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Genome-wide Analysis of Asthma Patients Implicates VNN1 Expression in Treatment Response

NEW YORK (GenomeWeb) – Through a genome-wide analysis, researchers from Cincinnati Children's Hospital Medical Center have linked the expression of the VNN1 gene to whether or not asthma patients responded well to corticosteroid treatment.

Examining gene expression levels in nasal tissue samples from children presenting to the emergency department due to an asthma attack, Cincinnati Children's Gurjit Khurana Hershey and her colleagues found that VNN1 expression could differentiate good responders to corticosteroid treatment from poor responders, as they reported in the Journal of Allergy and Clinical Immunology.

"This may serve as a clinically useful biomarker to identify a subset of difficult-to-treat asthmatic children, and targeting the VNN1 pathway may be useful as a therapeutic strategy," Khurana Hershey, the director of asthma research at Cincinnati Children's, said in a statement.

Some 26 million people — including 7 million children — in the US have asthma, and for a good portion of patients, treatment is either incomplete or ineffective, suggesting to Khurana Hershey and her colleagues that new therapeutic strategies are needed.

The researchers collected nasal epithelial samples from 15 patients between the ages of 5 years and 18 years old who went to the Cincinnati Children's Hospital Medical Center because of an asthma attack. They took one sample when the patients arrived at the ER and another sample 18 hours to 24 hours after treatment.

The researchers categorized patients who remained in the hospital less than 24 hours following treatment as good responders and those who had to stay longer as poor responders to treatment.

Using a gene expression microarray, the researchers homed in on genes that were either up- or down-regulated between the two time points in the group of good responders and overlaid that with genes whose expression varied between the good and poor responder groups.

Turning to a second cohort of 25 patients between 5 years old and 18 years old, the researchers validated one gene, VNN1, and its association with corticosteroid treatment response.

In addition, the researchers reported that methylation at a CpG4 site upstream from the VNN1 transcription start site was higher in good responders and lower in poor responders after treatment, and that there were differences in methylation at that site between the two time points. In addition, there was a positive correlation between DNA methylation there and VNN1 mRNA expression.

This suggested to Khurana Hershey and her colleagues that methylation at that promoter site might be a crucial regulator of VNN1 mRNA expression and could modulate corticosteroid treatment response.

In a mouse model, the researchers found that mice lacking the VNN1 gene were less responsive than wild-type mice to dexamethasone during an induced asthma attack. At the same time, though, the researchers noted it was harder to induce an asthma attack state in mice without the VNN1 gene, indicating that it could also have a role in asthma development. But as such a state could still be induced, it's likely not an essential role, the researchers added.

Still, they suggested that nasal VNN1 gene expression could be a useful biomarker to identify children with difficult-to-treat asthma and that the VNN1 gene pathway could represent a therapeutic target.