Scientists report link between high levels of a protein and severe asthma

Late last year two Yale researchers reported a link between severe asthma and a certain protein, YKL-40, which appeared in elevated levels in patients who used rescue inhalers and oral corticosteroids most frequently and required hospitalization for severe attacks.

Now, in findings published in the New England Journal of Medicine in April, Geoffrey L. Chupp, M.D., associate professor of medicine (pulmonary and critical care), and Jack A. Elias, M.D., Waldemar Von Zedtwitz Professor and chair of the Department of Internal Medicine, with colleagues at the University of Chicago and the University of Wisconsin-Madison, describe a single nucleotide polymorphism (SNP)—a one-letter change in the genetic code—that correlates with asthma and its severity. The SNP is located in the chitinase 3-like 1 gene (CHI3L1), the gene that encodes YKL-40.

“The first study demonstrated that YKL-40 was increased and that levels in the blood correlated with levels in the lungs. ... But it was possible that it was just a bystander and not part of the asthmatic pathway,” said Chupp. “This study strongly suggests that YKL-40 plays a significant role in the development of asthma.”

YKL-40 belongs to the family of chitinases and chitinase-like proteins. Chitinases bind to, chew up and digest chitin, a tough natural polymer found in the cell walls of fungi and the bodies and eggs of parasitic worms. Chitinaselike proteins, however, can’t digest chitin. YKL-40 and its role in asthma came to light several years ago when Elias and his colleagues found that chitinase and chitinase-like proteins were overexpressed in the lungs of mice with asthma-like diseases. The surprise discovery supported the idea that asthma is an antiparasitic response in a setting where parasites cannot be detected.

Unpublished studies suggest that YKL-40 controls inflammation in the asthmatic airway. “When YKL-40 is there, it keeps inflammatory cells alive longer, and when it is not, they die quickly,” said Elias.

In the future, YKL-40 could help doctors treat asthma by serving as a biomarker, notifying them of patients who are likely to have severe asthma. Pharmaceutical companies might also develop a drug that targets YKL-40 and use serum measurements of YKL-40 to help predict who will respond to these new therapies. “Ultimately,” said Chupp, “blocking the effects of YKL-40 may prove to be a novel and effective way to treat asthma.”