Pediatrics researchers
have identified a gene variant that raises a child's risk of Crohn's
disease, a chronic and painful condition attributed to inflammation of the
gastrointestinal tract.
The research reinforces previous results by German researchers, who
found the same gene variant associated with the adult form of Crohn's
disease.
Researchers from The Children's Hospital of Philadelphia and The
University of Pennsylvania reported their results in a letter in the August
issue of the journal Gut.
"Because Crohn's disease is complex, with multiple genes interacting
with each other and with environmental factors, it's important to sort out
specific genes and to replicate previous findings," said the study's first
author, Robert N. Baldassano, M.D., director of the Center for Pediatric
Inflammatory Bowel Disease at Children's Hospital. "There are different
types of Crohn's disease, so classifying types by genetic profiles may help
us select the most appropriate treatments for each patient."
The study compared the genomes of 143 children with Crohn's disease to
genomes of 282 matched control subjects. The study team found that 64
percent of children with Crohn's disease had a specific variant form of the
gene ATG16L1, compared with 52 percent of the healthy children. The odds
ratio for children with the gene variant was 1.62 compared to control
children, meaning that those who have the variant were 62 percent more
likely to have Crohn's disease than children with the more common allele.
A separate test that analyzed trios (a Crohn's patient and both
parents) also found an association between the ATG16L1 gene variant and
disease symptoms. This finding strengthened the results of the pediatric
case-control study.
The genome-wide association study, which used highly automated analytic
equipment to scan each patient's DNA for more than half a million genetic
markers, was performed at the Center for Applied Genomics at Children's
Hospital. The Center's tools spell out a patient's genotype -- the specific
pattern of variations among an individual's 30,000 genes. Established in
the summer of 2006, the center is taking on one of the largest genotyping
projects in the world, and is the largest one dedicated to genetic analysis
of childhood diseases.
"This study is among the first that our center has published on a gene
associated with a complex childhood disease, but we have many projects
under way," said senior author Hakon Hakonarson, M.D., Ph.D., the director
of the Center for Applied Genomics. "Our goal at the Center is to discover
the major disease-causing variants and genes that influence complex
pediatric diseases, thus providing a scientific foundation for translating
those discoveries into successful treatments." Earlier this month,
Hakonarson collaborated with researchers in Montreal to identify a gene
associated with insulin-dependent diabetes in children. Other projects at
the Center are seeking genes associated with pediatric asthma, allergy,
obesity, attention-deficit hyperactivity disorder, autism, hypertension,
juvenile rheumatoid arthritis and the pediatric cancer neuroblastoma.
The gene implicated in the current research, ATG16L1, plays an
important role in the autophagosome pathway, a sequence of biological
events involved in processing bacteria within cells. While the mechanisms
are not fully understood, said Baldassano, a mutation in the gene may
weaken a cell's ability to degrade cellular waste products, including
bacteria. When unprocessed waste products pile up within the cell, they may
stimulate the inflammatory response that characterizes Crohn's disease.
Although much research remains to be done, he added, better
understanding of the disease process may guide doctors to new and improved
therapies. "If an excess of bacteria is the problem, we may find
antibiotics effective in treating this type of Crohn's disease. Other
approaches may be to use immune- boosting drugs to blunt the inflammation,
or determining whether particular foods interact with genetic
susceptibilities to affect disease symptoms. Understanding gene influences
gives us a more targeted way to look at disease physiology, and also may
suggest targets for treatment." Baldassano and Hakonarson said that they
will continue to search for other gene variants associated with Crohn's
disease and the closely related bowel disorder ulcerative colitis.
Financial support for the study came from the National Institutes of
Health, the Edmunds Fund, the Heineman Foundation, the IBD Family Research
Council and The Children's Hospital of Philadelphia.
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 chop.
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