Philadelphia, PA August 31. 2008:  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.

    The Center for Pediatric Inflammatory Bowel Disease at Children's
Hospital currently treats 1,400 children annually for IBD, and has one of
the world's largest clinical research programs for IBD. The Center for
Applied Genomics, directed by Hakonarson, is currently the largest
pediatric genotyping program in the world. The Center's highly automated
analytic equipment scans each DNA sample for over half a million genetic
markers.

    Financial support for the study came from the National Institutes of
Health, the IBD Family Research Council, the Crohn's and Colitis Foundation
of America, the Koss Foundation, the NIH General Clinical Research Center
of the Medical College of Wisconsin, the Primary Children's Medical Center
Foundation, the Edmunds Fund, the Heineman Foundation, the Cotswold
Foundation, and The Children's Hospital of Philadelphia, which funded all
genotyping performed in the study.

    Baldassano's and Hakonarson's co-authors included Struan Grant, Ph.D.,
Jonathan Bradfield, Ph.D., David A. Piccoli, M.D., Petar Mamula, M.D.,
Robert Grundmeier, M.D., and Dimitri Monos, Ph.D., all of Children's
Hospital. Other co-authors were Subra Kugathasan, M.D. (formerly of the
Medical College of Wisconsin and currently at Emory University), who is
co-first author with Baldassano; Stephen Guthery, M.D., of the University
of Utah; Gitit Tomer, M.D., and Lee Denson, M.D., of Cincinnati Children's
Hospital Medical Center; Salvatore Cucchiara, M.D., Ph.D., of Sapienza
University, Rome, Italy; and Vito Annese, M.D., of "Casa Sollievo della
Sofferenza" Hospital, San Giovanni Rotondo, Italy.

    About The Children's Hospital of Philadelphia: The Children's Hospital
of Philadelphia was founded in 1855 as the nation's first pediatric
hospital. Through its long-standing commitment to providing exceptional
patient care, training new generations of pediatric healthcare
professionals and pioneering major research initiatives, Children's
Hospital has fostered many discoveries that have benefited children
worldwide. Its pediatric research program is among the largest in the
country, ranking third in National Institutes of Health funding. In
addition, its unique family-centered care and public service programs have
brought the 430-bed hospital recognition as a leading advocate for children
and adolescents. For more information, visit http://www.chop.edu.

CONTACT: Rachel Salis-Silverman
Phone: (267) 426-6063

SOURCE

Children's Hospital of Philadelphia