in the COAST cohort were associated with HRV wheezing illness in early life, but not with RSV wheezing illness. The association of 17q21 variants and the development of asthma was seen only in children who also had been ill with HRV wheezing illnesses, suggesting a significant interaction effect between the 17q21 variant and HRV in early life. The expression of 2 of the 17q21 genes, ORMDL3 and GSDMB, was significantly increased in HRV-stimulated PBMCs compared with unstimulated PBMCs.
This study revealed that the association between 17q21 genotypes and asthma is restricted to only those who also had HRV wheezing illness in early childhood. There is a significant interaction between 17q21 genotypes and HRV wheezing illness in early life with respect to childhood-onset asthma.
This study helps reinforce the idea that the pathogenesis of asthma involves complex interactions between genetic factors and environmental triggers. Whereas this report does not establish whether risk of asthma is correlated directly to wheezing illness (as both could be related to an underlying genetic susceptibility in a subgroup of this 17q21 genotype), it certainly underscores the importance of additional studies to better understand both the roles and potential interdependence of genetic factors and illness events early in life with regard to asthma risk. Because exacerbations are most likely an important influence in perpetuating asthma, this mechanism could shed some light on why some children are at higher risk of persistent asthma, whereas, in others, asthma is more likely to remit.
- Copyright © 2013 by the American Academy of Pediatrics