|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
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).
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Diseases and Conditions Index: Asthma