Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Japanese genomes inform on gut inflammation culprits

08.03.2010
Revealing genes linked to the inflammatory bowel disease ulcerative colitis may speed the development of treatments

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)

Saeko Okada | Research asia research news
Further information:
http://www.rikenresearch.riken.jp/eng/hom/6200
http://www.researchsea.com

More articles from Life Sciences:

nachricht Hunting pathogens at full force
22.03.2017 | Helmholtz-Zentrum für Infektionsforschung

nachricht A 155 carat diamond with 92 mm diameter
22.03.2017 | Universität Augsburg

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Pulverizing electronic waste is green, clean -- and cold

22.03.2017 | Materials Sciences

Astronomers hazard a ride in a 'drifting carousel' to understand pulsating stars

22.03.2017 | Physics and Astronomy

New gel-like coating beefs up the performance of lithium-sulfur batteries

22.03.2017 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>