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Researchers Link Variant to Severe Childhood Asthma

NEW YORK (GenomeWeb News) – An international team of researchers has homed in on a novel gene variant linked to severe asthma in children, as it reported in Nature Genetics yesterday.

The team, led by researchers at the Children's Hospital of Philadelphia in the US and the University of Copenhagen in Denmark, examined some 1,200 cases and 2,500 controls to uncover five variants associated with severe childhood asthma, one of which had not been linked previously to the disease.

"Identifying a risk susceptibility gene linked to this phenotype may lead to more effective, targeted treatments for this type of childhood asthma," said Hakon Hakonarson, the director of the Center for Applied Genomics at CHOP, in a statement.

Earlier large genome-wide association studies of asthma have linked a number of gene variants to the disease, but for this study the researchers concentrated on one particular phenotype of the disease, arguing that a finer focus would increase the power of the study and be more likely to discover a specific pathogenic mechanism.

"Because asthma is a complex disease, with multiple interacting causes, we concentrated on a specific phenotype — severe, recurrent asthma occurring between ages two and six," Hakonarson added.

Drawing on data from the Danish National Patient Register and samples from the Danish Neonatal Screening Biobank, the researchers identified more than 1,170 children born between 1982 and 1995 with recurrent hospitalizations for acute asthma, and they genotyped samples from those kids at more than 124,500 SNPs along with 2,511 controls. SNPs in five regions reached genome-wide significance. Retesting the cases against a separate control population validated those top SNPs, the researchers added.

In addition, the researchers replicated their findings in a separate cohort of childhood-onset asthma cases, and they particularly focused on the novel locus CDHR3 and replicated the finding in two additional cohorts of European ancestry and one of mixed ancestry, which included a subset of non-European ancestry.

For two of the replication cohorts, the researchers were also able to perform phenotype-specific replication prospectively. The risk allele rs6967330, they found, was associated with a greater risk of asthma hospitalizations.

The risk allele rs6967330 in the CDHR3 locus, the researchers noted, leads to an amino acid change from cysteine to tyrosine at position 529 in the protein it encodes. By making expression constructs with CDHR2 and introducing the Cys529Tyr mutation through site-directed mutagenesis, the researchers uncovered that the wild-type protein was expressed at low levels at cell surfaces while the Cys529Tyr mutant was expressed at cell surfaces at higher levels.

While the functions of CDHR3 is not known, the researchers noted that it is a transmembrane protein with six extracelluar cadherin domains and that it belongs to a family of transmembrane proteins that are involved in homologous cell adhesion. Further, the Cys529Tyr mutation associated with asthma risk, they said, appeared through protein modeling to be at an interface between two membrane-proximal cadherin domains. This, the researchers said, suggests that the risk variant may affect the stability or folding of the protein.

The researchers also traced expression of CDHR3 to both adult bronchial epithelium and fetal lung tissue, noting that it appears to be highly expressed during lung development. Hakonarson said that researchers have recently been interested in the role of the bronchial epithelium in asthma development.

"Abnormalities in the epithelial cells may increase a patient's risk to environmental triggers by exaggerating immune responses and making the airway overreact," he said. "Because the CDHR3 gene is related to a family of proteins involved in cell adhesion and cell-­to-­cell interaction, it is plausible that variations in this gene may disrupt normal functioning in these airway cells, and make a child vulnerable to asthma."

Interestingly, Hakonaron and his colleagues noted that the CDHR3 variant seemed to be the ancestral allele, suggesting that the risk allele may have been advantageous during human evolution.

"This phenomenon in which the ancestral allele is the risk allele is known for other common diseases and may reflect a shift from a beneficial to a deleterious effect for a particular allele as a result of a changing environment," the researchers said.

They added that future work into the role of CDHR3 variants in asthma development and exacerbation may help in better understanding and treating the disease.

"Our study supports the theory that asthma is not just a single disease, but a complex of several sub­types that should be genetically mapped and understood individually if we are to prevent and treat the disease properly in [the] future," added first author Klaus Bønnelykke from Copenhagen University Hospital.