An international research team has identified five new gene regions that raise the risk of early-onset inflammatory bowel disease. The study, published in Nature Genetics, is characterized as the largest, most comprehensive genetic analysis of childhood-onset of the condition. The findings were based on genome-wide association studies on DNA from over 3,400 children and adolescents with IBD, plus nearly 12,000 genetically matched control subjects, all recruited through international collaborations in North America and Europe.

 

The research team led by Hakon Hakonarson, director of the Center for Applied Genomics at The Children's Hospital of Philadelphia, says that the findings advance the scientific understanding of how IBD develops. “This is an evolving story of discovering what genes tell us about the disease,” says Robert Baldassano, a co-first author of the study and director of the Center for Pediatric Inflammatory Bowel Disease at Children's Hospital. “Pinpointing how specific genes act on biological pathways provides a basis for ultimately personalizing medicine to an individual's genetic profile.”

 

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 GI tract, and half have ulcerative colitis, which is limited to the large intestine.

 

Most gene analyses of IBD have focused on adult-onset disease, but the Center for Applied Genomics—one of the world's largest pediatric genotyping programs—at Children's Hospital has concentrated on childhood-onset IBD, which tends to be more severe than adult-onset disease.

 

The study team identified five new gene regions that raise the risk of early-onset IBD, on chromosomes 16, 22, 10, 2 and 19. The most significant finding was at chromosome locus 16p11, which contains the IL27 gene that carries the code for a cytokine, or signaling protein, also called IL27. This cytokine acts on a biological pathway, the T-helper 17 pathway, which plays a key role in causing intestinal inflammation. T helper 17 cells are recently discovered cells that lead to severe inflammation and tissue injury in autoimmune diseases. IBD is an autoimmune disease, in which a person's immune system runs out of control and attacks the body.

“There are many cytokines in our immune system, but our research strongly suggests that IL27 has a primary causative role in IBD,” says Hakonarson. “This gene discovery makes sense in terms of our functional understanding of the disease.”

 

Some current IBD drugs are monoclonal antibodies that act on another cytokine, called tumor necrosis factor, which contributes to inflammation. Although much research remains to be done, the current study may provide a basis for developing drugs that target the cytokine IL27's action, for patients with the disease-causing IL27 gene variant.