Sadeep Shrestha, Ph.D. (right), with a graduate student in the School of Public Health's Epidemiology and International Health Lab. Shrestha's new study used whole-genome sequencing to identify variations associated with treatment non-response in Kawasaki disease. Significantly, the study also found that these variations differ by patient ancestry.
ANDREA MABRY | Marketing and CommunicationsKawasaki disease, first reported about 50 years ago, remains a mysterious condition. The hallmarks are a persistent fever, rash, eye redness and swelling caused by inflammation of the blood vessels. It is more common in children under the age of 5 but can occur in children of all ages. It is more likely to affect boys than girls, and has strong seasonal patterns, with peaks in January and June/July. Genetics clearly plays a role as well. In Japan, where it was first reported, the incidence of Kawasaki disease is 264 per 100,000 children; it is 134 per 100,000 in South Korea, between 17 and 21 per 100,000 in the United States, and less than 16 per 100,000 in most countries in Europe, with the lowest incidence in Scandinavian countries.
Kawasaki disease is now considered the leading cause of acquired heart disease among children in developed countries such as the United States and Japan. In most cases, up to 80 percent, treatment with high-dose aspirin and intravenous gamma globulin, or IVIG, resolves symptoms. But children who do not respond to IVIG are at higher risk for the potential long-term complications of Kawasaki disease: coronary artery dilation and large aneurysms in those arteries that can lead to increased risk of heart attacks. Because of these heart issues, pediatric cardiologists closely monitor Kawasaki disease.
Study finds variations differ based on patient ancestry
“I don’t think anybody knows the cause of Kawasaki disease, and no one knows the mechanism behind how IVIG treatment works in Kawasaki disease,” said Sadeep Shrestha, Ph.D., professor in the Department of Epidemiology at the UAB School of Public Health. In January 2024, Shrestha and colleagues published the largest whole-genome sequencing study of Kawasaki disease patients, in the journal Frontiers in Immunology. Their study pinpoints a range of genetic variations associated with non-responsiveness to IVIG treatment — and significantly, these variations differ based on patient ancestry.
For most of the mutations seen, known as single nucleotide polymorphisms, or SNPs, “association was statistically significant in only one ancestral population,” the authors note.
Their top hits were associated with several genes that have biologically plausible connections with Kawasaki disease and IVIG non-response, including FANK1 (suppresses cell death) and HSP90AB1, a member of the HSP90 family of heat shock proteins that “may exaggerate the activation of immune cells and lead to a hyper-inflammatory response” if overexpressed, the authors write. Interestingly, the variations differed markedly between ancestral populations. The top variation seen in white non-responders, for example — in the CABP1 calcium binding protein — did not rise to significance in the other populations. For most of the mutations seen, known as single nucleotide polymorphisms, or SNPs, “association was statistically significant in only one ancestral population,” the authors note.
Markers of IVIG non-response could help in other conditions, too
The work “gives us some markers as to who is not going to respond to treatment and who is more likely to develop these aneurysms,” Shrestha said. The results could be used to develop rapid tests looking for these variations that could help doctors identify high-risk patients, he notes. Because IVIG is used to treat other conditions, including Guillain-Barre syndrome, myasthenia gravis and lupus, tests for IVIG response could be helpful in those diseases as well, Shrestha points out.
The results could be used to develop rapid tests looking for these variations that could help doctors identify high-risk patients.
Previous gene sequencing studies in Kawasaki disease looked only at common genes or subsets of the genome, Shrestha explains. “Kawasaki disease is rare to start with, and we wanted to look at non-responders, which is a subpopulation of that,” Shrestha said. “We thought there could be some rare or unknown variants involved.” That required whole-genome sequencing.
The study used patient samples collected by a large national consortium of Kawasaki disease researchers, led by paper co-author Michael A. Portman, M.D., pediatric cardiologist at the Seattle Children’s Hospital and professor of Pediatrics at the University of Washington. The researchers used deliberately strict criteria for inclusion: All participants had to have a definitive diagnosis of Kawasaki disease, have received timely high-dose aspirin and IVIG treatment, and have data available on their response to that treatment, strictly following the American Heart Association’s scientific statement.
The final study cohort consisted of 472 patients: 305 IVIG responders and 167 non-responders. The researchers subdivided the cohort into four groups based on ancestry information markers: Whites, African Americans, Asians and Hispanics. Even in this relatively small population, the data needs of whole-genome sequencing studies are significant. “We have 52.27 terabytes of data,” Shrestha said.
Ongoing UAB study collecting samples from patients, families
First described in Japan by Tomisaku Kawasaki, M.D., in 1967, Kawasaki disease has been considered “to be mainly an Asian disease based on epidemiological and hospital-based data,” Shrestha said. But Shrestha and collaborators at UAB, including Luz Padilla, M.D., an assistant professor in the Department of Epidemiology, have documented a substantial number of cases among African American patients in Alabama, along with incidence and seasonality patterns in those patients that differ from white patients. “We did the largest study of African American patients with Kawasaki disease here at Children’s of Alabama, where we see about 50 kids with Kawasaki disease each year, and 30 to 35 percent of them are African American,” Shrestha said.
Shrestha is principal investigator on a UAB research study designed to collect genetic samples from patients with Kawasaki disease and their families through cheek swabs. Learn more about the study by calling (205) 934–6459 or emailing kdgeneticsal@uab.edu.
This research is funded by a grant to Shrestha from the National Heart, Lung and Blood Institute, or NHLBI. “The grant is ending; but in our renewal, we are focusing on African American patients because not much is known about Kawasaki disease in African Americans and we observed a large number in Alabama itself,” Shrestha said.
Shrestha is principal investigator on a UAB research study designed to collect genetic samples from patients and their families through cheek swabs. One goal of the study, “Genetic Prediction for Treatment Resistance in Kawasaki Disease,” is to learn more about how the disease specifcally affects African Americans. It is led by the UAB Department of Epidemiology, in collaboration with the Department of Pediatric Cardiology and Portman at Seattle Children’s. Learn more about the study by calling (205) 934–6459 or emailing kdgeneticsal@uab.edu.
“Ultimately, the goal is to have these markers so that, when somebody walks in and you suspect it is KD, you can do this test,” Shrestha said. “That is where we are heading — personalized medicine.”
