Intercepting inflammation

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)