Genetic Landscape of Kawasaki Disease: An Update

Abstract

Kawasaki disease (KD), first identified in 1967 by Dr. Tomisaku Kawasaki, is an acute, self-limited vasculitis and remains the leading cause of acquired heart disease in children worldwide, particularly affecting those under the age of five. Clinically, it presents with persistent fever, mucocutaneous inflammation, skin rashes, and lymphadenopathy, with a marked tendency to involve the coronary arteries, potentially leading to serious complications such as coronary artery aneurysms. Despite extensive research spanning more than five decades, the precise etiology of KD remains unclear. However, accumulating evidence supports the significant role of genetic predisposition, highlighting the contribution of inherited factors in modulating immune responses and influencing disease susceptibility and severity. Emerging evidence highlights genetic susceptibility as pivotal, with genome-wide studies identifying polymorphisms in immune-related genes, such as ITPKC, CASP3, BLK, CD40, and ORAI1, which modulate disease risk and coronary complications. Epigenetic mechanisms, including DNA methylation and non-coding RNAs, bridge the gap between genetic and environmental factors, regulating immune responses and endothelial activation. Furthermore, emerging insights into autophagy-related processes provide a deeper understanding of the molecular mechanisms underlying the disease. This review aims to explore the current knowledge on the genetic landscape of KD, examine how these findings contribute to our understanding of its pathophysiology, and investigate the potential for genetically targeted therapeutic strategies in the future.

1. Introduction

Kawasaki disease (KD) is an acute, self-limiting vasculitis that primarily affects children, especially those of East Asian descent. It is now considered to be the most common cause of acquired heart disease in children worldwide [1]. Due to the absence of a single causative agent or pathognomonic biomarker, diagnosis relies on a constellation of clinical features, including prolonged fever, bilateral conjunctival injection, mucosal changes (e.g., strawberry tongue), polymorphous rash, extremity changes, and unilateral cervical lymphadenopathy. Several children with KD may not fulfil the diagnostic criteria; they are said to have incomplete/atypical KD. The proportion of children with incomplete/atypical KD may be as high as 30–50% in large cohorts [2].

A hallmark of KD is the inflammation of medium-sized arteries, especially those involving the coronary arteries, which can lead to thrombosis, aneurysms, and long-term cardiac complications. Early detection of KD is crucial, as most children respond to treatment. However, delays in diagnosis or the initiation of appropriate therapy can result in the development of coronary artery abnormalities (CAAs) in 15–25% of cases [3].

Despite advances, the pathophysiology of KD remains unclear. Current research suggests an abnormal immune response triggered by environmental or infectious factors in genetically predisposed individuals [4,5,6]. The seasonal nature of KD and its occurrence primarily in infants and young children suggests an infectious trigger, though no specific pathogen has yet been identified. Several lines of evidence suggest that genetics plays a crucial role in the susceptibility to KD. Family studies indicate that KD may cluster in certain families, with siblings of affected children at a significantly increased risk [7,8,9]. In addition, studies of twin populations have suggested a higher concordance for the disease in monozygotic twins compared to dizygotic twins, further supporting the genetic basis of KD [10]. To uncover disease-associated genes in KD, two main approaches have been employed: candidate gene studies and genome-wide association studies (GWASs). Both approaches involve genotyping genetic differences, primarily single-nucleotide polymorphisms (SNPs), in cases and controls [11]. Over the past two decades, numerous genetic association studies have identified potential risk loci for KD. The most significant findings have emerged from GWASs, which have provided a deeper understanding of the genetic underpinnings of the disease. This article focuses on SNPs in genes associated with KD susceptibility and CAAs, aiming to summarize current findings and guide future genetic research in KD.

2. Genetic Susceptibility and the Role of Host Genomic Variability

2.1. Immune System-Related Genes

The pathogenesis of KD is also known to involve a hyperactive immune response to an environmental or infectious trigger in genetically susceptible individuals [4,6]. The activation of both innate and adaptive immune responses leads to widespread inflammation, particularly in medium-sized arteries, with a predilection for the coronary arteries.

2.1.1. MHC Class I and II Genes

Glycoproteins on the cell surface, known as major histocompatibility complex (MHC) molecules, are essential to the immune system as they present peptides to the CD4+ T cells’ antigen receptor. Antigen presentation is crucial for maintaining self-tolerance and controlling immune responses. In fact, during CD4+ T cell maturation in the thymus, MHC expression guides both positive and negative selection mechanisms that influence the specificity of the T cell receptor repertoire. Studies have reported the significant role played by the MHC region in the susceptibility to autoimmunity, transplant acceptance, and infection resistance [12]. Despite this, the association between MHC and KD has not been well studied.

However, the HLA (human leukocyte antigen) region, particularly HLA-DRB1, has been known to be associated with the risk of developing KD, suggesting that T cell-mediated immune responses may play a key role in disease development. Several studies have examined the role of the HLA region in KD, with varying results. For instance, in a GWAS conducted on the Japanese population, HLA-DQB2-DOB at the rs2857151 locus was found to be significantly associated with the risk of KD [13]. It has been observed that specific HLA genotypes are related to certain populations in the context of susceptibility to KD. HLA types B5, B44, Bw51, DR2, and DRB3*0301 are reportedly associated with KD in Caucasians [14,15]; B54, Bw15, and Bw35 are associated with KD in Japanese individuals [16]; and Bw51 is associated with KD in Israeli individuals [17].

In contrast to the Japanese, the Korean population was found to have a higher prevalence of HLA-B35, B75, and Cw09 alleles, making them more susceptible to KD [18]. Nonetheless, the correlation with specific HLA-B alleles, which have been documented in some populations, has not been reliably validated in others [19]. Huang et al. reported the link between the MHC class I chain-related gene A (MICA) gene in a Southern Chinese population and suggested that the allele A4 has a protective role against developing CAA in children with KD [20].

Despite numerous research studies, the precise HLA allele or haplotype that confers vulnerability to KD has yet to be consistently identified. This inconsistency and variability across the population make it imperative for future researchers to study and better understand the role of HLA and MHC regions in KD.

2.1.2. FCGR2A

The term “Fc receptor” (abbreviated as “FcR”) refers to a transmembrane glycoprotein that binds to the Fc segment of IgG and is a member of the immunoprotein superfamily. The FCGR2A gene encodes the Fc gamma receptor IIa (FcγRIIa), which is expressed on the surface of various immune cells, including macrophages, neutrophils, and platelets, that bind to the Fc region of antibodies. When the Fc region of an antibody binds to FcR on an immune cell, it can activate a variety of cellular effector molecules and functions. Various GWASs have identified SNPs that result in amino acid substitutions and may increase susceptibility to KD across diverse ethnicities; however, the effect is more pronounced in Europeans and Asians. A plethora of studies have reported that a substitution of arginine for histidine at position 131 (H131R) in the FCGR2A gene results in an altered binding affinity of FcγRIIa, which in turn leads to an altered immune response. In a study, it was observed that individuals with the AA genotype demonstrated a higher efficacy in IgG2-mediated phagocytosis than those with the GG genotype [21].

According to Khor and colleagues, the A allele of the polymorphism rs1801274 is associated with an increased risk of KD. Onouchi and colleagues reached a similar conclusion [7]. Furthermore, a comparison of genotypes revealed that individuals with the AG + GG genotypes exhibited a trend toward a lower odds ratio for KD compared to those with the AA genotype. However, this difference did not reach statistical significance [16]. In contrast, Kwon and colleagues [21] found no substantial link between polymorphism and susceptibility to KD in females; other studies have similarly reported no apparent effect of the polymorphism rs1801274 on the overall occurrence of KD [22,23,24].

A recent meta-analysis revealed that the CD32a polymorphism rs1801274 allele A and the AA genotype could significantly alter susceptibility to KD, especially in Asians. In particular, the polymorphism increased the disease incidence in every subgroup under the corresponding genetic models following stratification analyses by ethnicity and control source, respectively, in addition to the total analysis under all five comparisons of AA vs. GG, AA + GA vs. GG, AA vs. GG + GA, A vs. G, and GA vs. GG [25,26]. Overall, the role of FCGR2A in KD remains unclear, and further studies are necessary to understand the relationship between this gene and the disease fully.

2.1.3. CD40/CD40L Pathway

CD40 is a co-stimulatory receptor expressed on antigen-presenting cells (APCs) like dendritic cells, macrophages, and B cells, while CD40L (also known as CD154) is primarily expressed on activated T helper cells. Owing to its involvement in B cell activation, T cell differentiation, and antibody production, it has a significant role in the pathogenesis of various autoimmune and inflammatory diseases. The excessive activation of immune cells, leading to inflammation and vascular injury, particularly in the coronary arteries in KD patients, has also been found to be an effect of the CD40/CD40L pathway.

Studies indicate that a higher expression of CD40L on CD4+ T cells and platelets is significantly associated with the occurrence of CAL in KD patients [27]. A decreased expression of CD40L after treatment with intravenous immunoglobulin (IVIg) suggests the modulation of this pathway and may mitigate the vascular damage associated with KD. Onouchi et al. reported that the presence of specific genetic polymorphisms (IVS4+121 A>G) in the CD40L gene has also been linked to an increased risk of CAL, particularly in male patients [28]. In contrast, Huang et al. found that a similar variant had no impact on Taiwanese children [29]. Nevertheless, an independent cohort of Taiwanese patients with rs1535045 was found to have a higher risk of developing CAA [30]. More recently, a study from Chandigarh, North India, reported no significant variation in the expression of CD40 and CD40 SNPs (rs4810485 and rs153045) between KD patients and healthy controls [31].

2.1.4. IL-1β (Interleukin-1 Beta)

IL-1β plays a crucial role in the inflammatory process by promoting the recruitment of immune cells, the production of other cytokines, and the activation of endothelial cells, which contributes to the initiation and resolution of inflammation. IL-1β not only promotes the inflammatory cascade but also affects endothelial cells and vascular smooth muscle cells, potentially leading to vascular injury and the development of coronary artery aneurysms, which are some of the most severe complications of KD.

Several single-nucleotide polymorphisms (SNPs) have been identified in the IL-1β gene that may influence its expression and the subsequent inflammatory response [32]. One of the most studied polymorphisms is the IL-1β-511 C/T polymorphism, located in the promoter region of the gene. This variant has been associated with increased IL-1β expression, which may lead to a more vigorous inflammatory response in susceptible individuals. Studies have shown that the T allele of the IL-1β-511 polymorphism is linked to higher levels of IL-1β production, which may contribute to the exaggerated inflammatory response observed in KD. Similar to the -511 C/T polymorphism, the T allele of the IL-1β -31 polymorphism has been linked to increased IL-1β expression and an enhanced inflammatory response [33]. Weng et al. demonstrated that the IL-1β (511 TT and IL-1β-31 CC) genotype polymorphism is associated with the failure of early intravenous immunoglobulin treatment in Taiwanese children with KD [34]. Furthermore, IL-1β has been implicated in the development of CAAs due to its ability to promote endothelial cell activation, vascular smooth muscle cell proliferation, and the recruitment of inflammatory cells to the vascular wall. For instance, the rs16944 GG and rs1143627 AA genotypes of the IL-1β gene may substantially increase the risk of CAL development in children under 12 months [35].

2.1.5. BLK

The BLK gene (B-lymphoid tyrosine kinase) phosphorylates the ITAM (immunoreceptor tyrosine-based activation motif) residues of Igα and Igβ molecules, playing a critical role in B cell receptor signaling and influencing B cell development, proliferation, differentiation, and immune tolerance. Reduced BLK expression in peripheral B cells during the acute phase of KD may impair antibody production and promote abnormal immune complex formation, which is implicated in the vascular inflammation characteristic of KD. Recently, Chen et al. reported a significant association between rs2254546, located in the intergenic region between the FAM167A and BLK genes, and susceptibility to KD [36]. Similar findings were reported earlier [37], thereby suggesting that a genetically determined differential in the rate or type of antibody generated in response to an infection is implicated in KD [38]. Furthermore, BLK variants underscore the significance of B cell-mediated immunity in KD pathogenesis, suggesting a genetic basis for the disease that involves both humoral and cellular immune mechanisms.

2.1.6. TNF (Tumour Necrosis Factor)

Polymorphisms in the tumor necrosis factor (TNF) gene, particularly the −308 G/A variant, have been extensively studied for their association with KD susceptibility. Studies have demonstrated that individuals with the A allele are more susceptible and may have an increased predisposition to KD and contribute to vascular complications such as arterial stiffness and intima–media thickening [39,40,41,42]. The association between the TNF-α-308 polymorphism and KD risk vary by ethnicity, with some studies and meta-analyses indicating no significant link [43]. These disparities are most likely caused by genetic variation, variances in sample size, and demographic diversity.

2.2. Calcium Signaling Pathway

2.2.1. ITPKC

Inositol-1,4,5-triphosphate (IP3) is an essential second messenger that causes the sarcoplasmic and endoplasmic reticulum to release calcium (Ca). Inositol-1,4,5-trisphosphate kinase C (ITPKC), in conjunction with other kinases, phosphorylates IP3, leading to the production of inositol-1,3,4,5-tetrakisphosphate (IP4), which inhibits Ca release through IP3. Signaling cascades that activate T cells and immune cells are triggered by the Ca influx, which in turn initiates the Ca²⁺/NFAT pathway and may result in autoimmune reactions or other immunological diseases. Furthermore, any mutation in the ITPKC gene would result in an imbalance in the T cell activation pathway. Among others, the ITPKC gene has been studied extensively for its role in the pathogenesis of KD. In a landmark study, Onouchi et al. reported that a functional polymorphism (rs28493229) in the ITPKC gene is substantially linked to an elevated incidence of CAAs and a vulnerability to KD in children from both Japan and the United States [44]. Following this discovery, several studies have reported a significant association between this variant and KD in the Indian, Chinese, and Japanese populations [45,46]. The mechanistic link is attributed to an alteration in the splicing efficiency of intron 1, resulting in reduced transcription of ITPKC mRNA. The significance of the CG + GG genotype of rs2290692 in the ITPKC gene was highlighted by a meta-analysis in Indian children, which also supported this connection [47]. Further evidence of the impact of this genetic polymorphism on the development and prognosis of KD comes from studies conducted in Korean children [48]. Similar findings were strongly reinforced by a recent meta-analysis comprising 2771 cases and 5357 controls from 10 different studies across various genetic models [49]. The findings from all the studies suggest that, compared to people without the allele, those who carry the risk allele for rs28493229 have a 52% higher chance of developing KD. While multiple studies [44,45,46,47,48,50] have reported an association between rs28493229 and KD susceptibility, inconsistencies in methodology, limited statistical power, and lack of replication across diverse cohorts undermine the robustness of these results. Natividad and colleagues, on the other hand, reported that a superantigen could play a role in KD, while the HLA-DRB1 exon 2, the TNF-α-308 region, and the ITPKC SNP rs28493229 may not be linked to the disease [51]. Therefore, comprehensive subgroup analyses and replication studies are required to substantiate this genetic association.

In contrast to the abovementioned variant, the rs7251246 polymorphism of the ITPKC gene did not show any significant association with KD susceptibility. However, there was an ambiguity in the data obtained from other studies. For instance, the first study examining the association between the severity of KD and the SNP rs7251246 in the ITPKC gene revealed a strong link between the development of CAL and the SNP. A haplotype analysis further strengthened these findings [52]. Recently, Liu et al. reported that despite not being substantially associated with KD susceptibility, the ITPKC rs7251246 T > C polymorphism was strongly associated with CAA risk in children with KD. Additionally, males with the CT/TT genotype were less susceptible to thrombosis [53].

2.2.2. ORAI1

ORAI1 (calcium release-activated calcium modulator 1) is a membrane-bound Ca²⁺ channel protein encoded by the ORAI1 gene that is involved in the Ca²⁺–calcineurin–NFAT signaling pathway. The role of ORAI1 gene polymorphisms in KD was first investigated in 2011 by Lee et al., who examined five tagging SNPs in Taiwanese populations but found no significant associations with KD susceptibility, CAL, or IVIG resistance [54]. While Lee et al. pioneered the investigation of the ORAI1 gene in KD, Onouchi et al. provided the first evidence of genetic associations, highlighting ORAI1’s potential role in KD pathogenesis through calcium channel regulation [55]. They reported that the risk allele frequency of rs3741596 was 20 times higher in Japanese populations compared to Europeans. Moreover, the risk allele of rs3741596 (G), as documented in the 1000 Genomes Project, is regarded as an ancestral allele of this SNP; nonetheless, it is nearly nonexistent in gene pools in groups other than East Asians and people of African heritage. Yet, given the conservation of the LD pattern between rs3741596 and other variants, it is quite likely that the rs3741596 G allele descended from a founder haplotype.

Recently, a whole-genome sequencing analysis on a patient with a presumptive diagnosis of KD revealed two single-nucleotide variants (SNVs) in disease susceptibility genes in Japanese KD patients: ORAI1 (rs3741596) and BLK (rs2254546). The presence of these variants was found to be linked to the refractory nature of the case [38]. The results were corroborated by another study that found a gain-of-function mutation in the ORAI1 gene and a missense mutation with a minor allele frequency of <0.001 that was strongly linked to KD in a collapsing method analysis. Additional evidence suggested that these differences could lead to an upregulation of the Ca/NFAT pathway, thereby increasing susceptibility to KD [56].

2.2.3. CASP3

The role of CASP3 gene polymorphisms in KD was first investigated by Onouchi et al. in 2010 via a genome-wide association study. They identified the rs72689236 variant in the 5′ untranslated region of the CASP3 gene as a key susceptibility factor in both Japanese and US populations of European ancestry [57]. This G-to-A substitution disrupts the binding of the nuclear factor of activated T cells (NFAT), thereby impairing the regulation of T cell activation and increasing the susceptibility to KD. Furthermore, the A allele of rs72689236 abolishes NFAT binding, resulting in reduced CASP3 expression in immune cells. This alters apoptosis regulation and promotes immune hyperactivation, the cornerstone of KD pathogenesis [58]. These findings were then confirmed by meta-analyses, which reported that the A allele increased KD susceptibility (OR = 1.34–1.44) and the risk of CAL (OR = 1.51–1.59) [59]. In Taiwanese cohorts, the A allele showed a borderline association with KD susceptibility (p = 0.053–0.057) but a significant association with aneurysm formation (p = 0.009) [60]. However, no significant association was found between IVIG resistance and the other variables. In a recent study from India, individuals with the CT genotype of rs113420705 were found to be more susceptible to KD. They also ascertained that the overexpression of the C allele was associated with a greater risk of developing CAAs [61]. While ITPKC SNPs (e.g., rs28493229) influence KD susceptibility and CAA development, CASP3 variants specifically affect disease onset but not treatment outcomes [58]. A later study [57] suggested that CASP3 and calcium-signaling genes, such as ORAI1, may interact to amplify immune dysregulation in KD.

2.2.4. STIM1

STIM1 and ORAI1 form the core components of the store-operated calcium (SOC) influx pathway, which is essential for T cell activation and immune responses. A specific polymorphism in the STIM1 gene (rs2304891) was associated with coronary artery dilation in KD patients, suggesting that variations in the STIM1 gene may influence the vascular complications of the disease. However, this polymorphism was not linked to resistance to IVIG treatment [62]. A few studies have also investigated the effect of rs1561876 on KD susceptibility. Additionally, this variant is predicted to influence transcription factor binding site activity and miRNA binding site interactions, offering potential directions for future investigation [63,64]. The involvement of STIM1 gene polymorphisms in KD patients further suggests that calcium signaling and immune cell activation pathways, including the Ca²⁺/NFAT pathway, play critical roles in KD pathophysiology.

2.2.5. SLC8A1

SLC8A1 (solute carrier family 8 member A1), also known as NCX1 (sodium/calcium exchanger 1), encodes a sodium/calcium exchanger involved in maintaining intracellular calcium homeostasis. Dysregulated calcium signaling through SLC8A1 can affect immune cell activation, vascular tone, and cardiac function, processes that are implicated in the pathogenesis of KD. Multiple single-nucleotide polymorphisms (SNPs) in the SLC8A1 gene, particularly rs13017968, have been consistently associated with an increased susceptibility to KD and a higher risk of coronary artery abnormalities in diverse populations, including European and Japanese cohorts. Patients homozygous for the A (risk) allele of rs13017968 showed significantly higher rates of coronary artery aneurysms and dilation (p = 0.029) [65]. A recent study evaluated the polymorphism rs13017968 in the SLC8A1 gene and hematological parameters as predictors of KD and observed no significant difference between the KD cases and controls, unlike other studies, which could be attributed to population-specific variations. However, a trend emerged suggesting that patients with the TT genotype of rs13017968 may have a higher tendency to develop CAA compared to those with the GG genotype (

Table 1. Studies highlighting genetic association of Kawasaki disease.

Author/Year	Gene/Gene Locus	Study Population	Association with KD	Function
Association with the occurrence of KD
Onouchi et al., 2012 [13]	Intergenic region between HLA-DQB2 and HLA-DOB (rs2857151), FAM167A-BLK (rs2254546), and CD40 (rs4813003)	Japanese KD patients (n = 428); healthy Controls (n = 3379)	Strong association with KD	HLA-DQB2/DOB: MHC class I alleles mediate antigen presentation to CD4+ T cells. BLK: Tyrosine kinase involved in B cell receptor signaling and affects B cell-mediated immune response
Duan et al. 2014 [66]	FCGR2A (rs1801274), HLA-DQB2 and HLA-DOB (rs2857151), and BLK (rs2254546)	Han Chinese KD patients (n = 358); healthy controls (n = 815)	Significant association with KD	FCGR2A: The FCGR2A gene encodes FcγRIIA, a low-affinity receptor for the Fc portion of immunoglobulin G (IgG). It helps in the phagocytosis of immune complexes and activation of pro-inflammatory signaling pathways (via ITAM motifs)
OH et al. 2008 [18]	HLA-B35, HLA-B75, and HLA-Cw09 alleles	Korean KD patients (n= 74); healthy controls (n = 159)	Increased susceptibility to KD	HLA-B35/B75: MHC class I alleles mediate antigen presentation to CD8+ T cells.
Kwon et al. 2017 [21]	FCGR2A (rs1801274), SEMA6A (rs12516652), IL17REL (rs5771303)	Korean KD patients (n = 249); healthy controls (n = 1000) Replication study in 671 Japanese cases and 3553 controls	FCGR2A, SEMA6A, and IL17REL variants were significantly associated with KD in males but not in females Functional polymorphism of FCGR2A (rs1801274; p. His167Arg) of FCGR2A was significantly associated with KD in males	SEMA6A: Regulates immune cell guidance and endothelial function IL17REL: Involved in modulating immune and inflammatory responses, potentially as part of the IL-17 cytokine signaling pathway.
Wang et al. 2020 [26]	FCGR2A (CD32a) gene polymorphism (rs1801274)	Asian (meta-analysis)	Genotype AA and allele A of CD32a polymorphism (rs1801274) may increase the KD susceptibility In Asian population	-
Onouchi et al. 2004 [28]	IL-1β gene (–31T/C polymorphism)	Chinese 100 KD patients and 100 healthy controls	-31T/C polymorphism of IL-1β gene is associated with genetic susceptibility to KD. TT genotype in is associated with low risk of KD.	IL-1β gene: Encodes IL-1β, a key inflammatory cytokine and is involved in stimulating the production of other cytokines (e.g., IL-6 and TNF-α) and enhancing endothelial activation and coagulation pathways
Thiha et al. 2019 [56]	ORAI1 gene novel variants	3812 Japanese patients with KD and 2644 healthy controls	6 novel, rare, and deleterious missense variants were detected only in KD patients, including 3 cases of refractory KD	ORAI1: Regulates calcium influx in immune cells (store-operated calcium entry).
Onouchi et al. 2010 [57]	CASP3 gene variants	920 Japanese KD patients 1409 Japanese healthy controls and 249 controls of European descent	Multiple variants in CASP3 gene confer susceptibility to KD	CASP3: It encodes caspase-3, a critical executioner enzyme in the apoptosis (programmed cell death) pathway. Regulates immune cell death and tissue remodeling.
	Association with the occurrence of CAAs in KD
Duan et al. 2014 [66]	FCGR2A (rs1801274), HLA-DQB2, and DOB intergenic region (rs2857151) and CASP3 (rs11340705)	Han Chinese KD patients (n = 358); healthy controls (n = 815)	High-risk genotypes (rs1801274, rs2857151, and rs11340705) associated with significantly higher risk of CAAs	FCGR2A: The FCGR2A gene encodes FcγRIIA, a low-affinity receptor for the Fc portion of immunoglobulin G (IgG). It helps in the phagocytosis of immune complexes and activation of pro-inflammatory signaling pathways (via ITAM motifs).
OH et al. 2008 [18]	HLA-DRB1 alleles	Korean KD patients (n = 74); healthy controls (n = 159)	Significantly increased frequency of the HLA-DRB1*11 allele in KD patients with CAAs compared with healthy controls
Huang et al. 2000 [20]	MHC-class-I-chain-related gene A (MICA)	70 Chinese children with KD and 154 healthy controls	Allele A4 was significantly less frequent and allele A5 was significantly more frequent in patients with CAAs. Allele A4 protects against KD CAAs	MICA: It encodes a stress-induced ligand that binds to NKG2D, an activating receptor present on natural killer (NK) cells, CD8+ T cells, and γδ T cells
Taniuchi et al. 2005 [24]	Polymorphism of FCGR2A, FCGR3B, and FCGR3A	56 Japanese KD patients who received IVIg therapy	60% of patients with the HR and RR alleles of FCGR2A polymorphism developed CAAs compared to 23% with HH allele. HR and RR alleles may predict the progression of CAAs in KD before the initiation of IVIg therapy	FCGR3A/FCGR3 B: IgG receptors on NK cells and neutrophils. Variants may alter immune complex clearance and inflammation.
Wang et al. 2020 [26]	CD40L polymorphism	427 Japanese KD patients and 476 healthy controls	SNP in intron 4 (IVS4+121 A>G) is marginally increased in KD patients compared to controls, especially in males. CD40L may play a role in CAA development	CD40L: Ligand for CD40, expressed on activated T cells and modulates immune activation.
Onouchi et al. 2004 [28]	CD40 polymorphisms (rs4810485 and rs1535045)	381 Taiwanese KD patients and 569 healthy controls	CD40 polymorphism (rs1535045) was significantly associated with KD CD40 polymorphism (rs4810485) showed a significant association with CAAs in KD patients	CD40: Encodes a co-stimulatory receptor expressed primarily on B cells, dendritic cells, monocytes, and endothelial cells. The CD40–CD40L interaction is essential for B cell activation, proliferation, and antibody class switching
Kuo et al., 2012 [30]	IL-1B Polymorphisms (rs16944 and rs1143627)	719 Southern Chinese KD patients and 1401 healthy children	rs16944 GG and rs1143627 AA genotypes may significantly increase the risk of CAAs in children below 12 months	IL-1B: Encodes IL-1β, a key inflammatory cytokine.
Weng et al. 2010 [34]	SNPs within introns of NUMBL, ADCK4, ITPKC, and FLJ41131 genes	637 Japanese KD patients and 1034 healthy controls	ITPKC intron 1 functional SNP is significantly associated with KD and CAAs C-allele may be associated with immune hyper-reactivity in KD	NUMBL: Notch signaling modulator that plays a role in vascular development and inflammation. ITPKC: Inhibits T cell activation via Ca2+ signaling pathways. ADCK4: Mitochondrial function and coenzyme Q biosynthesis and involvement in immune cell energetics.
Liu et al., 2023 [53]	ITPKC polymorphism (rs7251246 T > C)	221 Han Chinese children with KD; 262 children as healthy controls	CC/CT genotype was significantly associated with the risk of CAA in children with KD. Those with the CC genotype had a significantly higher risk of thrombosis. ITPKC mRNA levels were lower in children with CAA that was complicated by thrombosis	ITPKC: Inhibits T cell activation via Ca2+ signaling pathways
Kuo et al., 2011 [67]	ITPKC SNP rs28493229	341 Taiwanese KD patients and 1190 controls	C-allele is associated with the susceptibility to KD and coronary artery aneurysm formation in KD	ITPKC: Inhibits T cell activation via Ca2+ signaling pathways
Kanda et al., 2021 [38]	ORAI1 (rs3741596) and BLK (rs2254546) SNPs	8-month-old Japanese boy	ORAI1 (rs3741596) and BLK (rs2254546) SNPs were associated with refractory KD in the child along with CAAs	ORAI1: Regulates calcium influx in immune cells (store-operated calcium entry).
	CASP3 SNP (rs113420705)	45 cases of KD and 50 healthy controls	C allele was significantly higher in frequency in patients with KD with CAAs	CASP3: Executioner caspase in apoptosis. Regulates immune cell death; variants associated with KD and IVIg resistance
Association with the occurrence of IVIg resistance in KD
Kuo et al., 2012 [30]	IL-1B polymorphism	156 Taiwanese KD children treated with high-dose IVIG (136 with IVIg response and 20 without IVIG response)	IL-1B (−511 TT) and IL-1B (−31 CC) genotypes may be associated with IVIG failure at initial therapy	IL-1B: Encodes IL-1β, a key inflammatory cytokine.
Onouchi et al., 2013 [68]	ITPKC (rs28493229) and CASP3 (rs113420705) polymorphisms	539 Japanese patients who received IVIg	In IVIg non-responders, the susceptibility allele of both SNPs was overrepresented. Higher risk of IVIg unresponsiveness was found in patients with at least 1 susceptible allele at both loci	ITPKC: Inhibits T cell activation via Ca2+ signaling pathways
Kuo et al., 2010 [60]	CASP3 gene SNP (rs72689236)	341 KD patients and 751 controls	The A allele of rs72689236 was found in a higher frequency in KD patients and in patients and IVIg resistance and CAAs	CASP3: Executioner caspase in apoptosis. Regulates immune cell death; variants associated with KD and IVIg resistance
Association with the occurrence of BCG site reactivation in KD
Chi et al., 2010 [46]	ITPKC SNP (rs28493229)	280 Taiwanese children with KD and 492 healthy controls	The frequency of the C-allele (GC and CC genotypes) was higher in KD patients than in controls. GC or CC genotypes had a higher frequency of Bacille Calmette–Guérin (BCG) inoculation site reactivation in the acute phase than GG genotypes, especially in patients younger than 20 months old. This suggests the activation of a hyperimmune response due to this SNP.	ITPKC: Inhibits T cell activation via Ca2+ signaling pathways
Kim et al., 2017 [48]	ITPKC and SLC11A1 gene polymorphisms	299 Korean KD patients and 210 healthy controls	ITPKC SNP (rs28493229) was associated with KD and CAAs. SLC11A1 SNP (rs77624405) was associated with KD and BCG site erythema. Gene–gene interactions were also associated with BCG site erythema.	SLC11A1: Involved in macrophage activation and response to pathogens.

KD: Kawasaki Disease; IVIg: Intravenous Immunoglobulin; CAAs: Coronary Artery Aneurysm; BCG: Bacillus Calmette–Guérin; SNP: Single-Nucleotide Polymorphism; Ca²⁺: Calcium; NK cells: Natural Killer Cells; BLK: B-Lymphoid Tyrosine Kinase; SLC11A1: Solute Carrier Family 11; ITPKC: Inositol-Trisphosphate 3-Kinase C; CASP3:Caspase-3; IL-1B: Interleukin 1 Beta; ORAI1: ORAI Calcium Release-Activated Calcium Modulator 1; NUMBL: NUMB Like Endocytic Adaptor Protein; MICA: MHC Class I Polypeptide-Related Sequence A; SEMA6A: Semaphorin 6A; FCGR2A: Fc Gamma Receptor IIa.

).

2.3. TGF-β Pathway

Transforming growth factor-beta (TGF-β) is a multifunctional cytokine that is essential for orchestrating the balance between cell growth, differentiation, immune responses, and tissue remodeling, making it fundamental to both normal physiology and disease [69]. Genetic polymorphisms in key genes of this pathway, including TGFB2, TGFBR2, and SMAD3, have been consistently associated with increased KD susceptibility, coronary artery aneurysm formation, and aortic root dilatation in multiple populations of mainly European descent [69]. Notably, an SMAD3 haplotype and the intronic SNP rs4776338 showed strong associations with KD susceptibility [70]. Transcript and protein analyses revealed dynamic changes in TGF-β pathway gene expression and TGF-β2 plasma levels during the disease course, underscoring its involvement in immune activation and cardiovascular remodeling in KD. While some studies in Asian populations confirmed SMAD3 polymorphisms’ link to KD susceptibility, associations with coronary artery lesions and IVIG resistance varied. Overall, these findings highlighted the TGF-β pathway as a key genetic and molecular contributor to KD pathogenesis and a potential target for therapeutic intervention. Furthermore, a two-locus model, wherein the combined effect of SNPs in ADAM17 and other TGF-β signaling pathway genes, including TGFβ2 and SMAD3, was studied, suggesting that they had a greater impact on KD phenotypes than single SNPs [71].

2.4. Autophagy Pathway

The dysregulation of autophagy has been implicated in aberrant immune responses and endothelial dysfunction, both of which are central to the pathophysiology of KD. Comprehensive bioinformatics analyses identified a set of 20 autophagy-related genes (ARGs) with altered expression in KD, highlighting the central role of autophagy and macroautophagy pathways in the disease’s pathogenesis. Key genes such as WIPI1 and GBA were significantly upregulated in KD patients, suggesting their potential roles as biomarkers and therapeutic targets [72]. These genes are involved in crucial autophagic processes, including autophagosome formation and lysosomal degradation, which are essential for maintaining immune homeostasis and regulating inflammation. Studies have demonstrated that impaired autophagy and mitophagy exacerbate vascular inflammation and damage in KD, contributing to the development of coronary artery lesions [73]. In KD, altered expression or polymorphisms in these genes may disrupt normal autophagic flux, leading to excessive or dysregulated inflammation that contributes to vascular endothelial injury and the coronary artery lesions characteristic of the disease. Moreover, the expression levels of autophagy genes, such as ATG16L1, were altered in KD patients, particularly those with coronary artery lesions, indicating a protective role of autophagy in mitigating vascular injury [74]. Additionally, the interplay between ARG polymorphisms and immune cell infiltration, especially involving CD8+ T cells and neutrophils, further underscores the immunomodulatory effect of autophagy pathways in KD. Furthermore, the expression levels of autophagy markers such as ATG16L1, BECN1, and LC3II were significantly lower in IVIG-resistant KD patients, and these markers served as independent risk factors for predicting resistance to intravenous immunoglobulin therapy [75].

2.5. Miscellaneous Genes

Additionally, rare variants in genes associated with inflammatory regulation and vascular biology, such as PLCG2, RIG-I-like receptors, and TGFB2, suggest that diverse pathways influence disease pathology beyond classical immune activation. A groundbreaking family-based whole-genome sequencing study revealed a Toll-like receptor gene variant (TLR6) associated with fungal antigen recognition, suggesting that pathogen–host interactions contribute to susceptibility. Distinct genetic loci have also been linked to CAAs, including variants near MMP12 and FGFR2, which affect vascular remodeling and integrity. These findings highlight a dual genetic architecture: one set of variants increases general KD susceptibility through exaggerated immune responses to infections, while another causes aneurysm formation via vascular wall destabilization (

Table 2. Recent studies highlighting novel variants associated with Kawasaki disease.

SNo.	Author	Year	Ethnicity	Sample Size	Technique Used	Result	Gene Function
1.	Zhang et al. [77]	2023	China	KD patients (n = 93); non-KD control cases (n = 91)	WES and Sanger sequencing	Rare variants in MYH14 and RBP3	MYH14: Encodes a myosin heavy chain involved in cytoskeletal structure and intracellular transport. Mutations may affect vascular integrity and inflammation. RBP3: Encodes interphotoreceptor retinoid-binding protein; mainly retinal, but mutations may suggest broader immune or inflammatory roles.
2	Zhu et al. [72]	2023	China	KD patients (n = 55); non-KD control cases (n = 37)	GeneCards Database and Gene Expression Omnibus (GEO) database	WIPI1 and GBA, which are autophagy-related genes, could serve as biomarkers and potential therapeutic targets.	WIPI1: Autophagy-related gene involved in autophagosome formation; dysregulation may contribute to immune response anomalies in KD. GBA: Encodes glucocerebrosidase and is important in lysosomal function. Mutations can affect immune regulation via lysosomal pathways.
3	Wang et al. [78]	2022	China	KD patients (n = 1335); healthy controls (n = 1669)	Multiplex PCR for genotype of rs7404339 polymorphism in CDH5	Increased susceptibility in individuals with the AA genotype of rs7404339 in CDH5	CDH5 (VE-cadherin): Critical in endothelial cell adhesion and vascular integrity. Variants may lead to increased endothelial permeability and inflammation.
4	Yu et al. [79]	2022	China	IVIg-responsive KD patients (n = 795); IVIg-resistant KD patients (n = 234)	RT-PCR	The EIF2AK4/rs4594236 AG/GG genotype has a higher risk of IVIg resistance compared to the AA genotype.	EIF2AK4 (GCN2): Regulates translation under stress. Implicated in immune modulation and possibly IVIg resistance in KD.
5	Lu et al. [80]	2022	China	KD patients (n = 996)	ZNF112/rs8113807 and ZNF180/rs2571051 genotyping by RT-PCR	C and T carriers of ZNF112/rs8113807 and ZNF180/rs2571051, respectively, had a higher risk of IVIg resistance in KD.	ZNF112/ZNF180: Zinc finger proteins likely involved in transcription regulation. Altered expression may impact immune cell gene networks and inflammation.
6	Buda et al. [81]	2021	Poland	KD patients (n = 119); controls (n = 6071)	GWAS	Increased susceptibility to KD is linked to rs12037447 in a non-coding sequence, rs146732504 in KIF25, rs151078858 in PTPRJ, rs55723436 in SPECC1L, and rs6094136 in RPN2.	KIF25: Motor protein involved in mitotic spindle organization. May indirectly influence immune cell proliferation. PTPRJ: Protein tyrosine phosphatase involved in immune signaling and cell growth regulation. Implicated in vascular and immune response modulation. SPECC1L: Plays a role in cytoskeleton organization. Could affect immune cell migration or vascular structure. RPN2: Part of the oligosaccharyltransferase complex. Involved in protein glycosylation, possibly influencing immune function.
7	Li et al. [82]	2021	China	KD patients (n = 818); healthy controls (n = 1401)	Multiplex polymerase chain reactions	The T allele carriers of the platelet glycoprotein Ia/IIa may have a reduced risk of CAAs in KD patients, particularly in females and children under 60 months.	ITGA2 (Glycoprotein Ia/IIa): Platelet receptor involved in thrombosis. Variants may modulate the risk of coronary artery abnormalities (CAA).
8	Hoggart et al. [83]	2021	UK	KD patients (n = 200); controls (n = 276)	GWAS	An intergenic region on Chr. 20 is significantly associated with the formation of CAAs.	-
9	Wang et al. [84]	2021	China	KD patients (n = 760)	6 polymorphisms of the MRP4 gene using TaqMan methods	The c allele of the MRP4 rs1751034 is associated with increased risk of IVIg resistance in KD patients	MRP4: Encodes an ATP-binding cassette (ABC) transporter involved in the efflux of various endogenous and exogenous substances, including inflammatory mediators and drugs. Altered MRP4 function may impact immune regulation and drug responsiveness, thereby contributing to IVIg resistance
10	Lin et al. [85]	2021	China	KD patients (n = 1459); controls (n = 1611)	FNDC1 rs3003174 polymorphism	The C>T polymorphism may contribute to the development of CAAs in KD patients.	FNDC1: Encodes a protein that contains fibronectin type III domains, which are often involved in cell adhesion, growth, and signaling. It has been implicated in vascular remodeling and the regulation of the immune system.
11	Kuo et al. [86]	2020	Taiwan	KD patients (n = 49); healthy controls (n = 24); disease controls (n = 24)	Transcription levels of HP, CLEC4D, and GPR84 by RT-PCR	Increased expression of CLEC4D, GPR84, and HP genes in peripheral leukocytes may indicate acute-phase KD when compared to control patients.	HP, CLEC4D, GPR84: Acute-phase and immune signaling proteins. Upregulation is associated with involvement in innate immunity during KD.
12	Shi et al. [87]	2020	China	KD patients (n = 101); healthy controls (n = 105)	Three PPIA SNPs were genotyped by PCR	Individuals with promoter SNP (rs17860041 A/C) are more susceptible to KD in Chinese children	PPIA (Cyclophilin A): Facilitates protein folding and is involved in immune cell signaling. Promoter variants may enhance susceptibility to inflammation.
13	Nie et al. [88]	2020	China	KD patients (n = 173); healthy controls (n = 101)	Gene Expression Omnibus database	CXCL8, CCL5, CCR7, CXCR3, and CCR1 may have a significant role in the pathogenesis of KD	CXCL8, CCL5, CCR7, CXCR3, CCR1: Chemokines and receptors involved in leukocyte migration. Their dysregulation contributes to vascular inflammation in KD.
14	Wu et al [89]	2020	China	KD patients (n = 100); healthy controls (n = 102)	RT-PCR for studying the polymorphism in the MnSOD gene	Allele A in the MnSOD gene rs5746136 may be a risk factor for developing KD	MnSOD (SOD2): Antioxidant enzyme protecting cells from oxidative stress. Polymorphisms may influence inflammatory response severity.
15	Wang et al. [90]	2020	China	IVIg-resistant KD patients (n = 148); IVIg-responsive KD patients (n = 611)	5 polymorphisms of P2RY12: rs9859538, rs1491974, rs7637803, rs6809699, and rs2046934 by PCR	The rs6809699 polymorphism in P2RY12 could predict IVIg resistance in KD patients	P2RY12: Platelet receptor for ADP. Involved in clot formation and inflammation; variants may predict IVIg resistance.
16	Amano et al. [91]	2019	Japan	Complete KD patients (n = 75); incomplete KD patients (n = 7); and allergic subjects (n = 99)	Pooled genome sequencing	SNV rs563535954, located in the IL4R locus, could serve as a predictive indicator of IVIg unresponsiveness	The IL4R gene encodes the alpha chain of the interleukin-4 receptor, which binds both IL-4 and IL-13—key cytokines involved in Th2 immune responses, B cell proliferation, and immunoglobulin class switching. IL4R is critical in regulating allergic inflammation, antibody production, and immune homeostasis.
17	Kwon et al. [92]	2018	China	KD patients (n = 713)	GWAS	The TIFAB gene SNP (rs899162) is significantly associated with CAA development (diameter ≥ 5 mm) in KD patients.	TIFAB: Encodes a regulatory protein involved in modulating innate immune signaling, particularly through interaction with TRAF6, a key adaptor in the Toll-like receptor (TLR) and IL-1 receptor pathways. TIFAB negatively regulates TRAF6-mediated NF-κB activation, a major pathway in inflammation.
18	Ahn et al. [93]	2018	Republic of Korea	KD patients (n = 265); controls (n = 203)	Whole-genome sequencing	rs 412125 in HMGB1 may contribute to CAA and IVIg resistance in KD patients.	HMGB1: A nuclear protein that acts as a damage-associated molecular pattern (DAMP), triggering inflammatory responses
19	Zha et al. [94]	2018	China	KD patient (n = 120); healthy subjects (n = 126)	RT-PCR	The rs2910164 of miR-146a G/C genotype and rs57095329 of miR-155 A/G allele were found to be risk factors for CAL.	miR-146a: A microRNA regulating NF-κB pathway. Polymorphisms may lead to exaggerated inflammation. miR-155: Regulates immune response; alterations linked to autoimmune and inflammatory diseases.
20	Kim et al. [95]	2018	Republic of Korea	IVIg-resistant KD patients (n = 148); IVIg-responsive KD patients (n = 845)	GWAS	rs28662 in the SAMD9L is significantly associated with IVIg resistance in KD	SAMD9L: Associated with cell growth suppression and immune regulation. A variant may predispose individuals to IVIG resistance.

KD: Kawasaki Disease; IVIg: Intravenous Immunoglobulin; CAAs: Coronary Artery Aneurysm; GWAS: Genome-Wide Association Study; RT-PCR: Real-Time PCR; SAMD9L: Sterile Alpha Motif Domain Containing 9 Like; HMGB1: High Mobility Group Box 1 Protein; TIFAB: TRAF-Interacting Protein With Forkhead-Associated Domain, Family Member B; IL4R: Interleukin 4 Receptor; P2RY12: Purinergic Receptor P2Y12; MnSOD: Manganese Superoxide Dismutase; PPIA: Peptidylprolyl Isomerase A; HP: Haptoglobin; CLEC4D: C-Type Lectin Domain Family 4 Member D; GPR84: G-protein Coupled Receptor 84; FNDC1: Fibronectin Type III Domain Containing 1; MRP4: Multidrug Resistance-Associated Protein 4; ITGA2: Integrin Subunit Alpha 2; KIF25: Kinesin Family Member 25; PTPRJ: Protein Tyrosine Phosphatase Receptor Type J; SPECC1L: Sperm Antigen with Calponin Homology and Coiled-Coil Domains 1 Like; RPN2: Ribophorin II; ZNF112: Zinc Finger Protein 112; EIF2AK4: Eukaryotic Translation Initiation Factor 2 Alpha Kinase 4; CDH5: Cadherin 5; GBA: Glucosylceramidase Beta; WIPI1: WD Repeat Domain, Phosphoinositide Interacting 1; MYH14: Myosin Heavy Chain 14; RBP3: Retinol Binding Protein 3.

). Epigenetic modifications, including DNA methylation changes in regulatory regions of immune-related genes, are also being explored for their role in modulating disease onset and progression [76]. These emerging insights highlight the polygenic and multifactorial nature of KD pathogenesis, underscoring the need for further studies that integrate multi-omics approaches—combining genomics, transcriptomics, and epigenomics—to unravel the intricate genetic networks involved. Furthermore, the overlap between KD-associated genes and those involved in multisystem inflammatory syndrome in children (MIS-C) post-COVID-19 further emphasizes shared pathways in immune dysregulation [73]. Understanding these lesser-known genetic contributors not only enhances the biological understanding of KD but also opens the door for the development of more precise diagnostic biomarkers and targeted therapies, ultimately improving patient outcomes and paving the way for personalized medical strategies in pediatric vasculitis. As the genetic landscape continues to unfold, the potential for earlier diagnoses and more effective interventions in KD increases.

2.6. Host Defense and Microbial Interactions

KD has been hypothesized to result from an abnormal immune response to an infectious agent in genetically predisposed individuals. Although no specific pathogen has been definitively linked to KD, the seasonal patterns and clustering of cases support an infectious etiology, likely involving common viral or bacterial agents that initiate an exaggerated immune response. The innate immune system, particularly components that recognize pathogen-associated molecular patterns (PAMPs), is central to this response. Toll-like receptors (TLRs), particularly TLR2, TLR4, and TLR9, have been implicated in KD, as they mediate the recognition of bacterial and viral components, leading to the production of pro-inflammatory cytokines. Polymorphisms in these TLR genes may modulate host susceptibility by altering signaling pathways that regulate inflammation [96]. Another key player is the NLRP3 inflammasome, which regulates the maturation of IL-1β, a cytokine strongly linked to vascular inflammation in KD. Variants in NLRP3 and other inflammasome-related genes can enhance this response, potentially contributing to coronary artery complications [97]. A study has investigated the role of the NLRP3 inflammasome in a murine model of KD-like vasculitis induced by the water-soluble fraction of Candida albicans (CAWS) and concluded that NLRP3 inflammasome-driven IL-1 production is necessary for vasculitis development. The same study also discovered that both the priming and activation of the NLRP3 inflammasome were mediated by the Dectin-2/Syk/JNK/NF-B pathway and the Dectin-2/Syk/JNK/mitochondrial reactive oxygen species (mtROS) pathway, respectively [98]. In a global gene expression study, the whole-blood transcription profiles of KD patients in the acute (pre-treatment) and convalescent phases were examined, revealing a significant upregulation in the mRNA levels of TIFA, NLRP3, CASP1, CASP4, CASP5, and IL1B. The findings from this study again highlight the significance of the IL-1 signaling pathway, as well as a prominent signature of innate immunity and cell migration, in the acute phase of the illness [99]. These findings thus shed light on the role and mechanism of the NLRP3 inflammasome in the pathophysiology of KD, suggesting that the NLRP3 inflammasome may be a therapeutic target. Additionally, genes such as IFIH1 (which encodes MDA5, a viral RNA sensor), RIG-I, and OAS1 are part of the host’s antiviral defense. They may affect the severity of KD depending on the individual’s response to viral infections [2]. The interplay between these genetic factors and microbial agents may trigger an uncontrolled inflammatory cascade, ultimately resulting in the vascular injury characteristic of KD.

2.7. Impact of Genetic Variants on KD Susceptibility, CAAs, IVIg Resistance, and BCG Site Reactivation

A wide array of genes has been associated with the pathogenesis and clinical manifestations of KD, including susceptibility, CAAs, IVIg resistance, and BCG site reactivation (Table 1). Key immune-related genes such as ITPKC, CASP3, FCGR2A, CD40, and IL-1β have been consistently linked to KD susceptibility. For instance, polymorphisms in ITPKC (rs28493229) and CASP3 (rs113420705) predispose individuals to KD and correlate with IVIg resistance and CAAs. The FCGR2A (rs1801274) variant modulates phagocytosis and inflammatory response, influencing KD risk and CAA development. IL-1β polymorphisms are associated with increased inflammatory cytokine production and resistance to IVIg. Genes such as CD40 and CD40L further influence endothelial inflammation and immune activation, thereby affecting coronary outcomes. Additionally, BCG reactivation—a classical yet underrecognized clinical sign in KD—has been genetically linked to ITPKC and SLC11A1 polymorphisms. This phenomenon, most common in infants and young children, indicates hyperresponsiveness of innate immunity and is considered a surrogate marker of immune dysregulation in genetically susceptible individuals.

2.8. Gene–Environment Interactions

Although genetic susceptibility plays a significant role in KD, environmental triggers, such as viral or bacterial infections, are believed to be crucial in initiating the disease in genetically susceptible individuals. The identification of gene–environment interactions is a growing area of research. For example, it has been proposed that an infectious agent may trigger a dysregulated immune response in individuals with specific genetic predispositions, leading to the development of KD [4,5,6]. Moreover, geographic variations in KD incidence suggest that environmental factors, such as exposure to specific pathogens, may modulate the expression of genetic risk factors.

2.9. Advances in Genetic Testing and Personalized Medicine

The identification of genetic variants associated with KD has significant clinical implications. Understanding an individual’s genetic predisposition could help predict disease severity, make treatment decisions, and potentially identify those at higher risk for CAAs. For instance, genetic screening may allow for the identification of patients at higher risk for developing aneurysms, enabling early interventions with more aggressive treatment strategies, such as IVIG and corticosteroid therapy. Standard therapy (IVIG + aspirin) is effective in most patients, but ~10–20% are IVIG-resistant and have a higher risk of complications. Given the heterogeneity of immune responses in KD, personalized immune-modulating therapy offers an opportunity to optimize treatment efficacy and safety. Advances in biomarker discovery and immunophenotyping may enable the stratification of patients to receive targeted immunosuppressive or immunomodulatory interventions, such as corticosteroids, TNF-α inhibitors, IL-1 blockers, or novel biologics.

3. Future Directions

A. Functional Genomics: Understanding how identified genetic variants contribute to KD pathogenesis is essential for developing targeted therapies. Functional studies that investigate the molecular mechanisms through which these genes influence immune activation, inflammation, and cardiovascular outcomes are critical to advancing our understanding of the disease.

B. Longitudinal Cohorts and Genomic Databases: Large-scale, longitudinal cohort studies that integrate genomic data with clinical outcomes are necessary to better elucidate the role of genetics in KD. These studies could help identify biomarkers predicting disease course and treatment response.

C. Therapeutic Implications: As the genetic landscape of KD becomes clearer, targeted therapies that modulate the immune response or address specific genetic defects may offer new avenues to better treatment. Personalized medicine, guided by genetic profiles, may enhance the effectiveness of interventions and reduce the risk of long-term cardiovascular complications.

4. Conclusions

KD remains a major challenge in pediatric healthcare, with its complex pathogenesis involving genetic, immune, and environmental factors. Advances in genetic research have provided significant insights into the disease’s molecular basis, particularly regarding immune system regulation and host defense mechanisms. While much progress has been made, further studies are necessary to understand the intricate genetic networks involved in KD fully. As our knowledge expands, there is hope that genetic-based approaches will not only improve diagnosis and risk stratification but also pave the way for more effective, personalized therapies for KD patients.