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Gene Variant, Viral Exposure Together Increase Asthma Risk in Children

NEW YORK (GenomeWeb) – Children with a common PAI-1 gene variant who experienced a severe viral respiratory infection at a young age have a much higher risk of developing asthma, a new study has found.

As Rajesh Kumar from Ann & Robert H. Lurie Children's Hospital of Chicago and his colleagues reported in PLOS One today, variants in PAI-1 on their own don't contribute to asthma risk, but do when combined with an early-life lower respiratory tract infection. Children with both the variant and viral exposure are 12 times as likely to develop asthma later on — that risk climbed even higher if the viral infection progressed to bronchiolitis.

"Our findings suggest that genetic influences on asthma might be more pronounced in the context of early life environmental exposures, especially viral respiratory infections," Kumar said in a statement.

He and his colleagues genotyped 1,736 children with physician-diagnosed asthma and 1,746 healthy controls from the Genes-environments and Admixture in Latino Americans (GALA-II) study. The children were all Latino, and between the ages of 8 and 21.

In particular, the researchers focused their genotyping on the promoter site SNP rs2227631 for the PAI-1 gene. The A allele at this site is a gain-of-function mutation linked to higher levels of PAI-1 in plasma. PAI-1 is involved in the airway response to viruses, and the researchers noted that an exaggerated response might be harmful.

At the same time, the investigators queried the children's families as to whether they had been diagnosed with bronchiolitis, respiratory syncytial virus (RSV), or a chest illness before the age of 2. They then gauged any independent or joint effects of early-life lower respiratory tract infection or bronchiolitis/RSV and rs2227631 genotype on asthma risk.

They found that while the rs2227631 SNP alone doesn't increase asthma risk, an early-life infection does. And when present together, the combination dramatically increased asthma risk. Children with the AG or AA genotype who'd had an early-life lower respiratory infection had a nearly 12-fold increased risk of developing asthma. That risk increased to 17-fold for children with the AG or AA genotype who had specifically had an early-life RSV infection or bronchiolitis.

Children with the AG/AA genotypes also had two-times higher risk of being hospitalized, and had reduced lung function. This suggested to the researchers that the SNP, when combined with viral exposure, might lead to increased PAI-1 production in the airway and affect lung development to lead to asthma.

The researchers largely replicated their findings in separate cohort of 666 African Americans with asthma from the Study of African Americans, Asthma, Genes & Environments II (SAGE II), though they were limited in part by that cohort's smaller size.

These findings, the researchers suggested, could help identify at-risk kids. "These results could lead to studies moving towards the personalized prevention of asthma," Kumar said. "Further research is needed to see if we can intervene with genetically susceptible children prior to or during a lower respiratory tract infection to reduce their chances of developing asthma."