Nov 20, 2009 - Research

Piecing Together The Inflammatory Bowel Disease Puzzle


Inflammatory  bowel disease (IBD) is a chronic autoimmune disorder — encompassing both Crohn’s disease and ulcerative colitis —  that affects more than a million people in the United States. Normally, our immune system works to fight off harmful pathogens that might pass through our digestive tract. In IBD, however, the immune system stays in overdrive and attacks normal intestinal cells. The resulting chronic inflammation causes abdominal cramps, diarrhea, pain and fever, and weight loss.

Most studies of IBD have investigated genetic factors for Crohn’s disease, but a set of articles published this week in Nature Genetics on IBD address two less-explored angles. Two of the studies identify new genetic associations with ulcerative colitis in European and Asian populations. The third study focuses on early-onset IBD (diagnosed prior to age 19), which is typically more severe than adult-onset IBD and is believed to have a stronger genetic component.

In a joint effort, the UK IBD Genetics Consortium and the Wellcome Trust Case Control Consortium 2 identified three genetic variants associated with ulcerative colitis in a group of 4,682 people with the condition and over 10,000 healthy individuals, all of European ancestry. These variants are located in regions of the genome that had not previously been associated with ulcerative colitis .

Each of the three SNPs was associated with slightly increased odds of ulcerative colitis. The researchers highlight a number of proteins encoded by genes near these variants that help maintain the lining of the intestine and regulate cell-cell interactions, including HNF4a, E-cadherin, and laminin, though their exact roles in ulcerative colitis are unclear.

The second study, led by Kouichi Asano and Michiaki Kubo of the RIKEN Center for Genomic Medicine in Japan, looked for genetic variants associated with ulcerative colitis in a group of about 1,380 Japanese individuals with the disease and 3,050 individuals without it. Their two strongest associations were SNPs located near genes involved in immune response.

One of these SNPs is in a region of the genome that encodes antigen-presenting proteins — important for immune system recognition of “self” vs. foreign substances. Antigen-presenting proteins display bits and pieces of proteins or sugars (antigens) from cells and other microorganisms to immune cells that normally ignore “self” antigens but destroy foreign ones. In autoimmune diseases like IBD, the immune system loses the ability to distinguish between the two types of antigens and mistakenly reacts to the body’s own cells.

The other strongly associated SNP is located in the FCGR2A gene and causes a change to the encoded protein, which is expressed on the surface of several types of immune cells. Previous studies by other groups have shown that this SNP can play a significant role  in the development of other autoimmune disorders. The version of the SNP that increased risk for those other disorders, however, is the opposite version compared to the version associated with increased risk for ulcerative colitis in the current Japanese study.

In the third study, a team led by Marcin Imielinski and Hakon Hakonarson of the Children’s Hospital in Philadelphia identified genetic variants associated with early-onset IBD. Almost 3,500 individuals of European ancestry who had been diagnosed with IBD — either Crohn’s disease or ulcerative colitis — before their nineteenth birthday were compared to close to 12,000 individuals free of IBD.

Imielinski’s team identified three SNPs significantly associated with early-onset Crohn’s disease. For two of the SNPs, and , the less common version was associated with slightly increased odds of early-onset Crohn’s disease, while the less common version of was associated with slightly decreased odds. They also observed an association between and early-onset ulcerative colitis.

When they conducted a combined analysis of all early-onset IBD cases (Crohn’s and ulcerative colitis), the researchers found that the three genetic variants associated with early-onset Crohn’s disease were associated with early-onset IBD in general.   The effect sizes were similar to those seen when they looked at just Crohn’s disease.   In addition, they identified another SNP associated with early-onset IBD, .

Of the four genetic variants associated generally with early-onset IBD, Imielinski and his colleagues consider to be especially important given its proximity to IL27, a gene involved in the immune system. The researchers showed in a small sample that individuals with early-onset Crohn’s disease express the gene at much lower levels than healthy people. IL27 encodes a protein that suppresses inflammatory immune cells in the intestine, so it is possible that lower expression of IL27 contributes to a hyperactive inflammatory response.

Although the biology of IBD is complex, these three studies contribute to a more comprehensive picture of the genetic factors underlying the condition and suggest potential directions for the development of therapeutics.

“This is an evolving story of discovering what genes tell us about the disease,” said Dr. Baldassano from the Children’s Hospital team in a press release. “Pinpointing how specific genes act on biological pathways provides a basis for ultimately personalizing medicine to an individual’s genetic profile.”

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