Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Intercepting inflammation

Genetic data help scientists close in on the immunological malfunctions underlying a mysterious pediatric disorder

Scientists and doctors continue to find themselves baffled by Kawasaki disease (KD), an inflammatory disorder that represents the leading cause of pediatric heart problems in the developed world. “The cause of KD has remained unknown for more than 40 years since the first description of the disease by Dr. Kawasaki, and so there is no evidence-based therapeutic strategy,” says Yoshihiro Onouchi of the RIKEN Center for Genomic Medicine in Yokohama.

Onouchi has partnered with other scientists in Japan and the United States to identify chromosomal regions containing genes potentially associated with this condition, uncovering strong evidence that KD arises in part from improper regulation of the immune system. Based on this hypothesis, he and his colleagues recently examined loci within chromosomal region 4q35, which contains a diverse array of genes relevant to this process1.

The researchers were especially interested in the gene encoding caspase-3 (CASP3), an enzyme that participates in the initiation of programmed cell death and thereby helps to mitigate the extent of T cell-mediated immune responses. By comparing data from a cohort of Japanese individuals affected with KD relative to their unaffected counterparts, they were able to identify more than two dozen sequence variations near CASP3 that appear to preferentially associate with disease onset.

Functional analysis of the gene revealed the presence of an ‘enhancer’, a stretch of DNA where regulatory proteins can bind to help ratchet up expression levels, surrounding one of the variants identified in this initial screen. The researchers determined that the genomic sequence alteration linked with KD appears to impair enhancer binding by the transcriptional regulator nuclear factor of activated T cells (NFAT), and this reduced NFAT binding in turn leads to significantly reduced CASP3 expression. Importantly, this variant is also significantly associated with disease susceptibility in European populations.

Onouchi and colleagues have previously identified another KD-associated variation (or SNP) in the gene encoding inositol 1,4,5-trisphosphate 3 kinase-C (ITPKC), an enzyme that downregulates a T cell signaling cascade in which calcium ion (Ca2+) flux is coupled with NFAT activation2. In combination, these findings suggest that NFAT may offer a promising drug target. “The calcineurin enzyme plays a key role in the Ca2+/NFAT pathway, and we are now interested in the potential of calcineurin inhibitors like cyclosporin A as a therapeutic option,” says Onouchi. “Our team is now collaborating with several medical institutes in Japan in an attempt to evaluate the effectiveness of cyclosporin A on refractory KD cases.”

The corresponding author for this highlight is based at the Laboratory for Cardiovascular Disease, RIKEN Center for Genomic Medicine

Journal information

1. Onouchi, Y., Ozaki, K., Burns, J.C., Shimizu, C., Hamada, H., Honda, T., Terai, M., Honda, A., Takeuchi, T., Shibuta, S. et al. Common variants in CASP3 confer susceptibility to Kawasaki disease. Human Molecular Genetics published online 10 May 2010 (doi: 10.1093/hmg/ddq176)

2. Onouchi, Y., Gunji, T., Burns, J.C., Shimizu, C., Newburger, J.W., Yashiro, M., Nakamura, Y., Yanagawa, H., Wakui, K., Fukushima, Y. et al. ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms. Nature Genetics 40, 35–42 (2008)

gro-pr | Research asia research news
Further information:

Further reports about: Burns CASP3 CASP3 expression Genetics Honda Kawasaki disease NFAT chromosomal region 4q35 genomic

More articles from Life Sciences:

nachricht Novel mechanisms of action discovered for the skin cancer medication Imiquimod
21.10.2016 | Technische Universität München

nachricht Second research flight into zero gravity
21.10.2016 | Universität Zürich

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

Im Focus: New Products - Highlights of COMPAMED 2016

COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.

In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...

Im Focus: Ultra-thin ferroelectric material for next-generation electronics

'Ferroelectric' materials can switch between different states of electrical polarization in response to an external electric field. This flexibility means they show promise for many applications, for example in electronic devices and computer memory. Current ferroelectric materials are highly valued for their thermal and chemical stability and rapid electro-mechanical responses, but creating a material that is scalable down to the tiny sizes needed for technologies like silicon-based semiconductors (Si-based CMOS) has proven challenging.

Now, Hiroshi Funakubo and co-workers at the Tokyo Institute of Technology, in collaboration with researchers across Japan, have conducted experiments to...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

Resolving the mystery of preeclampsia

21.10.2016 | Health and Medicine

Stanford researchers create new special-purpose computer that may someday save us billions

21.10.2016 | Information Technology

From ancient fossils to future cars

21.10.2016 | Materials Sciences

More VideoLinks >>>