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From: zumone2002 on 31 Aug 2008 18:17
http://www.eurekalert.org/pub_releases/2008-08/chop-ngf082708.php

New genes found for inflammatory bowel disease in children
Finding may refine drug targets for personalized treatments

Researchers have discovered two new genes that increase the risk of
developing inflammatory bowel disease (IBD) in childhood.

While further study is needed to identify the specific disease-causing
mutations in these new genes, the researchers say the genes are
particularly strong candidates to be added to the list of genes
already known to affect IBD. "As we continue to find genes that
interact with each other and with environmental influences in this
complex, chronic disease, we are building the foundation for
personalized treatments tailored to a patient's genetic profile," said
co-first author Robert N. Baldassano, M.D., director of the Center for
Pediatric Inflammatory Bowel Disease at The Children's Hospital of
Philadelphia.

"We will resequence the gene regions we have identified to pinpoint
the causative mutations in these genes," added study leader Hakon
Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics
at Children's Hospital. "We strongly suspect one gene will provide a
compelling target for drug development, given what's known about its
biology."

Both authors direct research programs at Children's Hospital and are
also faculty members of the University of Pennsylvania School of
Medicine. Their study, performed in collaboration with researchers
from the Medical College of Wisconsin, The University of Utah,
Cincinnati Children's Hospital and two research hospitals in Italy,
appears in advance online publication Aug. 31 in Nature Genetics.

IBD is a painful, chronic inflammation of the gastrointestinal tract,
affecting about two million children and adults in the United States.
Of that number, about half suffer from Crohn's disease, which can
affect any part of the gastrointestinal tract, and half have
ulcerative colitis, which is limited to the large intestine.

IBD that begins in childhood tends to be more severe than adult-onset
disease, and is more likely to affect the colon than other areas of
the GI tract. Those age-related differences in IBD spurred the current
research team to do their gene hunting in childhood-onset disease.
"Although the gene variants we found may have a stronger signal in
pediatric IBD than in adult-onset IBD, we do not believe them to be
limited to varieties of the disease that begin in childhood," said
Baldassano.

The researchers performed a genome-wide association study, searching
for genetic variations in DNA samples from 1,000 patients with
childhood-onset IBD, compared to samples from 4,250 healthy subjects.
Both patients and controls were of European ancestry.

In addition to finding gene variations previously reported by other
groups, the study team identified two novel gene variants, one on
chromosome 20 and the other on chromosome 21. They then replicated
their findings with studies using additional samples from other
sources.

The researchers say that the TNFRSF6B gene on chromosome 20 is a
compelling candidate, because it is already known to participate in
the biological pathway of a protein called tumor necrosis factor
(TNF). TNF is a cytokine, a chemical messenger that plays a key role
in the harmful inflammation characteristic of IBD.

Some current treatments for IBD use monoclonal antibodies that
selectively bind to a type of TNF involved in the disease (Among those
drugs are infliximab, adalimumab and certolizumab). "As we better
understand the complex gene interactions in IBD, we may be able to
diagnose patients by their genetic profile to predict who will better
respond to anti-TNF drugs," said Hakonarson. Anti-TNF medications such
as those mentioned above are currently given intravenously or as
injections, said Baldassano, who added, "If better knowledge of the
disease pathway enables pharmaceutical companies to develop anti-TNF
drugs in pill form, the medications will be easier to deliver as well
as more customized to each patient."

The study team also found an association between ulcerative colitis
and genes on the major histocompatiblity complex (MHC) on chromosome
6. The MHC is a large group of genes with important roles in the
immune system, and this finding may help refine diagnostic techniques
that would allow physicians to administer more specific therapies to
their patients.

--
Luke
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