Gene Linked To Inherited Blood Biomarker Associated With Asthma Risk

Risk for developing asthma is linked to variants in a gene called CHI3L1, which can be measured by checking levels of an inherited blood protein regulated by that gene, according to new research sponsored by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health.

Researchers identified gene variants which are associated with increased susceptibility to asthma and reduced lung function in three study populations. The variants regulate the level of a blood protein called YKL-40, which, through previous NHLBI-funded research, has been shown to be elevated in people with asthma and correlate with asthma severity. This new research shows that the YLKL-40 protein is inherited, and can be measured from birth.

The research is published online on April 9, 2008, by the New England Journal of Medicine and will appear in print on April 17, 2008.

"The investigators followed up on the discovery of a novel blood biomarker to identify a gene, which may have important implications in the early identification of susceptibility to, and prevention of asthma," said Elizabeth G. Nabel, M.D., director, NHLBI.

Building on the previous finding that the protein is a blood marker for asthma, researchers looked at the gene that regulates the protein. The relationship between the gene, the protein and asthma was first seen in a genetically and environmentally similar population, 700 members of an isolated religious community, the Hutterites, who are closely related and of European descent. The close-knit community has little exposure to smoking and similar exposures to environmental triggers for asthma. These factors make it easier to identify small differences in the genetic code.

Researchers then confirmed the connection between the gene and YKL-40 protein in three additional, more genetically diverse white groups in Chicago, Wisconsin, and Freiburg, Germany. In two of those populations, they confirmed the connection between the gene variants and asthma. One of the three groups, made up of 178 American children studied from birth in the NHLBI-funded Childhood Origins of Asthma (COAST) study, did not yet show a relationship between the gene and diagnosed asthma, but showed that the associations between YKL-40 levels and the gene variants were present at birth.

"YKL-40 appears to serve as a marker for genetic susceptibility to asthma and decline in lung function," said James P. Kiley Ph.D., director, NHLBI Division of Lung Diseases. "These findings will help pave the way for more research on pre-empting the development of disease."

Additionally, while one form, or allele, of the CHI3L1 gene is associated with an increased risk of asthma, another form is protective against asthma and decline in lung function. One DNA base pair in the CHI3L1 gene can be comprised of combinations of cytosine or guanine. The YKL-40 level and prevalence of asthma, at 18 percent, was highest among the Hutterites with two copies of cytosine. The Hutterites with cytosine and guanine had intermediate levels of YKL-40 and an asthma rate of 11 percent. The YKL-40 level and asthma rate, 7 percent, was lowest among those with two copies of guanine.

"Knowing the variations in this one gene may help us learn more about how immune system development affects the risk of developing asthma," said Carole Ober, Ph.D., Department of Human Genetics, University of Chicago, and study author.

YKL-40 is a chitinase-like protein; chitinases are enzymes, which break down chitins. Chitin is an element that comprises the exoskeletons of dust mites, cockroaches, fungi and parasites -- all known to be allergenic and related to asthma. YKL-40 does not have chitinase enzyme activity but is thought to play an important role in immune responses to chitin or other airborne particles. These proteins have been shown to play a role in animal models of asthma as having an important effect on airway inflammation.

Asthma is a chronic, treatable 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, according to the Centers for Disease Control and Prevention (CDC).