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European Consortium IDs Genetic Variants Involved in Asthma

By Andrea Anderson

NEW YORK (GenomeWeb News) – A genome-wide association study appearing online today in the New England Journal of Medicine is underscoring the genetic heterogeneity of asthma — pointing to distinct risk variants for asthma cases diagnosed in childhood.

"Asthma has often been considered a single disease, but our genetic findings suggest that childhood-onset asthma may differ biologically from asthma that is acquired in adult life," co-author David Strachan, an epidemiology researcher at St. Georges Hospital in London, said in a statement.

Members of the GABRIEL consortium, who are involved in a multi-disciplinary study of the genetic and environmental factors behind asthma, did a GWAS involving tens of thousands of individuals. Their search turned up variants linked to asthma overall on several chromosomes, and confirmed a previously detected association between a chromosome 17 locus and childhood asthma.

Given the genes implicated in asthma so far, those involved in the study say the GWAS approach may offer a step toward more targeted asthma treatments.

"It looks quite promising for several of these genes," corresponding author William Cookson, a respiratory genetics researcher affiliated with Imperial College and the Royal Brompton and Harefield National Health Service Foundation Trust, told GenomeWeb Daily News. "They could be targets for treatment — either drugs or antibodies."

Asthma is thought to stem from a combination of genetic and environmental factors, the researchers explained. For instance, a study of about 1,000 children with asthma by members of the same team implicated the chromosome 17 locus 17q21 in childhood asthma.

But although it tends to run in families, they explained, many of the underlying genetic factors remain undiscovered.

"Genetic risk factors may be useful for identifying sub-types of asthma and determining whether intermediate phenotypes … are causally linked to disease," the team wrote, noting that genetic studies "offer a structured means of understanding the causes of asthma as well as identifying targets that can be used to treat the syndrome."

The researchers used the Illumina 650K array to genotype 10,365 individuals who had been diagnosed with asthma, along with 16,110 unaffected, ancestry-matched controls, at more than 580,000 SNPs each.

The participants had been recruited through nearly two dozen studies done in Europe, the US, Canada, and Australia and included individuals diagnosed with asthma as children, those diagnosed later in life, as well as occupational asthma cases and individuals with severe asthma.

The team's search turned up several variants linked to asthma in the group as a whole. Many of these asthma-associated variants tended to fall in and around genes contributing to processes related to adaptive immunity, immune response to skin damage, and airway inflammation.

Among the top SNPs: a chromosome 2 SNP in the neighboring genes IL1RL1 and IL18R1, a chromosome 6 SNP in a major histocompatibility complex gene region known as HLA-DQ, a SNP on chromosome 9 near the IL33 gene, and a SNP in the IL2RB gene on chromosome 22.

In general, Cookson explained, childhood asthma appeared to have a stronger genetic influence than adult onset asthma. Moreover, the researchers again found that the chromosome 17 locus 17q21 was specifically associated with asthma diagnosed before the age of 16 years old. Variants in this region, in turn, affected the expression of at least two genes: ORMDL3 and GSDMB, they noted.

But while the team expected to pick up variants affecting genes that modify allergy, Cookson explained, most of the associated SNPs fell in and around genes involved with unknown functions or involved in other processes.

And when the team looked at genetic variants associated with levels of the antibody immunoglobulin E, or IgE, in a group of 7,087 individuals with asthma and 7,667 controls, they found that IgE-related SNPs were distinct from those involved in asthma, suggesting asthma is probably not just a consequence of elevated IgE production.

"Allergy and asthma are not the same thing and we would have thought they were at least partly the same thing," Cookson said.

"Our interpretation of those results is that the allergies are secondary to the asthmatic process," he added, noting that the largest genetic effect in childhood asthma cases appears to involve the ORMDL3 gene, which has unknown functions.

Cookson cautioned that the risk variants detected so far don't yet appear to be useful for predicting which children will go on to develop asthma. For instance, when the team tested for seven childhood-associated SNPs in 517 individuals with asthma and nearly 3,500 controls, they found that the SNPs offered little information about individual asthma risk.

"If you took this panel of genes and tested them in children, you would not have very much success at all in predicting who would get asthma or not," Cookson explained. "And I think it's unlikely that you would, certainly at this stage, on the basis of genes be able to predict response to particular therapies."

In contrast though, those involved in the study touted the genetic findings as a potential jumping off point for finding new treatment targets for different asthma sub-types.

In the future, members of the GABRIEL consortium plan to do genetic analyses of thousands more individuals with asthma. Cookson noted that the team also is pursuing environmental and epigenetic studies to complement such genetic approaches.

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