An international team led by University of Pittsburgh School of Medicine researchers has identified genetic markers associated with risk for ulcerative colitis.  The findings, which appear today as an advance online publication of the journal Nature Genetics, bring researchers closer to understanding the biological pathways involved in the disease and may lead to the development of new treatments that specifically target them.

Ulcerative colitis is a chronic, relapsing disorder that causes inflammation and ulceration in the inner lining of the rectum and large intestine.  The most common symptoms are diarrhea (oftentimes bloody) and abdominal pain.  Ulcerative colitis and Crohn’s disease, another chronic gastrointestinal inflammatory disorder, are the two major forms of inflammatory bowel disease (IBD).

“Ulcerative colitis and Crohn’s disease are chronic conditions that impact the day-to-day lives of patients,” said senior author of the study Richard H. Duerr, M.D., associate professor of medicine and human genetics at the University of Pittsburgh School of Medicine and Graduate School of Public Health.  “IBD is most often diagnosed in the teenage years or early adulthood.  While patients usually don’t die from IBD, affected individuals live with its debilitating symptoms during the most productive years of their lives.”

Because IBD tends to run in families, researchers have long thought that genetic factors play a role.  Technology developed in recent years has enabled systematic, genome-wide searches for gene markers associated with common human diseases, and the discovery of more than 30 genetic risk factors for Crohn’s disease has been one of the major success stories in this new era of research.  While some genetic factors associated with Crohn’s disease also predispose individuals to ulcerative colitis, markers specific for ulcerative colitis had yet to be found.  To do so, researchers performed a genome-wide association study of hundreds of thousands of genetic markers using DNA samples from 1,052 individuals with ulcerative colitis and pre-exisiting data from 2,571 controls, all of European ancestry and residing in North America.  Several genetic markers on chromosomes 1p36 and 12q15 showed highly significant associations with ulcerative colitis, and the association evidence was replicated in independent European ancestry samples from North America and southern Italy.  Nearby genes implicated as possibly playing a role in ulcerative colitis include the ring finger protein 186 (RNF186), OTU domain containing 3 (OTUD3), and phospholipase A2, group IIE (PLA2G2E) – genes on chromosome 1p36, and the interferon, gamma (IFNG), interleukin 26 (IL26), and interleukin 22 (IL22) genes on chromosome 12q15.  RNF186 and OTUD3 are members of gene families involved in protein turnover and diverse cellular processes.  PLA2G2E, IFNG, IL26 and IL22 are known to play a role in inflammation and the immune response.  The study also found highly suggestive associations between ulcerative colitis and genetic markers on chromosome 7q31 within or near the laminin, beta 1 (LAMB1) gene, which is a member of a gene family known to play a role in intestinal health and disease, and confirmed previously identified associations between ulcerative colitis and genetic variants in the interleukin 23 receptor (IL23R) gene on chromosome 1p31 and the major histocompatibility complex on chromosome 6p21.

“My laboratory is focused on studying the genetic basis for IBD,” said Dr. Duerr.  “Through genetic mapping, we and our collaborators are successfully identifying regions of the genome that contain IBD genes.  The next steps are to understand the functional significance of IBD-associated genetic variants, and then to develop new treatments that specifically target biological pathways implicated by the genetic discoveries.  The overall goal of this work is to improve the lives of the millions of patients worldwide that suffer from IBD.”

A new medication appears to offer significant relief to patients with severe chronic constipation while minimizing the likelihood of cardiac-related side effects, according to results of a study published this week in the New England Journal of Medicine.The trial involved 38 medical centers and was led by Michael Camilleri, M.D., a Mayo Clinic gastroenterologist. Patients who met the study criteria were randomly assigned to receive either of two dosage levels of prucalopride, a medication that stimulates protein receptors involved in contraction of the colon, or a placebo.

“Many more of the patients taking prucalopride were able to have spontaneous bowel movements without having enemas or taking laxatives, as compared to those who were given placebo,” says Dr. Camilleri. “The time it took to have a first bowel movement was much shorter, and quality of life and other abdominal symptoms also were improved for those taking the study drug.”

Constipation is a common medical problem, affecting about 15 percent of Americans who spend several billion dollars each year on laxatives and other treatments. Prevalence is higher among women and African-Americans and is particularly increased in the elderly. This study involved patients with an extreme but common version of constipation called severe chronic constipation. To participate, patients had to have at least six months of constipation, defined as an average of fewer than three bowel movements a week. Those who had more than four bowel movements during the two-week “run-in” period before treatment began were not eligible.

“The normal range of bowel movements is anywhere from three per day to three per week,” explains Dr. Camilleri. “The 620 patients studied in this trial were severely constipated, averaging only one bowel movement during the two weeks before entering treatment, and most had struggled with the problem for several years, not merely months.”

The 2 milligram (mg) and 4 mg doses of prucalopride appeared roughly equal in benefit, with about 30 percent of patients averaging three bowel movements per week during the 12-week study. Only 12 percent of patients on placebo averaged three bowel movements per week. Nearly half (47.3 and 46.6 percent, respectively) of the patients taking prucalopride increased their bowel movements by at least one per week, while about a quarter (25.8 percent) of those on placebo had a similar improvement.

The most common adverse effect from the drug was diarrhea, which tended to occur in the early stages of treatment, but most patients later settled into a more normal routine of bowel movements. Increased bowel movements and diarrhea are expected effects of the drug. Only 1.5 percent and 4.4 percent of patients treated with 2 mg and 4 mg of prucalopride, respectively, stopped the drug due to diarrhea. “This suggests that the diarrhea was less bothersome than the constipation had been,” Dr. Camilleri says. Headaches were a less frequent side effect.

Dr. Camilleri says the cardiac risk issues that have been raised about related drugs for constipation including tegaserod, appear to be less of a concern for prucalopride. “Prucalopride is highly selective in its effect, and doesn’t interact significantly with other protein receptors, such as those involved in regulating heart rhythm,” he explains. “We conducted electrocardiogram testing during the study and did not find heart rhythm issues, although two of the three patients who withdrew from the study did have symptoms, palpitations and dizziness that may have been attributable to an effect on the cardiovascular system.”

Prucalopride is not yet approved for use in the United States or in any other country.

Dr. Camilleri says results from other studies will need to be compiled and published, and safety and efficacy data submitted to the Food and Drug Administration for review, before it can be approved in the United States as a treatment for chronic constipation.