Researchers from Japan's RIKEN SNP Research Center, collaborating with a team at the University of California, San Diego (UCSD), have discovered a new genetic variation that affects a child's risk of getting Kawasaki disease (KD), an illness characterized by acute inflammation of the arteries throughout the body.
The genetic variation influences immune activation and the response to standard treatment, as well as the risk of developing coronary artery aneurysms – a swelling of the artery that can result in blood clots and heart attack – as a complication of KD.
Lead author, Yoshi Onouchi, M.D., Ph.D., SNP Research Center, RIKEN, Yokohama, Japan, used DNA from hundreds of U.S. children and their parents, collected through the Kawasaki Disease Research Center at Rady Children's Hospital San Diego (RCHSD), Department of Pediatrics, UCSD School of Medicine.
“This was a wonderful collaboration,” said co-author, Jane Burns, M.D., professor and chief, Division of Allergy, Immunology, and Rheumatology, UCSD Department of Pediatrics. “Dr. Onouchi used our DNA to make this observation. Now we are building on that observation.”
Kawasaki Disease, a pediatric illness characterized by fever and rash, is not a rare illness but it is most prevalent in Japan. In San Diego County, 20 to 30 children per 100,000 children less than five years of age are affected each year. More than 50 new patients are treated annually at RCHSD. The illness is four to five times more common than some more publicly recognized diseases of children such as tuberculosis or bacterial meningitis.
If untreated, KD can lead to lethal coronary artery aneurysms. KD tends to run in families, suggesting that there are genetic components to disease risk. It is also 10 to 20 times more common in Japanese and Japanese American children than in children of European descent.
Researchers identified a region on chromosome 19 linked with the disease. In particular, a series of variants across four genes in the region appeared more frequently in individuals with the disease than those in the healthy control group.
The team focused on one of these genes, ITPKC, which appeared to be the most likely candidate. The gene lies in a signaling pathway that affects the activation of T cells, one arm of the body's immune response system. ITPKC encodes an enzyme that is part of a signaling pathway with a critical role in T cell activation. The authors showed that one of the risk variants reduces the expression of ITPKC, and that lower levels of ITPKC lead to over-activation of T cells.
“This single gene jumped out as an obvious candidate because it is involved in immune activation, and KD is a disease of immune over-activation,” said Burns. “This was great detective work to decipher the function of this variant.”