Gene variant increases risk of asthma

A tiny variation in a gene known as CHI3L1 increases susceptibility to asthma, bronchial hyperresponsiveness and decline in lung function, researchers report early online in the New England Journal of Medicine. (The printed version will appear in the April 17 issue). The gene variant causes increased blood levels of YKL-40, a biomarker for asthma. A slightly different version of the genetic variation lowers YKL-40 levels and protects against asthma.

Although the original discovery came from a study of a genetically isolated population, the Hutterites of South Dakota, the researchers were able to confirm the same connections between the CHI3L1 variations, YKL-40 levels and asthma susceptibility in three genetically diverse Caucasian populations from Chicago; Madison, Wisconsin; and Freiberg, Germany.

This gene, "may have important implications in the early identification of, susceptibility to, and prevention and treatment of asthma,” said Elizabeth G. Nabel, M.D., director, the National Heart, Lung, and Blood Institute.

"This is exciting because it connects asthma susceptibility to a whole new pathway at the protein and the genetic levels," said study author Carole Ober, professor of human genetics at the University of Chicago Medical Center. "There is a good deal more we need to find out about this connection, but now we know where to look."

"This is also the most significant genetic discovery based on our years of gathering data on asthma in the Hutterites," Ober added. "This is a group with enormous potential to advance our understanding of the genetic underpinnings of disease. We now have a remarkable collection of data, which we expect will lead us to many more insights."

Ober and colleagues at the University of Chicago had long been searching for genetic factors that could influence the risk of common diseases, such as asthma. To simplify this quest, they have focused since 1994 on the Hutterites, a genetically isolated U.S. religious community descended from about 90 people. The Hutterites came to the United States in 1874 and settled in small communal farming colonies in what is now South Dakota. Today Hutterite communities are present in the Dakotas, Minnesota, Montana, Washington and Canada.

They provide an ideal community for genetic studies because they are all members of a large pedigree that is known back to the 1700's and they live communally, sharing resources and maintaining a traditional lifestyle. "They eat the same food, live off the same allowance and have the same education," said Ober, who has been working with them since 1979. They have similar, but not identical genomes. "So the genes that make a difference are easier to detect."

In 1996 and 1997, Ober's team gathered clinical data about asthma from more than 700 members of the Hutterite communities, and stored blood samples that were recently used to measureYKL-40 levels. About 11 percent of Hutterites had asthma and another 12 percent had bronchial hyperresponsiveness.