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New 'asthma gene' could lead to new therapies

ANN ARBOR, Mich.—A gene that is strongly associated with a risk of developing childhood onset asthma was identified by an international team of scientists, whose findings are published today in the journal Nature.

In a genetic study of more than 2,000 children, scientists from the University of Michigan and colleagues from London, France and Germany found genetic markers that dramatically increase a child's risk for asthma. These markers are located on chromosome 17, and children with this marker had higher levels of a new gene called ORMDL3 in their blood, which occurs in higher amounts in children with asthma. The presence of the disease-associated version of ORMDL3 increases the risk of asthma by 60-70 percent, the study suggests.

"In terms of an asthma gene, there have been quite a few reports but not one that can be clearly reproduced in samples," said Goncalo Abecasis, associate professor at the U-M School of Public Health. "I think eventually it will lead to new therapies because it points to a specific biological molecular pathway. Once we understand the biology and we know the players, it's possible to target with specific drugs."

Childhood asthma treatments are heavily focused on allergic responses, since most children with asthma also have many allergies. The discovery of a so-called 'asthma gene' would provide a new set of mechanisms to try and modify and manage childhood asthma, Abecasis said.

"Before we finished the paper, we would have guessed (ORMDL3) would be a gene with a well-understood role in allergic responses, but that is not what we found," said Abecasis, noting that the gene has no known relation to allergic responses.

Asthma, a complex disease caused by a combination of genetic and environmental factors, is the most common chronic disease of childhood. Asthma occurs in 7-10 percent of children in the United States and one child in seven in the United Kingdom. Its prevalence differs widely among different geographic areas.

To account for the environmental factors associated with the disease, researchers structured their investigation to ensure that cases of childhood asthma were matched to children without disease from the same geographical areas.

The team of scientists, including Liming Liang, a U-M doctoral student in Abecasis' lab and co-first author on the paper, compared the genetic makeup of 994 patients with childhood onset asthma and 1,243 non-asthmatics. They looked at mutations in the building blocks that make up DNA, called nucleotides. There are mutations in around one in every 600 nucleotides, and scientists examined more than 317,000 of these mutations, known as single-nucleotide polymorphisms, to find those specific to childhood asthma. The researchers also looked at how genes were being expressed within human blood cells. The U-M was one of the major data analysis sites.

The team confirmed its findings by analyzing the genetic makeup of more than 2,000 children from Germany and more than 3,000 subjects from the United Kingdom born in 1958 and monitored until now for the presence of disease.

"This is a large study involving doctors and scientists from many countries, and we are confident that we have discovered something new and exciting about childhood asthma," said Dr. Miriam Moffatt of the National Heath and Lung Institute, Imperial College, London, and one of the first authors of the study. "These novel findings do not explain completely how asthma is caused, but they do provide a further part of the gene-environment jigsaw that makes up the disease. We and our colleagues are currently preparing even bigger studies to find other genes of smaller effect and to relate these to environmental factors that increase asthma risk."

Professor William Cookson, also of the National Heart and Lung Institute and coordinator of the study, said the results are the strongest genetic link yet to child onset asthma.

The work was funded by the Wellcome Trust, UK Medical Research Council, French Ministry of Higher Education and Research, German Ministry of Education and Research, National Genome Research Network, National Institutes of Health and the European Commission. The study is a component of the EU-funded GABRIEL Integrated Project to investigate genetic and environmental causes of asthma in the European Union. GABRIEL is coordinated by Professor William Cookson at Imperial College and Professor Erika von Mutius at the University of Munich.

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