Gene Variants Detected in Very Early Onset Inflammatory Bowel Disease


Melding together genomics technology, disease patterns, immunology, and microbiology, physician-scientists at The Children’s Hospital of Philadelphia are finding new and individualized therapies for patients with very early onset inflammatory bowel disease (VEO-IBD), IBD that presents before age 5.

IBD is a chronic inflammatory disease of the gastrointestinal (GI) tract that can result in ongoing inflammation, leading to a variety of symptoms including diarrhea, abdominal pain and cramping, fatigue, and weight loss. Children with VEO-IBD are a unique population who frequently present with more severe symptoms and greater extent of GI tract involvement than older children and adults with IBD. In addition, these patients tend to respond poorly to conventional IBD therapies used for older patients. These factors suggest that VEO-IBD is a distinct, more aggressive process with a strong genetic contribution to the disease.

“We currently have a cohort of about 250 patients with VEO-IBD, many of whom have significant symptoms that affect their overall quality of life,” said Judith Kelsen, MD, who is a pediatric gastroenterologist and researcher in the Center for Pediatric Inflammatory Bowel Disease at CHOP. “These children were the impetus for the initiation of our research, as we worked to identify therapies to improve their symptoms and treat their disease. We started to realize that VEO-IBD is a different disease with a different etiology, meaning the reasons for having the disease were different than older patients.”

Dr. Kelsen and her colleagues hypothesized that there are strong genetic drivers to the disease involving rare or novel genes. They are using next generation sequencing technology to allow them to detect genetic variants that they believe are enriched in patients with VEO-IBD.

In an article published online in the journal Gastroenterology, the study team reported the results from performing exome sequencing analysis of 125 patients ages 3 weeks to 4 years with VEO-IBD. They identified several novel and rare gene defects in genes associated with primary immunodeficiencies. Some of these pathways are involved in regulation of the immune response, which protects the body from potentially harmful microbes, such as viruses and bacteria.

These gene variants appear to influence both arms of the immune system, the innate response — our body’s first line of defense — and adaptive response — a more sophisticated response that is not immediately activated. The adaptive immune system includes two types of cells, known as B-cells and T-cells. Their jobs are to alert your body to intruders, fight the infection, and then remember the invaders to protect against future attacks. If B- and T-cells are not functioning correctly, they may result in a defective or inappropriate response that contributes to the development of VEO-IBD.

“As we begin to identify the different components of the immune system involved, including B- and T-cell pathways, we can begin to individualize our therapy to the specific patient,” the study authors wrote.

At CHOP, an interdisciplinary team of physicians who specialize in gastroenterology and immunology meet once a month in a VEO-IBD clinic to better target therapies to patients’ underlying genetic defects. Dr. Kelsen and Kathleen Sullivan, MD, PhD, chief of the division of Allergy and Immunology, run the clinic. In many cases, instead of prescribing traditional IBD drugs, they are now using therapies that are directed to diseases of the immune system. Some patients may require more intensive interventions, such as a patient Dr. Kelsen described who is undergoing a stem cell transplant due to the identification of a whole gene deletion (the whole gene is missing) that is critical for the immune system to work appropriately.

Dr. Kelsen also works with Marcella Devoto, PhD, of CHOP’s Division of Human Genetics, and Noor Dawany, PhD, of the department of Biomedical and Health Informatics, to analyze and identify the genes that are responsible for the disease. It is combining the clinical data and the genetics that has proved to be the most successful in treating these children.

As the incidence of VEO-IBD is rising rapidly — accounting for about 6 to 15 percent of pediatric IBD cases — there are many different research avenues to explore, Dr. Kelsen said. In addition to genetic contributors, she and her team, including Maire Conrad, MD, a GI IBD fellow, are studying how differences in the communities of microbes made up of bacteria, viruses, parasites, and fungi that normally reside in our intestinal tract, known as the microbiome, may be partly responsible for triggering the disease. In a study published in August in the journal Inflammatory Bowel Disease, Dr. Kelsen found several bacterial lineages are potentially associated with pediatric Crohn’s disease, a type of IBD.

Families of children with VEO-IBD have been extremely supportive of Dr. Kelsen’s investigations, as she attempts to unravel this complex disease for which there currently is no standard of care for evaluation and treatment.

“I think it is hard at any age to have inflammatory bowel disease, but in many cases, patients with VEO-IBD have a particularly difficult burden due to their young age,” Dr. Kelsen said. “These children often are chronically ill and have not had the opportunity to experience feeling well and participating in everyday childhood activities; therefore, their parents are very willing and generous with their time to help with the research. Without them, we would not be successful in learning more about this disease, so we are incredibly appreciative.”

Dr. Kelsen’s research is supported by a career development award from the National Institute of Diabetes and Digestive and Kidney Diseases.

Share This