ITPKC and CASP3 polymorphisms and risks for IVIG unresponsiveness and coronary artery lesion formation in Kawasaki disease

Abstract

Functional single-nucleotide polymorphisms (SNPs) in inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) (rs28493229) and caspase-3 (CASP3) (rs113420705; formerly rs72689236) are associated with susceptibility to Kawasaki's disease (KD). To evaluate the involvement of these 2 SNPs in the risk for intravenous immunoglobulin (IVIG) unresponsiveness, we investigated 204 Japanese KD patients who received a single IVIG dose of 2 g kg(-1) (n=70) or 1 g kg(-1) daily for 2 days (n=134). The susceptibility allele of both SNPs showed a trend of overrepresentation in IVIG non-responders and, in combined analysis of these SNPs, patients with at least 1 susceptible allele at both loci had a higher risk for IVIG unresponsiveness (P=0.0014). In 335 prospectively collected KD patients who were treated with IVIG (2 g kg(-1)), this 2-locus model showed a more significant association with resistance to initial and additional IVIG (P=0.011) compared with individual SNPs. We observed a significant association when all KD patients with coronary artery lesions were analyzed with the 2-locus model (P=0.0031). Our findings strongly suggest the existence of genetic factors affecting patients' responses to treatment and the risk for cardiac complications, and provide clues toward understanding the pathophysiology of KD inflammation.

RETRACTED ARTICLE: Meta-analysis of the relationship between single nucleotide polymorphism rs72689236 of caspase-3 and Kawasaki disease

“…Whether rs72689236 polymorphism is associated with Kawasaki disease is controversial [8,10,11]. Onouchi reported that the A-allele of rs72689236 was very likely to be a risk allele in the development of Kawasaki disease [8,11].…”

Specific expression and function of inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) in wild type and knock-out mice

“…KD may lead to formation of coronary artery aneurysms and to ischemic heart disease, myocardial infarction and sudden death (Hata and Onouchi, 2009). The link between this ITPKC polymorphism and KD (or resistance to KD treatment) was confirmed in other studies, but others failed to reproduce these results and no association of the ITPKC locus with KD was detected (Burgner et al, 2009;Khor et al, 2011;Kuo et al, 2011;Lin et al, 2011;Onouchi et al, 2013;Peng et al, 2012).…”

The genetics of Kawasaki disease

“…For example, association of the SNPs near BLK gene which was identified in two independent GWAS from Japan 20 and Taiwan 21 as strongest signals in these two populations was weaker in Europeans. 20,38 Moreover, although repeatedly associated with KD in Japanese, 13,20,36 Europeans 18 and Taiwanese, 39 no association signals were observed near ITPKC gene in the Korean population which is ethnologically closest to Japanese. 23,33 Association of the HLA class II SNP (rs2857151) identified 20 and successfully replicated in Japanese (unpublished International Journal of Rheumatic Diseases 2018; 21: 26-30 data) was not validated in GWAS from the other populations.…”

“…Onouchi et al reported that KD patients with susceptibility alleles of ITPKC and/or CASP3 were more prone to resistance to intravenous immunoglobulin (IVIg) treatment and to developing CALs. 36 Because both ITPKC and CASP3 might have roles as negative regulators for the signaling cascade mediated by inositol 1,4,5-trisphosphate (IP3) and nuclear factor of activated T-cells (NFATs) (Ca 2+ /NFAT pathway; Fig. 1) and susceptibility alleles of both genes are reducing their mRNA expression which in turn may lead to increased signal transduction of the pathway, investigators were prompted to verify the efficacy of cyclosporine A (CsA), an inhibitor of the Ca 2+ /NFAT pathway which has long been used as an immunosuppressant for pediatric patients of organ transplantation or nephrotic syndrome, in treating refractory KD patients.…”