In a three-year analysis of more than 10,500 genes,
one-third of the human genome, researchers at Johns Hopkins
have found a starting point to establishing the genetic
basis for sinus disease and the growth of nasal polyps,
illnesses not well understood despite their prevalence The
findings, published Oct. 8 in the Journal of Allergy and
Clinical Immunology online, could lead to development
of targeted gene therapies or other treatments to control
these conditions.
"This was a fishing expedition of sorts for sinusitis
research, and a nontraditional approach from a scientific
standpoint," said study lead author and
otolaryngologist Jean Kim, assistant professor in the
School of Medicine. "The result was a host of very
interesting leads as to which genes may play a role in
controlling this illness and how we might prevent it in the
future.
"There is no cure for chronic sinusitis and nasal
polyps. The symptoms associated with this condition, such
as facial pain and postnasal drip, are much more
incapacitating to the patient than a common cold," Kim
said. "One of the most common treatments is surgery to
remove swollen tissue and nasal polyps, but soon after we
cut them out, the polyps usually keep growing back and
symptoms return. This also happens after treatment stops
with other medications, such as oral or nasal steroids."
The National Health Interview Survey by the Centers
for Disease Control estimated that approximately 15 percent
of the American adult population suffers from sinusitis,
the most common respiratory complaint in the United States.
Nearly 20 percent of patients with chronic sinusitis
develop nasal polyps. These conditions can have serious
health consequences: swelling of the tissues within the
sinus cavity, which, in turn, results in the loss of sense
of smell and slowing down of air circulation and drainage,
causing mucous to build up, thus creating a breeding ground
for infections.
Figuring out how these effects were related to the
body's immune response was the objective of this study, one
of the first studies to evaluate the genetic details of
these two illnesses. As a first step, the researchers
conducted a broad molecular analysis of both healthy and
diseased sinus tissue from 14 patients. Using a "reverse
genetics" methodology — in which no single gene is
suspected in the hunt for causality — the researchers
compared extracted RNA, a product of genes, from diseased
tissue samples with RNA from normal tissue. The researchers
then used a specially designed gene chip that allows for
bulk testing of more than 10,000 genes, a robotic testing
method called a microarray analysis, to determine if the
increased actions or inactions of any particular genes
stood out.
Of the genes studied, the researchers found that 192
were up-regulated, or present in increased amounts, while
another 156 were down-regulated, or present in decreased
amounts in the diseased tissue samples. In the diseased
tissue, a gene was determined to be "up" if there was at
least a twofold increase in its amount in samples tested,
and a gene was "down" if it had at least a 50 percent
decrease in amount.
The researchers then narrowed their initial focus to
the top-four "up" genes and the most common "down" gene to
see if any proteins, as the products of genes, were also
present in significantly larger or smaller amounts than
normal. Changes in proteins and genes can be clues to a
genetic basis or origin of a disease. This may subsequently
lead to the development of new therapy for a condition (by
controlling the actions of the protein).
Three of the four "up" genes, including two proteins
known to have antibacterial activity, had their increased
amounts confirmed by specific mRNA and protein analysis.
Actual increases in the amounts of the fourth gene could
not be validated.
Further analysis confirmed that one particular
protein, called CC10, was present in severely depleted
quantities as the single most down-regulated gene. CC10 is
a protein, found primarily in the airways of the lung,
among other organs. This protein is thought to be a potent
anti-inflammatory molecule and one that plays an important
role in the immune response. While its precise biochemical
and molecular functions are unknown, CC10 is used as a
treatment for underdeveloped lungs in premature babies,
where it suppresses inflammation.
"We were particularly surprised and excited to find
low levels of this protein CC10," said senior author Bruce
Bochner, professor of medicine and director of
Hopkins'
Division of Allergy and Clinical Immunology. "This
protein is usually increased by steroid therapy, yet it was
extremely low in all of our study subjects despite their
use of steroid sprays into the nose. So, it raises the
possibility of one day treating these defects with a nasal
spray that is specific to raising levels of CC10."
Kim said, "This study lays the initial groundwork for
additional studies on what has been up until now a poorly
understood and confounding illness. We now have many lead
candidate genes which may play a role in causing sinus
disease. These studies may lead to new treatments for
patients with chronic rhinosinusitis and nasal polyps."
The study, which ran from March 2000 to March 2004,
was funded by the National Institutes of Health. Another
Hopkins investigator in this research was Zheng Lui.
Sinusitis is a prevalent and costly disease, with
annual U.S. health care expenditures of nearly $6 billion,
according to the U.S. government's Agency for Health Care
Research and Quality. Every year, sufferers make more than
18 million office visits to the family doctor, and each
person misses on average four days of work. Sinusitis rates
are relatively high in the Midwest and South compared with
the Northeast and western regions of the country.