Molecular Genetics of Kawasaki Disease

Abstract

Kawasaki disease (KD) is a leading cause of acquired cardiac disease of children in the developed countries. The pathogen that triggers this perplexing disease is still unknown after 40 y from the first description. Epidemiologic findings have made us believe that there are considerable genetic components in the etiology and some candidate genetic variations, which confer susceptibility to KD or risk for coronary artery lesions have been identified. However, most of them remain to be definitively confirmed by replication studies with large cohorts. In this article, I review the candidate gene association studies to date. I also introduce our recent findings in genome-wide approach, which revealed the importance of Ca 2ϩ / nuclear factor of activated T-cells pathway in the pathogenesis of KD.

Identification of Pathogenic Cardiac CD11c + Macrophages in Nod1-Mediated Acute Coronary Arteritis

“…These proteases may exacerbate arteritis by directly targeting elastic fibers, as recent studies demonstrate the genetic association between MMPs and KD. 28,29 Given that the control of progression during the destruction phase is important for the prognosis of KD, more detailed studies are needed to clarify the molecular mechanisms acting at this critical stage. On the other hand, the characteristics of cardiac CD11c + macrophages might suggest a physiological role for this population during infection or noninfectious insults, such as mediation of antimicrobial activity or tissue remodeling/repair.…”

Adjunctive therapies for Kawasaki disease

“…Onouchi and colleagues studied candidate genes using a genome wide approach. 31 InositolTriphosphate 3-Kinase C (ITPKC) encodes an enzyme that negatively regulates T cell activation through the calcineurin/NFAT pathway. A risk allele for KD susceptibility and CAA in ITPKC was associated with reduced enzyme activity that may lead to enhanced T cell activation.…”

“…A risk allele for KD susceptibility and CAA in ITPKC was associated with reduced enzyme activity that may lead to enhanced T cell activation. 31 Cyclosporin A (CyA) is strong suppressor of T cell activation and may be a potential treatment for refractory KD. A pilot trial was conducted in 28 Japanese children who were resistant to two doses of IVIG and were then treated with oral CyA.…”

Precision Medicine for Kawasaki Disease

“…The marked susceptibility of individuals of Northeast Asia descent to KD, compared with the susceptibility of those of European descent, has been maintained following the migration of North Asians to countries where there is a low incidence of the disease (44). Moreover, siblings with KD have a 10-fold higher risk of developing KD than the general population does, and children whose parents had KD have a twofold increased incidence of developing the disease (40,(45)(46)(47)(48)(49). Based on a linkage analysis performed in Japanese KD sibling-pair samples, a functional polymorphism in the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene was identified (39).…”