Researchers have developed the first genetic profile for Crohn's disease and ulcerative colitis, two types of inflammatory bowel disease, or IBD. The feat, reported in the March issue of Human Molecular Genetics, is a key step toward understanding and defining new treatments for IBD, which afflicts millions of Americans.
"Before this study, only a few genes involved in these diseases were known, but that list has been significantly expanded to 170 genes," says Shukti Chakravarti, an assistant professor of medicine at the School of Medicine. "Some of the identified genes may be involved in primary events, directly causing disease, whereas others are likely important in determining the course of disease. For instance, some of these genes play a role in the wounding and healing process, secondary events that lead to tissue damage and fibrosis."
Chakravarti, lead investigator of the study, says that in addition to paving the way for better therapies, the genetic "fingerprints" also should help physicians more specifically diagnose patients who remain in the vague category of having "some type of indeterminate bowel disease." The two diseases share many similar characteristics and thus are sometimes hard to differentiate, but they clearly have very different genetic profiles.
Applying DNA microarray technology, the most powerful method for gene expression profiling, Chakravarti analyzed colon tissue from six individuals who had Crohn's disease, 12 with ulcerative colitis and six unaffected controls. The scientists screened 7,306 human genes, searching for ones that were activated or repressed in patients, and identified 29 genes uniquely altered in expression in Crohn's disease, 108 in ulcerative colitis and 33 additional genes involved in both conditions.
Many of the genes identified were not previously recognized as having anything to do with either disease. Although further investigation is needed, Chakravarti speculates that the "REG" genes highly overexpressed in ulcerative colitis and Crohn's disease play a role in cell proliferation during inflammatory responses, while increased expression of collagen and other connective tissue genes contribute to thickening and scarring of tissue characteristic of inflammatory bowel disease. Many studies have observed increased rates of colon cancer in people with ulcerative colitis, and the overexpression of several cancer genes in ulcerative colitis patients strengthens the tie between this disease and colon cancer. Finally, increased expression of anti-germ genes in Crohn's disease primarily and to a lesser extent in ulcerative colitis further fuels the long-standing suspicion that microbes play a major role in the initiation of the condition.
The study used a recently developed DNA microarray technology, which enables the simultaneous screening of thousands of genes for expression. Scientists isolate total RNA, a pool of all gene products from colonic tissue, and make complementary DNA to probe the gene chip. If the gene is expressed, its product in the pool will bind or hybridize to the gene probe on the chip. In the final step, a reader scans the material to see which genes are highly expressed or turned off. "These diseases are complex, involving genetic, environmental and microbial factors in their etiology," Chakravarti says. "Our next step is to follow patients over the course of the diseases and use genetic profiling to track disease progression, identify early and late changes, and ultimately help to develop better predictors of severity as well as target therapies for each IBD type."
Crohn's disease and ulcerative colitis primarily affect the intestines, resulting in pain, severe diarrhea, intestinal bleeding, weight loss and fever. Symptoms vary in severity and duration; some patients suffer frequent prolonged attacks, and others have fewer recurrences. The disease usually starts in the adolescent or young adult years. In ulcerative colitis, the inner lining of the colon is inflamed. People with Crohn's disease have similar inflammation, but it extends deeper into the intestinal wall and also can involve the small and large intestine.
Other authors of the study are Ian Lawrance and Claudio Fiocchi from Case Western Reserve University School of Medicine. Shukti Chakravarti performed the study at Case Western Reserve and is now at Johns Hopkins. The study, which can be found at hmg.oupjournals.org/, was supported by funds to Chakravarti from Case Western Reserve University School of Medicine and the Crohn's and Colitis Foundation of America.
To learn more about inflammatory bowel syndrome, go to www.hopkins-gi.org.