While further study is needed to identify the specific disease-causingmutations in these new genes, the researchers say the genes are particularlystrong candidates to be added to the list of genes already known to affectIBD. "As we continue to find genes that interact with each other and withenvironmental influences in this complex, chronic disease, we are building thefoundation for personalized treatments tailored to a patient's geneticprofile," said co-first author Robert N. Baldassano, M.D., director of theCenter for Pediatric Inflammatory Bowel Disease at The Children's Hospital ofPhiladelphia.
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"We will resequence the gene regions we have identified to pinpoint thecausative mutations in these genes," added study leader Hakon Hakonarson,M.D., Ph.D., director of the Center for Applied Genomics at Children'sHospital. "We strongly suspect one gene will provide a compelling target fordrug development, given what's known about its biology."
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Both authors direct research programs at Children's Hospital and are alsofaculty members of the University of Pennsylvania School of Medicine. Theirstudy, performed in collaboration with researchers from the Medical College ofWisconsin, The University of Utah, Cincinnati Children's Hospital and tworesearch hospitals in Italy, appears in advance online publication Aug. 31 inNature Genetics.
IBD is a painful, chronic inflammation of the gastrointestinal tract,affecting about two million children and adults in the United States. Of thatnumber, about half suffer from Crohn's disease, which can affect any part ofthe gastrointestinal tract, and half have ulcerative colitis, which is limitedto the large intestine.
IBD that begins in childhood tends to be more severe than adult-onsetdisease, and is more likely to affect the colon than other areas of the GItract. Those age-related differences in IBD spurred the current research teamto do their gene hunting in childhood-onset disease. "Although the genevariants 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 diseasethat begin in childhood," said Baldassano.
The researchers performed a genome-wide association study, searching forgenetic variations in DNA samples from 1,000 patients with childhood-onsetIBD, compared to samples from 4,250 healthy subjects. Both patients andcontrols were of European ancestry.
In addition to finding gene variations previously reported by othergroups, the study team identified two novel gene variants, one on chromosome20 and the other on chromosome 21. They then replicated their findings withstudies using additional samples from other sources.
The researchers say that the TNFRSF6B gene on chromosome 20 is acompelling candidate, because it is already known to participate in thebiological pathway of a protein called tumor necrosis factor (TNF). TNF is acytokine, a chemical messenger that plays a key role in the harmfulinflammation characteristic of IBD.
Some current treatments for IBD use monoclonal antibodies that selectivelybind to a type of TNF involved in the disease (Among those drugs areinfliximab, adalimumab and certolizumab). "As we better understand the complexgene interactions in IBD, we may be able to diagnose patients by their geneticprofile to predict who will better respond to anti-TNF drugs," saidHakonarson. Anti-TNF medications such as those mentioned above are currentlygiven intravenously or as injections, said Baldassano, who added, "If betterknowledge of the disease pathway enables pharmaceutical companies to developanti-TNF drugs in pill form, the medications will be easier to deliver as wellas more customized to each patient."
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