Kawasaki disease is a self-limiting acute febrile systemic vasculitis that usually involves small and medium vessels, particularly coronary arteries.11 The most serious complication, CALs (coronary artery involvement), is reported in 15–25% of untreated cases.12 CALs coronary involvement rate was found 17.6% in our study group.
It has been reported that the probability of developing coronary artery lesions decreases with high dose IVIG treatment administered in the acute period of the disease. Therefore, the response of patients to standard therapy is an important factor that determines the risk of complications. In their study, Fabi et al. showed the frequency of CALs in the patients with IVIG response and resistance in 19.6% and 37.2%, respectively (p = 0.01).13 In our study, this rate was found to be 17.3% and 42.2% in the resistant group with IVIG response, respectively (p < 0.001).
The incidence of resistance to IVIG is generally reported in the literature between 10–20%.14–16 Classification of patients according to the risk of IVIG resistance could inform decisions to administer more aggressive initial treatment, with the aim of reducing the risk of coronary artery lesion development.10
Many risk scoring systems have been developed so far with the idea of coronary complications can be reduced by using aggressive treatment regimens in the early period if the response to treatment can be predicted at the beginning of the disease.6–9 These scoring systems, which were developed based on clinical findings and laboratory parameters, have not been widely used worldwide since their prediction power varies according to the population they are applied to.17–21 In the studies conducted in Northern American Cohort,18 US Midwest,19 Spain,20 The UK,21 German,22 France23 populations, IVIG resistance was found at different rates. The determination of IVIG resistance at different rates in different races led to genetic studies.
In the last ten years, with the rapid advancement of next generation sequencing techniques reserachers identified variants related to responsiveness to treatment, the risk of complications and mortality in multifactorial diseases including KD. In a recent study, Kim et al. performed WES to 296 KH patients, in which 101 cases were IVIG resistant, and identified different SNP variants in five different gene loci related to immune response.10 They obtained a broad-based risk analysis by adding the results of replication studies of two separate cohorts with 903 with IVIG response and 352 with IVIG resistance. In GWAS analysis of these variants were: "rs11556218" (p.Asn1147Lys) [OR = 1.89 p = 0.0042] in the IL16 gene; "rs344560" (p.Lys214Glu) [OR = 2.26 p = 0.0096] in the TNFSF14 gene and "rs12479626" (p.His446Arg) [OR = 2.79 p = 0.0035] located in the NFATC2 gene; “rs1128127” (p.Ala211Val) in the DERL3 gene [OR = 2.45 p = 0.0109]; “rs10488532” (p.Val266 with) located in the SAMD9L gene [OR = 3.46 p = 0.0067].
Here we report only three of them had an estimated relative risk (OR) greater than 1.
These were localized polymorphisms in the IL16
gene (rs11556218), the TNFSF14
gene (rs344560) and the NFATC2
gene (rs12479626), respectively. Since p
values > 0.05 were not statistically significant this may be related to patient number whic is lower than Kim et al.’ study.
In general, KD develops as a result of irregularity in the immune response. It has been suggested that there is a similarity between KD and the pathogenesis of autoimmune diseases.24 T lymphocytes are predominant in the immunopathogenesis of KD. Increased T lymphocyte activation leads to the production of cytokines responsible for the pathogenesis of the disease.
Interleukin-16 (IL-16) encoded by the IL16 gene is a pileiotropic cytokine that acts as a modulator in T cell activation and was first described in 1982.25 IL-16, which shows chemoattractant function mainly on CD4 + T lymphocytes, has an effect on CD4 + / CD8 + ratio. IL-16, which showed an inhibitory role in HIV replication in the 1990s26, has been associated with a number of diseases that progress with inflammation or autoimmunity in different studies. Disorders in the IL16 gene play an important role in the pathophysiology of these diseases with CD4 + / CD8 + ratio and CD8 + T cell activation. The diseases associated with IL-16 are bronchial asthma,27 Crohn's disease28, systemic lupus erythematosus,29 rheumatoid arthritis,30 and multiple myeloma.31IL16 variant of "rs11556218 (T / G)" identified by Kim et al.10 On IVIG resistance in IL16 gene in KD was associated with a predisposition to multiple sclerosis.32
TNFSF14 gene encodes one of the tumor necrosis factor (TNF) ligands. The receptor to which it binds is a member of the tumor necrosis factor receptor superfamily (TNFRSF14) and is also known as the herpesvirus entry mediator (HVEM). The encoded protein provides co-stimulation for T cell activation. In this way, it plays a preventive role in herpesvirus infections. It has also been shown to stimulate T cell proliferation and trigger apoptosis of various tumor cells.33
NFATC2 gene is a member of the nuclear factor (NFAT: Nuclear factor of activated T-cells) family of activated T cells, and the product it encodes is a DNA-binding protein. The protein contained in the T cell cytosol induces nuclear transcription complexes by binding to the nucleus when the T cell receptor (TCR) is activated.34 Nuclear Factor of Activated T cells (NFAT) family members are known for their roles in T cell development and activation but still largely undetermined in CD8 + T cell differentiation in vivo. NFAT1 and NFAT2 in T cells display a significant increase in KLRG1hi CD127hi population and are unable to clear an acute viral infection.35 NFAT-deficient CTLs showed different degrees of impaired IFN-γ and TNF-α expression with NFAT1 being mainly responsible for IFN-γ production upon ex-vivo stimulation as well as for antigen-specific cytotoxicity.
SAMD9L is adjacent to its close paralog sterile alpha motif domain-containing protein 9 (SAMD9) on chromosome 7q21.2 and encodes a cytoplasmic protein that has important roles in multiple cellular processes such as cell proliferation (most likely as a tumor suppressor), the neoplastic phenotype, and the innate immune response to viral infection.36,37 The physiological functions of SAMD9L currently remain poorly understood, but its importance has recently been emphasized during the discovery of the genetic cause of a rare, life-threatening human disease.38 In the study Kim at al., although associations between SAMD9L variants and KD susceptibility or IVIG resistance have not been reported, it is most likely that the role of SAMD9L in IVIG resistance could be mediated through various immune signaling pathways in which SAMD9L plays important roles in immune-related diseases.39