Recently, a single nucleotide polymorphism (SNP) of the
inositol 1,4,5-triphosphate kinase C (ITPKC), rs28493229, was found to passively confer susceptibility for
Kawasaki syndrome (KS) and subsequent coronary arterial lesions. This association is believed to be the result of defective phosphorylation of
inositol 1,4,5-triphosphate (IP3), which releases
calcium from intracellular stores, resulting from reduced genetic expression of ITPKC in carriers of the SNP. Reduced ITPKC activity would increase IP3 levels, and thus, increase
calcium release. We hypothesized that an environmental agent which influences IP3-mediated
calcium release is potentiated by the ITPKC SNP. This led us to an attractive candidate,
thimerosal, an organomercurial medical preservative still used in several pediatric
vaccines.
Thimerosal is well-known to sensitize IP3 receptors via its induction of oxidative stress, resulting in enhanced release of intracellular
calcium with distinctive consequences for various cell types. Dysregulated calcium signaling in T cells and other immune cells can result in autoimmunity, while hyperpolarization of vascular smooth muscle cells secondary to the stimulation of
calcium-activated potassium channels can result in increased vascular permeability and arterial relaxation. We propose that ITPKC susceptibility in KS is related to its synergy with environmental triggers, such as
thimerosal, which alter
calcium homeostasis and promote oxidative stress. Therefore, carriers of the ITPKC SNP are more susceptible to
thimerosal-induced autoimmunity and coronary arterial lesions observed in KS. This would explain why only a susceptible subset of children develops KS although pediatric
thimerosal exposure is nearly universal due to vaccination. As was experienced with the infantile
acrodynia epidemic, only 1 in 500 children developed the disease although pediatric
mercury exposure was nearly ubiquitous due to the use
calomel teething powders. This hypothesis also mirrors the current leading theory for KS in which a widespread
infection only induces the disease in susceptible children. We conclude that KS may be the acute febrile form of
acrodynia.