Blood Protein Levels Associated with Asthma Risk

A new study links variants in a gene to the risk for developing asthma. The variants affect levels of a protein that can be measured in blood, raising the possibility that asthma risk could one day be measured with a simple blood test.

Asthma is a chronic disease that causes narrowing of the airways, making breathing difficult at times. More than 22 million people in the United States have asthma, including 6.5 million children under age 18.

Previous studies showed that levels of a blood protein called YKL-40 were elevated in people with asthma and correlated with the disease’s severity. YKL-40 is thought to have an effect on airway inflammation, but its role isn’t yet understood. With funding from NIH’s National Heart, Lung and Blood Institute (NHLBI) and National Center for Research Resources (NCRR), a research team led by Dr. Carole Ober at the University of Chicago asked whether this protein might cause, or be a marker for, asthma.

As reported on April 9, 2008, in the online edition of the New England Journal of Medicine, the researchers examined over 750 members of an isolated community, the Hutterites, who live on communal farms in South Dakota. Studying a group of such closely related people who live in a similar environment makes it easier for researchers to identify differences in the genetic code that affect disease.

The researchers found that blood serum levels of YKL-40 were 15% higher in Hutterites with asthma than in those without. They also found that differences in blood levels of YKL-40 were due almost entirely to inherited genetic differences.

The most significant effects on YKL-40 levels were variations in the “promoter” of the gene for YKL-40. Promoters are genetic regions that regulate gene expression, or how active a gene is. Higher expression of this gene results in more YKL-40 in the blood.

A change in a single letter of the genetic code in the promoter region of the gene that encodes YKL-40, the researchers estimate, can account for almost 10% of the variation in blood YKL-40 protein levels among Hutterites. This single-letter change was associated with both reduced lung function and asthma. Those with 2 copies of 1 version had an asthma rate of 18%; those with 2 copies of the other had a rate of 7%. Those with 1 of each had rates in between, at 11%.

The researchers studied 3 additional, more genetically diverse white groups in Wisconsin, Chicago and Freiburg, Germany. They saw a connection between the variants and asthma in 2 of the 3 groups. Those with 2 copies of 1 version of the gene had double the risk of developing asthma as the others.

Larger studies will be needed in the future to confirm these associations. Further study of YKL-40 and how it works may help us understand how immune system development affects the risk of developing asthma.

Knowing an individual’s genetic type or blood levels of YKL-40 may also serve as a useful marker for detecting and treating asthma early. Dr. James P. Kiley, director of NHLBI’s Division of Lung Diseases, said, “These findings will help pave the way for more research on pre-empting the development of disease.”