BioWorld International Correspondent

LONDON - In a discovery that marks a milestone for asthma research, scientists have found a gene that increases the risk of developing childhood-onset asthma. Although the function of the gene is currently unknown, future studies will reveal more about it, and may suggest new ways of treating the disease.

Mark Lathrop, director of the National Genotyping Centre in Evry, France, told BioWorld International, "The gene we have identified may one day prove to encode a potential drug target. This is an intriguing possibility, but any such development is currently a long way off."

The finding, he added, is the first clear-cut identification of a DNA variant associated with increased risk of developing childhood asthma.

An account of the study that led to the discovery appears in the July 4 online edition of Nature titled, "Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma."

The study was part of the GABRIEL project, a multicenter collaboration funded by the European Union (EU), which aims to investigate the genetic and environmental causes of asthma in the EU. The GABRIEL project is coordinated by William Cookson of the National Heart and Lung Institute in London, UK.

Childhood asthma is thought to cost the EU more than 53 billion each year, with the 10 percent of children who have severe disease accounting for 60 percent of that expenditure.

Lathrop, together with collaborators throughout Europe, including Cookson, conducted a genome-wide association scan to find single nucleotide polymorphisms (SNPs) that occur more commonly in people who had been diagnosed with childhood-onset asthma than in controls matched for age and geographical location.

There are estimated to be more than 7 million common SNPs in the human genome, but because recombination generally takes place at particular "hotspots," many of the SNPs commonly are inherited together. Researchers therefore can use a panel of SNPS (known as tags) to infer which groups of SNPs have been inherited by people with a particular disease and which by healthy controls.

Further investigation of stretches of the genome that are pinpointed by that process can then help scientists pinpoint variations such as mutations and SNPs.

In the study, the collaborators characterized more than 317,000 SNPs in DNA from 994 patients with childhood-onset asthma, and from more than 1,200 people who did not have asthma.

They found that several SNPs on chromosome 17q21 were strongly associated with childhood-onset asthma. Further investigations showed that it was possible to reproduce the result in two other sets of data, one involving more than 2,300 German children and the other involving more than 3,300 British children.

The next step in the study was to examine the expression of genes found on this part of chromosome 17. That information was available for 14 out of 19 annotated genes in this part of the genome.

Lathrop said: "We were able to demonstrate that the same variants that were associated with disease were also strongly associated with modulation of the level of expression of one particular gene, called ORMDL3. This provides a mechanism to obtain information on a pathway by which these particular genetic variants may biologically be affecting a gene that is the basis for the asthma trait."

Little is known about ORMDL3 other than that it encodes a transmembrane protein found in the endoplasmic reticulum of cells.

Cookson said: "We do not yet know how ORMDL3 affects asthma susceptibility. Similar genes are found in primitive organisms such as yeast, so we suspect that ORMDL3 may be a component of quite ancient immune mechanisms. It does not seem to be part of the allergic process."

It is not currently possible, Lathrop said, to rule out the chance that there may be other genes in the same region that are also associated with childhood-onset asthma.

The GABRIEL collaborators are planning numerous other studies. "First of all, we want to study this region of the genome in other forms of asthma, such as adult asthma and atopic dermatitis," said Lathrop. "We hope this will provide us with further confirmation of these results. Secondly, we will look for other genes associated with asthma in this region. Thirdly, we want to study the biology of this gene, for example using model systems."

Finally, the teams will try to understand the broader role of the gene and particularly how it interacts with known environmental triggers for asthma, as in occupational asthma.