Digestive Diseases News
Spring/Summer 2008

Genomics Research Yielding Personalized Approach to IBD Treatment

Doctors may soon consider a person’s genes when treating inflammatory bowel disease (IBD) and other conditions. This new, personalized approach is possible through the translation of genomics research into clinical practice, a process recently discussed at a 2-day meeting at the National Institutes of Health (NIH) in Bethesda, MD.

“Translation is something that moves discovery into health practice: from the bench to bedside in the first stage and then from the bedside to the general public,” said National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Director Griffin P. Rodgers, M.D., M.A.C.P., who set the stage for the meeting “Genes, Environment, and Health Initiative (GEI): Translating Whole Genome Association Data into Clinical Practice.”

Genome-wide association studies compare the genetic profiles of healthy individuals with those with specific health conditions. Such studies have uncovered at least 30 genes related to IBD and others involved in diseases such as diabetes, cancer, and heart disease. Improved strategies for gene hunting and cheaper sequencing techniques are quickening the pace of discovery, helping scientists develop new diagnostic tools and strategies and target-specific therapeutics.

Gene-Environment Interactions

The GEI was launched in 2006 by U.S. Department of Health and Human Services Secretary Michael O. Leavitt to help understand how genes and environmental exposures influence health and disease. Most common health conditions are thought to arise from complex gene-environment interactions (GxE). For fiscal year 2007, $40 million for the GEI was added to $28 million the NIH already had slated for GxE research. The first grants were announced in September 2007.

“We are at an interesting juncture,” National Human Genome Research Institute Director Francis S. Collins, M.D., Ph.D, told meeting attendees. “The amount of discovery that has occurred in the area of genetics of common diseases is breathtaking and the challenge now is to try to build upon that.”

IBD is a chronic, painful condition resulting from inflammation of the gastrointestinal tract. Crohn’s disease and ulcerative colitis are the two major types of IBD. Diverse clinical features of Crohn’s and ulcerative colitis have been linked to multiple genes—some of which appear to be interacting with each other and environmental factors, such as smoking—suggesting IBD is not one or two diseases but many.

Judy Cho, M.D., associate professor of medicine and genetics at the Yale University School of Medicine, highlighted successes of the NIDDK IBD Genetics Consortium, including the discovery of variants of the gene that encodes for IL-23R, a receptor found on immune cells that triggers inflammatory pathways in response to bacteria. Specifically, IBD is believed to result from an inappropriate immune response to nonpathogenic bacteria in the gastrointestinal tract.

Cho, the principal investigator of the Consortium’s data coordinating center, said identifying genes that regulate these immune responses has been enormously helpful in understanding the pathophysiologic mechanisms contributing to IBD and the development of much-needed new therapeutic interventions.

The NIDDK IBD Genetics Consortium, established in 2002, coordinates analysis of IBD genetics data collected by six American and Canadian research centers. See the box for a list of participating centers.

Improved Outcomes

“Very potent biologics, in particular the development of monoclonal antibodies against TNF, have profoundly improved the outcomes of patients with inflammatory bowel disease,” said Cho. “However, these new biologics can be associated with significant infectious complications.” Monoclonal TNF antibodies, used in the biologic treatments infliximab (Remicade) and adalimumab (Humira), interrupt the inflammatory process in IBD by blocking TNF, a proinflammatory cytokine.

In addition, not all people with IBD will benefit from taking these new therapies. “There is a group of people with IBD that does very well on new anti-TNF biologics for IBD,” said Stephan Targan, M.D., director of the Inflammatory Bowel Disease Center at the Cedars-Sinai Medical Center in Los Angeles. “But there is a group that doesn’t do so well—in fact, some people don’t even respond.”

Targan believes genomics data will help doctors identify people at increased risk of IBD and better match patients with effective drugs. “A patient-specific treatment will be dialed in based upon the different pathways that may be associated with different IBD subtypes.”

For more information about IBD, see the NIDDK fact sheets about Crohn’s disease and ulcerative colitis under the A to Z list of topics and titles at www.digestive.niddk.nih.gov.

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NIH Publication No. 08–4552
July 2008