Identification of Genetic Markers for Ulcerative Colitis Could Modify Treatment

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The Inflammatory Bowel Disease (IBD) Genetics Consortium funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) has identified genetic markers that are associated with risk for ulcerative colitis. The findings, published January 4, 2009, in the advance online edition of 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 such pathways.

“Our identification of some of the genes that lead to ulcerative colitis are giving us a first look into the causes of this debilitating disease and provides strong leads as to improved diagnosis and treatment,” said, Dr John D. Rioux, Professor of Medicine at the Université de Montréal and the Montreal Heart Institute, one of the lead researchers of the study.

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 >30 genetic risk factors for Crohn's disease has been among the major success stories in this new era of research.

Although 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, the researchers performed a genome-wide association study of hundreds of thousands of genetic markers using DNA samples from 1052 individuals with ulcerative colitis and preexisting data from 2571 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, 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.

Consortium member institutions include the University of Pittsburgh, Cedars–Sinai Medical Center in Los Angeles, the University of Chicago, The Johns Hopkins University, Université de Montréal and the Montreal Heart Institute, Mount Sinai Hospital in Toronto, and Yale University. Other study authors who collaborated with the NIDDK IBD Genetics Consortium to enable the study include researchers from Carnegie Mellon University, the Cleveland Clinic Foundation, The Feinstein Institute for Medical Research, Massachusetts General Hospital, CHUM—Hôpital Saint-Luc in Montreal, The Hospital for Sick Children and Princess Margaret Hospital in Toronto, CHAUQ—Hôpital du St-Sacrement in Quebec, and the IRCCS-CSS Hospital in S. Giovanni Rotondo, Italy.

For more details, see: “Ulcerative colitis–risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study,” Nat Genet 2009;41:216–220 (Epub January 4, 2009).