Recent advances in research on gene polymorphisms in Kawasaki disease

Abstract

Kawasaki disease (KD) is a systemic vasculitis primarily affecting children, and represents a major cause of acquired heart disease in this population. Although the etiology of KD remains incompletely understood, existing genome-wide association studies and genome-wide linkage studies have uncovered various susceptibility genes and their associated chromosomal regions as closely related to the onset and progression of KD. With the rapid advancement of high-throughput DNA sequencing technology, an increasing amount of genomic information pertinent to KD has been discovered, offering new perspectives to investigate the pathogenesis of KD. In particular, genetic polymorphisms play a pivotal role in the immune response, coronary artery lesions, and treatment responsiveness in KD, providing fresh insights into optimizing diagnostic and therapeutic strategies. This article aimed to review and summarize the crucial role of genetic polymorphisms in the pathogenesis of KD, analyze the latest advancements in current research, and discuss the potential applications of gene polymorphism studies in the future diagnosis and treatment of KD.

Key Words: Kawasaki disease; Genetic polymorphism; Coronary artery lesion; Immune response; Environmental factors

Core Tip: Genetic polymorphisms significantly contribute to the susceptibility, pathogenesis, and progression of Kawasaki disease (KD). These genetic variations impact immune responses, coronary artery lesions, and treatment effectiveness, offering insights into personalized diagnostic and therapeutic strategies. Advances in genomic research, particularly through genome-wide association studies and gene-environment interactions, provide a promising direction to understand the complex etiology of KD and to improve treatment outcomes.

INTRODUCTION

Definition and epidemiology

Kawasaki disease (KD), or mucocutaneous lymph node syndrome, is an acute febrile exanthematic disorder characterized by inflammation of medium and small-sized arteries throughout the body. This condition typically affects children under the age of 5 and exhibits significant racial and age distribution characteristics. Common clinical manifestations include persistent high fever, bilateral non-exudative conjunctivitis, changes in the lips and oral mucosa, extremity tip lesions, rash, and cervical lymphadenopathy[1]. Additionally, KD is accompanied by pronounced immune response manifestations, particularly in pediatric patients, where its clinical features demonstrate high heterogeneity.

The pathological changes in KD involve medium and small arteries, particularly the coronary arteries, with coronary artery lesion (CAL) and coronary artery aneurysms (CAA) being the most severe complications thereof. Manifestations of CAL include coronary artery dilation, which may lead to aneurysm formation; if left untreated, these lesions can cause myocardial infarction, sudden death, or other severe cardiovascular issues[2]. Currently, intravenous high-dose immunoglobulin (IVIG) is the standard treatment for KD. By reducing the systemic inflammatory response and improving the inflammatory state of the vascular wall, IVIG can significantly decrease the incidence of CAL. However, approximately 10%-20% of patients with KD still exhibit persistent high fever or disease recurrence after IVIG treatment, and the therapeutic regimen for these patients often poses significant challenges. Therefore, finding more effective treatments to address this subset of refractory patients, particularly in terms of coronary artery damage, has become a critical issue in clinical treatment.

KD typically occurs in children aged 6 months to 5 years, with a male incidence rate of approximately 1.5 to 1.8 times that of females[3]. The epidemiological profile of KD also shows significant differences among different regions and ethnicities. Epidemiological data indicate that the incidence is highest among Asian populations, particularly in Japan, South Korea, and Taiwan, where the number of affected children is significantly higher than in European and American regions. Even within European and American regions, the incidence of KD among immigrant children of Asian descent remains higher than that of local European and American residents[4]. This racial disparity suggests that the occurrence of KD may be closely related to genetic factors.

Family history is an important risk factor for KD, especially in children with parents or siblings who have had KD and who have a significantly increased risk of developing the disease. Existing epidemiological data indicate a higher incidence in monozygotic twins, further supporting the role of genetic factors in the onset of KD. These studies reveal the multifactorial pathogenesis of KD, particularly the complex interaction between genetic susceptibility and environmental factors (such as infections and climate changes).

As research into the etiology of KD continues to deepen, an increasing number of immunological, genomic, and environmental factors are considered closely related to the onset thereof. Although a single pathogen has not yet been definitively linked to the occurrence of KD, researchers have identified multiple genetic loci associated with KD susceptibility through methods such as genome-wide association studies (GWAS). These findings provide new insights into understanding the pathogenesis of KD and may offer a theoretical basis for early clinical diagnosis and the formulation of individualized treatment plans. With the development of modern high-throughput gene sequencing technology, research on the genetic susceptibility and immune mechanisms of KD has made significant progress. Through a comprehensive analysis of genomic data, researchers have revealed that some key genes and genetic variations may play important roles in the immune response in KD. These genetic polymorphisms may affect the occurrence, development, and clinical outcomes of KD by regulating the activity of immune cells, the release of inflammatory factors, and the structural function of blood vessels (Table 1).

Table 1 Genetic polymorphisms linked to susceptibility and complications of Kawasaki disease.

Gene	SNP/Locus	Variant	Functional impact	Association with KD	Population-specific risk	Ref.
ITPKC	rs28493229	C→T	Downregulates gene expression, impairing immune regulation; affects mRNA stability/splicing	Increased susceptibility to KD and risk of CALs	Significant in both Asian and Caucasian populations	[10]
CASP3	rs113420705	G→A	Alters inflammatory cytokine clearance during apoptosis, leading to sustained inflammation	Correlated with KD severity and CALs development	Strongest association in East Asian cohorts	[11]
CD40	rs153045	T→C	Enhances T-cell/B-cell activation and macrophage-mediated inflammation via CD40-CD40L interaction	T-allele is linked to higher KD susceptibility (Asian populations); there is no significant association in North Indian populations	Ethnic variability (Asian-specific)	[12,13]
HLA	HLA-B51, HLA-C03	–	Triggers aberrant immune responses against the vascular endothelium via HLA-mediated antigen presentation	Strongly associated with KD onset and CALs (e.g., Japanese cohort)	Highly population-dependent (HLA diversity)	[14]
FCGR2A	rs1801274	A→G	Modulates IgG receptor affinity, impairing immune complex clearance	Predicts IVIG resistance and CALs progression	Pediatric KD patients (global, with varying effect sizes)	[15,16]

¹Functional impact: ITPKC and CASP3 variants disrupt immune homeostasis, promoting CALs; FCGR2A polymorphism affects intravenous high-dose immunoglobulin efficacy via Fcγ receptor modulation; HLA alleles contribute to population-specific Kawasaki disease risk due to MHC diversity.

Clinical implications: Biomarker potential: ITPKC, CASP3, and FCGR2A may predict CALs or IVIG resistance; Therapeutic targeting: CD40 and HLA pathways could inform personalized immunomodulatory strategies.

Population heterogeneity: Asian populations show stronger associations for ITPKC, CASP3, and CD40; HLA and FCGR2A effects vary by ancestry, underscoring the need for diverse genetic studies.

CAL: Coronary artery lesions; IVIG: Intravenous high-dose immunoglobulin; KD: Kawasaki disease.

In summary, the high incidence, refractory nature of KD, and its close relationship with CAL make in-depth research into its pathogenesis clinically significant. With the continuous development of genomics, immunology, and epidemiology, future research may provide new directions to better understand the pathogenic mechanisms of KD, predicting susceptible individuals, and developing novel treatment approaches.

Research background

Despite a clear understanding of the clinical characteristics, diagnosis, and treatment protocols of KD, its pathogenesis remains incompletely elucidated. The onset and progression of this disease involve multiple complex factors, including genetic susceptibility, environmental factors, and immune responses. Although clinical medicine currently has certain norms and standards for the diagnosis and treatment of KD, we still lack a comprehensive understanding of the precise pathogenesis. While the clinical manifestations and pathological features of KD exhibit high specificity, its etiology lacks a clear etiological basis.

Based on existing clinical and epidemiological research findings, the occurrence of KD may be induced by immune responses triggered by certain environmental factors (such as infections), particularly during specific seasons or pandemics (e.g., the coronavirus disease 2019 pandemic), when incidence rates significantly increase. Therefore, infection is considered one of the important triggering factors for KD onset. However, to date, researchers have yet to identify specific pathogens with a clear causal relationship to KD occurrence. Clinical observations indicate that KD demonstrates a notable seasonal pattern, typically occurring in winter and spring, providing indirect evidence for the role of infectious factors in KD onset[4]. Whether pathogenic micro-organisms such as viruses and bacteria directly participate in the occurrence of KD remains a hotly debated topic in current research and requires further in-depth exploration.

With advancements in science and technology, especially in genomics and molecular biology, increasing evidence suggests that the occurrence of KD is closely related to immune responses and exhibits a certain degree of genetic susceptibility. GWAS are important genetic research tools that have successfully revealed multiple genes closely associated with the onset of KD and the formation of its complications[5,6]. These genes and genomic regions may directly or indirectly affect the occurrence and clinical outcomes of KD by regulating immune responses, inflammatory responses, and vascular repair. For example, certain gene variants related to immune response, cellular apoptosis, and vascular repair play crucial roles in the pathological process of KD. Through large-scale sample analysis, GWAS has revealed multiple gene loci associated with KD, including HSPG2 and CDSN. These gene loci are not only related to the susceptibility of KD, but may also influence the severity of the disease and treatment response[7].

Gene polymorphism plays a significant role in individual susceptibility to KD and differences in disease outcomes. Different genotypes may lead to differential immune system responses, thereby affecting the severity of KD, the risk of CALs, and treatment responses. Genetic susceptibility provides an explanation for individual differences in KD. By analyzing variations in specific genes, researchers have discovered several genes closely related to KD susceptibility, such as those involved in immune responses, inflammatory responses, and cellular signaling conduction. Although current GWAS studies have provided numerous clues regarding the genetic background of KD, there are still many challenges in translating these research findings into practical clinical applications. Future research needs to explore genes and signaling pathways related to KD, combining clinical features and environmental factors to reveal the specific mechanisms of KD onset. This will help further improve early diagnostic capabilities for KD, develop more targeted treatment strategies, and provide a more precise basis for individualized treatment. Therefore, a deep understanding of the pathogenesis of KD is not only of great significance for early diagnosis and prevention of the disease, but also provides valuable research directions to develop new treatment methods and improve clinical treatment effects. Future research should integrate multidisciplinary data from genetics, immunology, environmental science, and epidemiology to further unravel the complex etiology of KD, laying the foundation for comprehensive prevention and control as well as individualized treatment.

RELATIONSHIP BETWEEN GENE POLYMORPHISM AND KD

Gene polymorphism refers to the existence of multiple alleles at specific loci in the genome of the same species, with the frequency of these variants exceeding 1% in the population. Gene polymorphism is characterized by single nucleotide polymorphisms, which involve changes in a single base, such as from A to G. Polymorphism can influence gene expression, protein function, and metabolic processes. KD, a common systemic vasculitis in childhood, has an uncertain exact etiology, but recent research has found that gene polymorphism plays a crucial role in disease susceptibility, pathogenesis, and the formation of complications such as CALs. Some gene polymorphisms may affect the structural integrity of coronary arteries and increase the risk of lesions by regulating the expression of inflammatory factors [e.g., interleukin (IL)-6, tumor necrosis factor-alpha] or genes related to endothelial function (e.g., MMP-9). For instance, specific variations in the HLA-B gene are significantly associated with a high risk of CALs, while polymorphisms in ITPKC may exacerbate lesion formation by modulating the Ca²⁺/NFAT signaling pathway[8]. Studies have also explored key differentially expressed genes and their regulatory pathways in KD, including immune system-related processes and inflammatory responses[9].

Polymorphism of the ITPKC gene: Rs28493229 (C→T)

Calcium signaling plays a pivotal role in regulating immune responses and cellular functions. The ITPKC gene influences T-cell activation and immune responses by participating in the regulation of calcium signaling. The mutation at the rs28493229 Locus (C→T) leads to decreased expression levels of this gene, weakening immune regulatory functions. Research has found that this mutation may affect mRNA levels and stability by interfering with RNA splicing processes, thereby triggering abnormal immune responses. This mutation has shown a significant association with susceptibility to KD and the risk of CALs in both Asian and Western populations. In particular, individuals with this mutation among patients with KD are more prone to coronary artery dilation or aneurysms[10]. These findings provide important clues to understand the immune regulatory mechanisms of KD and suggest that the ITPKC gene may serve as a susceptibility gene with profound implications for the clinical prognosis of KD.

Polymorphism of the CASP3 gene: Rs113420705 (G→A)

The mutation at the rs113420705 Locus of the CASP3 gene (G→A) may affect the clearance efficiency of inflammatory factors during apoptosis, leading to persistent or abnormal inflammatory responses, and thus increase the risk of vascular damage. Studies have shown a significant association between this polymorphism and the onset and severity of KD, particularly in East Asian populations. Since KD involves vascular inflammation and excessive activation of the immune system, polymorphisms in the CASP3 gene may increase the occurrence of CALs and other severe complications by regulating the clearance efficiency of inflammatory responses[11]. Therefore, the CASP3 gene may serve as a potential biomarker to predict the severity of KD and treatment response, especially in patients who do not respond to IVIG therapy.

Polymorphism of the CD40 gene: Rs153045 (T→C)

The T-allele at the rs153045 Locus of the CD40 gene is closely related to susceptibility to KD and the occurrence of CALs. CD40 enhances the activity of T-cells, B-cells, and macrophages through interactions with CD40 L, thereby promoting inflammatory responses. Polymorphisms in the CD40 gene exhibit variability across different populations. Some studies have shown a significant association between the T-allele at rs153045 and the occurrence of KD, especially in Asian populations, where T-allele carriers have a higher risk of KD. However, studies in other regions, such as northern India, have not found a significant correlation between this locus and KD occurrence[12,13]. These results suggest that polymorphisms in the CD40 gene may play different roles in the pathogenesis of KD across different races or regions. Future research needs to further explore the mechanism of action of the CD40 gene in the pathogenesis of KD and how it interacts with environmental factors (such as infections) to influence KD onset.

Polymorphism of the HLA gene: HLA-B51 and HLA-C03

In the pathogenesis of KD, polymorphism in the HLA gene is considered an important factor influencing immune and inflammatory responses. Subtypes such as HLA-B51 and HLA-C03 are significantly associated with the occurrence of KD and CALs. Specifically, studies in Japanese populations have shown a significant correlation between HLA-B51 and the risk of KD onset and CAL development. The HLA gene may enhance inflammatory responses, leading to immune system attacks on vascular endothelial cells, thereby promoting the onset of KD and coronary artery damage[14]. Polymorphism in the HLA gene may also be associated with treatment response and prognosis in KD, especially in patients with poor IVIG treatment response. Therefore, polymorphism in the HLA gene not only helps to reveal the immunopathological mechanisms of KD but may also provide potential biomarkers for individualized treatment.

Polymorphism of the FCGR2A gene: Rs1801274 (A→G)

The FCGR2A gene encodes IgG receptors, which are important in the immune system and involved in the clearance of immune complexes and antibody-dependent cellular cytotoxicity. The variation at the rs1801274 Locus (A→G) may affect the clearance efficiency of immune complexes by altering the affinity of IgG receptors. Studies have shown that polymorphism in the FCGR2A gene is closely related to the occurrence of KD and the risk of severe coronary artery damage. Especially in pediatric patients, individuals with the rs1801274 variation may exhibit poor IVIG treatment response and be prone to persistent inflammatory responses and CAL[15,16]. These findings provide new perspectives on KD treatment strategies, especially in the design of individualized treatment plans. Polymorphism in the FCGR2A gene may become an important basis to predict treatment responses. Detection of the FCGR2A gene may help screen high-risk patients and enable precise prediction and intervention of KD treatment responses in clinical practice.

COMBINED EFFECTS OF GENE POLYMORPHISM AND ENVIRONMENTAL FACTORS ON THE DEVELOPMENT OF KD

Infection and gene polymorphism

Infectious factors such as viruses or bacteria are important environmental triggers for the onset of KD. Numerous studies have indicated that specific infectious stimuli (e.g., viral and bacterial infections) may exacerbate the influence of gene polymorphisms related to KD on individual susceptibility by enhancing immune system responses. Polymorphisms in the ITPKC and CASP3 genes promote the occurrence of KD by enhancing immune responses and causing immune system imbalances. ITPKC gene mutations may affect the activation of immune cells by regulating calcium-signaling pathways, thereby intensifying inflammatory responses. Variations in the CASP3 gene may lead to abnormal clearance of immune responses during cellular apoptosis, thus increasing the immune system’s attack on blood vessels[10,15,17]. Interactions between infections and gene polymorphisms may result in excessive immune system activation, increasing the risk of KD onset, particularly in susceptible individuals. This gene-environment interaction may be one of the key factors in the pathogenesis of KD.

The seasonal incidence pattern of KD is associated with the seasonal prevalence of specific viruses or bacteria. Winter and spring are peak periods for respiratory viruses and other infections, and the incidence of KD significantly increases during this time, further supporting the important role of infectious factors in the onset of KD. Research on gene-environment interactions can help better understand these complex interactions and provide a basis to formulate effective prevention strategies in the future.

Diet and microbiota

The gut microbiota serves as an important immune regulatory system in the human body. Gut microbiota imbalance can profoundly affect the function of the immune system, thereby contributing to the onset of immune-mediated diseases, including KD. The gut microbiota regulates immune responses, influencing the production of inflammatory factors and the activity of immune cells. Certain dietary components, especially high-fat and low-fiber diets, may lead to gut microbiota imbalance, thereby affecting the stability of the immune system and increasing susceptibility to KD. Seasonal variations in diet may be related to fluctuations in KD incidence, especially during the transition from winter to spring. With changes in ambient temperature and periods of high infection incidence, immune system function may also be affected, leading to changes in KD incidence. The interaction between diet and gut microbiota, especially with KD-related genes (such as CD40), may be another mechanism driving the onset of KD[18]. Gut microbiota imbalance not only affects local immune responses, but may also impact systemic immune responses through the gut-immune axis, further promoting inflammatory responses. Research into gene-diet-microbiota interactions has significant potential to reveal the etiology of KD. Future studies may discover that improving the balance of gut microbiota may help reduce the risk of KD onset.

Comprehensive analysis of gene-environment interactions

By integrating research on gene polymorphism and environmental factors, especially environmental factors such as infections, diet, and climate change, a more comprehensive understanding of the pathogenesis of KD can be obtained. Comprehensive analyses of gene-environment interactions not only aid in understanding the multidimensional mechanisms of diseases, but may also provide a basis for clinically individualized risk prediction and early intervention. By analyzing the interactions between gene polymorphisms and specific environmental factors (such as infections and seasonal changes), the risk of KD onset in certain susceptible populations can be more accurately predicted, and personalized prevention and control measures can be formulated based on individual genetic backgrounds and living environments. With the combination of genomics and epidemiology, gene-environment interaction research may become a key direction in understanding the pathogenesis of KD and improving clinical treatment outcomes in the future[19].

The interaction between environmental factors and genes is associated with rheumatoid arthritis. Research related to rheumatology and immunology can be expanded by referencing KD, which also falls under immune-related conditions. Environmental factors regulate the impact of gene polymorphisms through various mechanisms such as epigenetic regulation, gene-environment interactions, and changes in metabolic states. These insights can guide clinical practice[20]. Considering the roles of both genetic and environmental factors may help reveal the complex pathogenesis of KD and provide a new perspective for the prevention, early diagnosis, and treatment of related diseases. With the deepening of multidisciplinary research and the joint application of bioinformatics and big data technologies, research into gene-environment interactions will continue to advance, providing us with more precise etiology analysis and precision treatment strategies for KD.

IMPACT OF GENE POLYMORPHISM ON DISEASE PROGRESSION AND PROGNOSIS

CAL is one of the most severe complications of KD, typically manifesting as coronary artery dilatation and CAA. These lesions can further lead to severe cardiac complications such as myocardial infarction, heart failure, and sudden death. Gene polymorphism plays a crucial role in the risk of CAL development, especially in patients who do not respond to IVIG treatment. The ITPKC gene (rs28493229) significantly increases the risk of CAL by influencing calcium-signaling pathways, particularly in patients with IVIG treatment failure, where the risk of CAL is higher. By regulating calcium ion signaling and the activation of immune cells, the ITPKC gene affects vascular inflammatory responses and repair processes, leading to coronary artery damage. In patients with IVIG treatment failure, the polymorphism of this gene may make the inflammatory response more persistent, thereby exacerbating the development of CAL[21]. The CASP3 gene (rs72689236) is closely related to the process of apoptosis, and mutations may lead to persistent inflammation by affecting cellular apoptosis and inflammatory repair processes, thereby increasing the occurrence of coronary artery dilatation and aneurysms. The polymorphism of this gene is associated with the risk of CAL in patients with KD, and it may be an important genetic factor exacerbating lesions in severe and high-risk patients[16].

IVIG is the standard treatment for KD, effectively alleviating acute inflammatory responses and reducing the occurrence of CAL. However, approximately 10%-20% of patients with KD still experience treatment failure or relapse after IVIG therapy. The FCGR2A gene (rs1801274), which encodes IgG receptors and is one of the key regulatory factors in the immune system, has an A→G mutation that may lead to the failure of IVIG treatment responses. Carriers of this variant may exhibit persistent inflammation after treatment, with CAL not effectively controlled. This variation may affect the efficacy of IVIG treatment by altering the affinity of IgG receptors, thereby influencing the clearance efficiency of immune complexes. The close relationship between the FCGR2A gene polymorphism and persistent inflammation in patients with KD suggests that this gene can serve as a potential biomarker to predict IVIG treatment responses[16].

One of the treatment goals of KD is to control inflammatory responses and prevent disease recurrence through timely immunotherapy. However, some patients still experience persistent inflammation or recurrence after treatment, increasing the risk of CAL. Polymorphism in the CD40 gene, with variants related to the regulation of immune cell activity, can lead to excessive or incompletely controlled immune responses, thereby increasing the risk of KD recurrence. Variations in the CD40 gene may lead to chronic immune responses by affecting the maintenance of immune activity, thus increasing the recurrence risk and inflammation persistence in patients with KD[13,14]. Therefore, CD40 gene polymorphism can serve as a biomarker to predict inflammation persistence and recurrence in KD, providing a reference for clinical treatment decisions.

The sequelae of KD are not limited to acute coronary artery damage but can also lead to cardiovascular problems later in childhood. The ACE gene, involved in blood pressure regulation and vascular wall remodeling, is an important genetic factor in cardiovascular diseases. Polymorphism in the ACE gene, especially variations affecting angiotensin-converting enzyme activity, may lead to hypertension and other cardiovascular problems in the later stages of KD. Variations in the ACE gene are associated with the risk of long-term cardiovascular diseases in patients with KD and may accelerate the progression of atherosclerosis in patients with CAL[22,23]. ACE gene polymorphism not only affects disease progression during the acute phase of KD but may also be an important factor in predicting later-stage cardiovascular complications of KD.

FUTURE DIRECTION

Gaps and challenges in the study of KD gene polymorphisms

Despite some progress in the study of gene polymorphisms related to KD, there remain several unresolved gaps, particularly regarding the interaction between genes and environmental factors. Environmental factors such as infections, dietary habits, and pollution have been implicated in the onset of KD, but their interaction with individual genetic susceptibility has not been fully elucidated. Inflammatory cytokines like IL-6 and IL-17 are believed to play crucial roles in the formation of CAL, yet the specific gene-environment interaction mechanisms require further investigation. The impact of gene polymorphisms on KD susceptibility, pathological development, and treatment response needs more systematic exploration.

Most existing studies focus on gene polymorphisms (e.g., GWAS analyses), and there is still a lack of integrative cross-omics research. Although studies in transcriptomics, proteomics, and epigenetics have provided valuable insights into disease mechanisms, multi-omics integration is still in its early stages, and cross-ethnic, multicenter studies are insufficient. Especially in the development of genetic biomarkers to predict long-term cardiovascular complications, relevant research has yet to reach a consensus, lacking systematic biomarkers to assess the long-term prognosis of KD.

Addressing the demand for personalized treatment, although some gene polymorphisms (such as variations in the ITPKC and CASP3 genes) have been found to affect the efficacy of IVIG, there is currently a lack of reliable genetic biomarkers widely used in clinical practice. Further research is needed in this field to develop biomarkers suitable for individualized treatment, thereby improving treatment outcomes and reducing the risk of disease recurrence or treatment failure for patients.

Prospects for advancing KD gene polymorphism research through new technologies

With the continuous development of gene-editing technologies, single-cell sequencing technologies, and big data analysis tools, KD gene polymorphism research may usher in new opportunities. CRISPR gene-editing technology provides a powerful tool to study the roles of KD-related genes in pathogenesis. By precisely editing specific loci of KD-related genes (such as ITPKC or CASP3), we can directly observe the specific effects of these genetic variations on immune responses and coronary artery damage. The application of CRISPR screening technology can not only identify new genes associated with IVIG treatment responsiveness and CAL development, but also potentially drive the development of personalized treatment strategies, such as gene therapy targeting the correction of harmful variations. Although issues related to the safety and specificity of gene editing in clinical applications still need to be addressed, this technology undoubtedly opens new pathways for precision medicine.

The introduction of single-cell RNA sequencing (scRNA-seq) technology has revealed the unique nature of immune cell type-specific gene expression in patients with KD, particularly the transcriptional characteristics in peripheral blood monocytes and coronary artery cells. This technology not only enables in-depth analysis of the roles of various immune cells in inflammatory responses but can also study the impact of gene polymorphisms on chromatin accessibility and immune regulation through epigenetic techniques combined with ATAC-seq and other technologies. As time-resolved single-cell sequencing technology continues to improve, we can dynamically observe gene regulatory networks at different stages of the acute and convalescent phases, providing more precise data support to understand the immune dysregulation in KD. However, the processing and integrated analysis of single-cell data remains challenging, and the acquisition of clinical samples and data standardization urgently need optimization.

By combining technologies such as CRISPR, single-cell sequencing, proteomics, and metabolomics, researchers can more comprehensively explore how gene polymorphisms regulate the occurrence and development of KD through molecular pathways. The introduction of artificial intelligence (AI) and machine learning technologies can help integrate high-dimensional biological data, discovering new biomarkers and potential therapeutic targets. With the deep integration of genomics and data science, the application of AI in biological data analysis will facilitate research on large-scale population samples, providing theoretical support for individualized treatment and precise prevention.

Promoting multidisciplinary collaboration to advance the study of KD gene polymorphisms

The complexity of KD necessitates interdisciplinary collaboration for its research. Through collaborative efforts in immunology, genetics, clinical medicine, and other fields, the study of gene polymorphisms can gain a deeper understanding of the pathogenesis of KD. Collaboration with immunologists can combine gene polymorphism research with the exploration of immune responses and inflammatory mechanisms, revealing the interaction between genes and environmental factors (such as infections). Close cooperation with clinicians can help researchers obtain patient data, driving the clinical translation of laboratory research results to optimize treatment regimens and improve patient prognosis.

The integration of genomics and data science is also an important direction for future research. With the widespread use of high-throughput genomics technologies (such as GWAS) and single-cell sequencing technologies, the role of data scientists in processing and analyzing complex biological data is increasingly important. Through interdisciplinary collaboration, researchers can better integrate gene polymorphism and phenotypic data, providing theoretical support to discover new biomarkers and therapeutic targets. Collaboration with epidemiologists, clinical researchers, and biostatisticians can help validate laboratory research results and provide more precise data support for individualized treatment and early diagnosis in large-scale population samples.

The continuous development of new technologies provides a new perspective for KD gene polymorphism research, and collaboration with bioengineers and technology developers will help develop new technological means. The continuous advancement of these technologies will not only enable a more precise understanding of the genetic background of KD, but also open new pathways for early diagnosis and personalized treatment. Through interdisciplinary collaboration, KD gene polymorphism research can not only promote in-depth basic research, but also accelerate the clinical translation of new diagnostic methods and treatment regimens, providing more personalized treatment options for patients with KD[24,25].

In some severe cases, the condition may further progress to CAA rupture, even triggering fatal complications such as myocardial infarction and sudden death. These complications not only threaten the life safety of affected children but also severely impact their growth and development, imposing a heavy psychological and economic burden on them and their families. Chronic complications of KD, such as hypertension and arteriosclerosis, may also persistently affect patients’ long-term health status and increase the risk of cardiovascular diseases. Therefore, early identification of susceptible populations and timely, effective intervention and treatment are crucial to reduce the susceptibility to KD and its disease progression. Polymorphisms in many genes are closely associated with the occurrence of KD, particularly those related to the formation and severity of CALs. Studying these genes is of great significance to understand the pathogenesis of KD, screening susceptible individuals, and optimizing clinical treatment. Although research on KD susceptibility genes and CAL development is gradually increasing, most studies still suffer from limitations such as small sample sizes and single-center designs. Moreover, the research content often focuses on a single gene, lacking a comprehensive analysis of multiple genes and gene-environment interactions. Research on how interactions between different genes and gene-environment interactions jointly affect the pathogenesis of KD remains scarce. Further research needs to be conducted with in-depth exploration from multiple dimensions and disciplines to reveal the complex genetic background of KD and its interaction with environmental factors. Systematic research on KD susceptibility genes and genes related to CAL development can help us better understand the pathogenesis of KD.

CONCLUSION

Research on KD susceptibility genes and CAL-related genes can not only help elucidate the pathogenesis of KD but also provide new ideas for clinical screening and treatment. With the conduct of multicenter studies with large sample sizes and the integration of multi-omics data, more precise genetic biomarkers may emerge in the future to provide stronger support for the early diagnosis, treatment, and long-term prognosis assessment of KD. This will improve the treatment outcomes and quality of life of patients with KD, reducing the burden on their families and society.