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Researchers Pinpoint Genes Linked to Childhood Inflammatory Bowel Disease

Two genes that up the risk of IBD in kids offer new therapy targets



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Researchers have identified a pair of genes that increase a child's risk of developing inflammatory bowel disease (IBD) before the age of 19—adding to a growing list of 30 known genetic factors for the malady.

Inflammatory bowel disease is a chronic condition that affects an estimated 1.4 million people in the U.S., according to the Centers for Disease Control and Prevention (CDC) . Abnormal immune responses lead to inflammation in the digestive tract lining causing several disorders, the most common of which are Crohn's disease (usually affecting the small intestine) and ulcerative colitis (restricted to the colon).

A new study, published in the journal Nature Genetics, is the first to focus specifically on the genetics of pediatric IBD. Adult-onset IBD is more common but typically less severe than the childhood varieties, the latter of which also have a stronger family history. Because environmental exposures have not had time to impact IBD progression in children, researchers have a clearer genetic picture of the disease allowing them to pick out additional genes overlooked in adult research, says senior study author Hakon Hakonarson, director of the Center for Applied Genomics at The Children's Hospital of Philadelphia.

Over 1,000 pediatric IBD patients of European ancestry were recruited for the study in the U.S. and Italy. Researchers compared more than 600,000 genetic markers spanning the genome of IBD sufferers with the same markers in a control group of 4,250 healthy kids.

The genetic analysis revealed two new IBD-associated genes: PSMG1 and TNFRSF6B. Little is known about the first gene, although it belongs to a class known as chaperones that generally capture and neutralize molecules in the body, Hakonarson says. The second gene, TNFRSF6B, encodes a receptor related to those that bind tumor necrosis factor (TNF)—a key chemical signal for triggering inflammation in IBD as well as in patients with other autoimmune disorders such as rheumatoid arthritis and psoriasis.

Children with the TNFRSF6B gene variant were more prone to IBD and had higher levels of the receptor in their intestines and bloodstreams as compared with healthy kids. The receptor is believed to inhibit the ability of immune cells to autodestruct when they have outlived their usefulness, resulting in higher concentrations of proinflammatory signals (such as TNF) in the intestines of IBD patients. Hakonarson hopes that his team's discovery will lead to better therapies by designing small molecules to bind this receptor—thereby reducing the destructive inflammation.

These new therapies could alleviate some of the problems plaguing current treatments for IBD, namely injections of antibodies that target and clear excess TNF. Although the antibody approach has been successful, it increases the risk of severe allergic reactions as well as the possibility that the patient's immune system will become sensitized, destroying the antibodies and making long-term treatment less effective. An inert tablet designed to block the receptor—rather than targeting TNF itself —could circumvent these issues and alleviate the inflammation of IBD.

"In the next 10 years these studies will identify potential pathways for new therapies," says Judy Cho, director of Yale University School of Medicine's Inflammatory Bowel Disease Center, who was not involved in this research. Although antibody treatment is helpful, she sees a clear need for new drugs—and this type of data will help to prioritize the candidate drug targets.

The discovery is also a step in the direction of personalized medicine. "By looking at genetic profiles, we may be able to tell what is the appropriate therapy for each person," says study co-author Robert Baldassano, director of the Center for Pediatric Inflammatory Bowel Disease at Children's Hospital. Genetic tests could one day indicate if patients are predisposed to high levels of TNF—possibly associated with the newly identified receptor gene variant—helping to identify patients that will respond to antibody therapy.

Stefan Schreiber, director of clinical molecular biology at Christian-Albrechts-University in Kiel, Germany, believes that the study is a mandate for revamping the development of effective treatments. Although the disease may look the same to physicians treating children and adults, the underlying genetics can clearly be different, Schreiber says, and "researchers should not anticipate that children will react to therapy like adults."

Ultimately, the study goes beyond just adding two more genes to the list of IBD risk factors. It also brings new hope for developing novel treatments and highlights the need to identify IBD sufferers who will benefit most.

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