With the identification of several genes associated with ulcerative colitis, relief may be a step closer for sufferers of this chronic, inflammatory condition of the large intestine.
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Ulcerative colitis is characterized by chronic inflammation of, and ulcers in, the large intestine. It has complex genetic and environmental causes, and is thought to be related to the other main cause of inflammatory bowel disease, Crohn’s disease.
Few genes conferring susceptibility to ulcerative colitis have been identified; partly because researchers had considered the condition to have relatively low heritability. Mark Seielstad, formerly from the Genome Institute of Singapore, A*STAR, and co-workers have now identified several, previously unknown, ulcerative susceptibility genes and described their relationship to Crohn’s disease.
The researchers performed two separate genome-wide association studies and combined the data with those from a previously published study to compare the genomes of 2,693 ulcerative colitis patients with those of 6,791 healthy controls. They also tested 2,009 other patients and 1,580 controls.
In addition to confirming several genetic variants previously associated with ulcerative colitis, this joint analysis identified an additional 14 variants thought to be associated with this disease and a further ten already associated with Crohn’s disease and inflammatory bowel disease.
Most of the genes identified encode proteins of unknown function. Two of them, however, were already known to contain domains that regulate immune system function by modifying other proteins, and a third encodes an enzyme called phospholipase A2 (PLA2), which is involved in producing small molecules that mediate inflammation.
The researchers examined the activity of six of these genes, and found that they have very different expression patterns. Several are expressed in the large intestine, with one expressed specifically at the base of epithelial cells, while others are more active in the immune system. They discovered that one of the genes, ORMDL3, is expressed in a structure called the endoplasmic reticulum, and is involved in a cellular stress response. Surprisingly, they revealed that the PLA2 gene is expressed in the small, but not the large, intestine.
This study brings the total of variants associated with ulcerative colitis to 27. It implicates a number of processes in the development of the condition, including aberrant regulation of immune responses and reduced integrity of the epithelial cells in the small intestine, the researchers note. The findings also confirm that ulcerative colitis shares some susceptibility genes and pathological mechanisms with Crohn’s disease, but that some of the genes and mechanisms are specific to each.
The researchers write that the challenge now is both to identify additional genetic factors and to translate these advances into real benefits for individuals with ulcerative colitis.
The A*STAR-affiliated authors in this highlight are from the Genome Institute of Singapore.
