Japanese genomes inform on gut inflammation culprits

Ulcerative colitis is an inflammatory disease of the colon characterized by ulcers in that organ as well as by severe abdominal pain and chronic diarrhea during the active phase of the disease. Anti-inflammatory or immunosuppressive drugs are often used to treat ulcerative colitis, but in severe cases, the only known cure is surgical removal of the colon.

The cause of ulcerative colitis thus far remains a mystery. Studies aiming to determine genetic variations that are more frequently found in individuals with the disease are a first step in determining what may go wrong in the gut of affected individuals to cause the onset of ulcerative colitis. Developing drugs against the proteins that are encoded by these genes may represent future avenues for therapeutic discovery.

Now, as reported in the journal Nature Genetics, Japanese scientists have uncovered five discrete areas of the genome that are linked to ulcerative colitis in the Japanese population. The study was led by Michiaki Kubo from the RIKEN Center for Genomic Medicine in Yokohama, Japan.

Genome-wide hunt extends to Japan

The approach that the researchers took was called a ‘genome-wide association study’ (GWAS). Instead of searching for differences within only one gene of interest that may explain disease susceptibility, Kubo and colleagues looked for genetic variation across the entire genomes of the individuals in the study. This allows for an unbiased approach to gene discovery, which may uncover novel mechanisms by which the disease is initiated.

Previous GWAS studies, focused on individuals of European ancestry, have identified genes linked to ulcerative colitis. But because different ethnic groups may harbor different susceptibility genes for the same disease, the genes linked to ulcerative colitis in Europeans may not relate to this disease in the Japanese population or in other ethnic groups. In fact, the researchers found that although the European and Japanese populations share a few of these susceptibility genes, they don’t share some of the other genes identified in the European study.

Also, Kubo and colleagues identified some genes linked to ulcerative colitis in the Japanese that were not identified in the European studies. Knowing these genetic differences—and similarities—is important when trying to create a drug that will work in as many ethnic groups as possible.

Common Culprits

Major histocompatibility (MHC) molecules, which are expressed on the surface of cells, are involved in presenting antigens to the immune system to initiate—or to halt—an immune reaction. The region of the genome containing the MHC genes, found on chromosome 6 in humans, has been linked to many inflammatory diseases, and has been associated with ulcerative colitis in Europeans. The researchers also found a strong link between the MHC region and ulcerative colitis in the Japanese population.

Crohn’s disease is another type of inflammatory bowel disease that affects a larger portion of the gastrointestinal tract than ulcerative colitis and lesions of the gut lining from this disease appear quite different to those caused by ulcerative colitis. Because the two diseases look so dissimilar, separate genes could be expected to play a role in their induction. However, Kubo and colleagues found a genomic region linked to ulcerative colitis in the Japanese population that had previously been reported to play a role in Crohn’s disease. This locus had also been identified in the European ulcerative colitis GWAS. Future experiments are needed to determine why one genomic locus could enhance disease susceptibility for two different types of inflammatory bowel disease.

The guilty parties

In the five areas linked to ulcerative colitis in the Japanese, Kubo and colleagues identified three areas that had not been previously associated with this disease. One area, on chromosome 13, did not contain any known genes. The researchers suggest that this region could control the expression of nearby genes. Additional studies are necessary to understand how this control could occur.

The other two areas contain the genes FCGR2A and SLC26A3. FCGR2A encodes a receptor protein found at the cell surface of immune cells. When this receptor binds to antibodies, it can cause secretion of cytokine molecules from the immune cells, which may then trigger inflammation. Since the FCGR2A gene variant associated with ulcerative colitis would bind more tightly to antibodies, it may enhance the activation of immune cells, leading to the inflammation that is observed in ulcerative colitis. Surprisingly, previous findings indicated that an opposing change in the FCGR2A gene, which would instead reduce antibody affinity to the receptor, was linked to three autoimmune diseases: lupus, multiple sclerosis and type 1 diabetes. Why altering the affinity of this receptor for its antibody ligand would induce so many different types of disease is a key question for future work.

SLC26A3 encodes a transporter of chloride and bicarbonate ions that is expressed on gut epithelial cells. The expression of this transporter is reduced in humans with ulcerative colitis. Because the change in this area of the genome, which the researchers report as linked to ulcerative colitis, was outside of the protein coding region of the SLC26A3 gene, it is likely that this change in the DNA would regulate the expression of SLC26A3.

Kubo and his colleagues now plan to examine exactly how the observed variation in FCGR2A and SLC26A3 affect susceptibility to ulcerative colitis. Because the link between these genes and ulcerative colitis had not been made before, these findings “will open the door to further understanding of the mechanism of ulcerative colitis,” says Kubo.

Michiaki Kubo

Michiaki Kubo was born in Miyazaki, Japan, in 1963. He graduated from the Faculty of Medicine, Kyushu University in 1988, and started his work as a medical doctor at the Second department of Internal Medicine, Kyushu University. He started his clinical research as a research fellow of clinical epidemiology at the Hisayama study, a prospective population-based study of cardiovascular disease since 1995. He started genetic research as a visiting fellow of the Institute of Medical Science, the University of Tokyo (Professor Yusuke Nakamura Lab) from 2003 and found two susceptibility genes for brain infarction in 2007. He joined the RIKEN Center for Genomic Medicine as a group director of Research group of Genotyping in 2006. Since then, he is working on to find the susceptibility genes of common diseases using genome-wide association study.

Asano, K. Matsuhita, T., Umeno, J., Hosono, N., Takahashi, A., Kawaguchi, T., Matsumoto, T., Matsui, T., Kakuta, Y., Kinouchi, Y., et al. A genome-wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population. Nature Genetics 41, 1325–1329 (2009)