Kawasaki disease is an immune angioinflammatory disease characterized by a fever that persists for 1–2 weeks, conjunctivitis, redness of the lips and mouth, enlarged non-suppurative lymph nodes in the neck, and peeling of the hands and feet (Kato et al., 1975; Newburger et al., 2004). Coronary artery disease is the most common and intractable complication of KD. In the most serious cases, it can become coronary artery aneurysm (CAA) and endanger the life of patients (Tacke et al., 2014). Coronary artery lesion (CAL) caused by KD have became the most common cause of acquired heart disease in children in some countries (Newburger et al., 2004; Tacke et al., 2014; Singh et al., 2015; Kumrah et al., 2020). Therefore, intravenous gamma globulin is often used for the anti-inflammatory treatment of acute phase of KD in clinic (Gupta et al., 2001; Kumrah et al., 2020). At present, it has been more than 50 years since the first diagnosed KD case, and researches on its etiology and pathogenesis continue continuously, but its etiology and pathogenesis are still an unsolved mystery (Tacke et al., 2012). A growing number of studies have claimed that genetic variations associated with immune response function are associated with increased susceptibility to KD and development of CAL (Kuo et al., 2015; Kumrah et al., 2020).

Tumor necrosis factor α(TNF-α), a member of Tumor necrosis factor superfamily (Aggarwal, 2003), is one of the cytokines produced by immune cells during inflammation (Gupta et al., 2001; Wang et al., 2011; Kumrah et al., 2020). It is believed that it plays an indispensable role in the body’s resistance to infection and immune response (Yamaji et al., 2019; Halim et al., 2021). Numerous reports have confirmed that high level of TNF can induce inflammatory response in children with KD, and is closely related to vascular endothelial damage and the incidence of CAA in KD closely (Fiers, 1991; Aeschlimann and Yeung, 2016). In addition, Furukawa et al. (1994) showed that TNF-TNF receptor signals were abnormally activated in the acute phase of KD. Yasumura et al. (2020) found that ratio of sTNFR-I/II was lower in both the acute and non-acute phases of TNF-recurrent syndrome than that in autoinflammatory diseases including KD Mizuta et al. (2021) showed that serum levels of STNFR-1, STNFR-2, and STNFR-I/II were significantly higher in patients with KD complicated with macrophage activation syndrome than that in patients with acute KD (Jinkawa et al., 2019). Stringer and Yeung (2008) suggested that TNFRs contained several functional motifs which were interacted with intracellular proteins, directed intracellular signal transduction, and further activated transcription factors, which ultimately led to increasing expression of pro-inflammatory cytokines and leukocyte recruitment. Weiss first reported that the TNFR blocker infliximab can be used in children with KD who were resistant to Immunoglobulin C (Weiss et al., 2004). Moreover, some studies have further verified in animal experiments that the mouse model without tumor necrosis factor or using tumor necrosis factor blocker were not easy to develop CAL (Oharaseki et al., 2013). While Chien et al. (2003) found no significant correlation between TNF-α promoter region gene polymorphism and susceptibility to KD or CAL in Taiwan population. In addition, TNF and TNFRs promoter region gene polymorphisms may be associated with the occurrence of a variety of tumors (Gupta et al., 2008). More and more studies, have led us to speculate about the association between polymorphisms in other TNFR loci and KD. As a member of the tumor necrosis factor receptor superfamily, TNFRSF11A is also known as nuclear factor-κB receptor activator (RANK) (Yang et al., 2004). The RANK/RANK ligand (RANKL)/osteoprotection axis (RRO axis) was first identified in the immune system and skeletal system (Anderson et al., 1997; Lacey et al., 1998). As we all know, KD is also an immune vasculitis disease (Che et al., 2018b). However, there haven’t any reports on the relationship between TNFRSF11A gene polymorphism and susceptibility to KD and CAL. In the present study, we aimed to explore the association between TNFRSF11A (rs7239667) gene polymorphism and genetic susceptibility to KD and CAL in southern Chinese population.

In the present study, we evaluated the association between TNFRSF11A gene polymorphism (rs7239667 C) and susceptibility to KD and the severity of coronary artery damage in children with KD in 1396 patients (408 with CAA and 988 without CAA) and 1673 healthy controls. Our results showed that TNFRSF11A (rs7239667), the selected SNP, was not associated with KD susceptibility in children from southern China. Interestingly, when we compared KD patients with or without CAA, we found that TNFRSF11A (rs7239667 C) variant genotype significantly reduced the degree of coronary artery damage in KD patients.

Although the etiology and pathogenesis of KD remain unclear, systemic vascular disease is the most prominent manifestation of KD (Wang et al., 2011). A large number of studies have shown that in the occurrence of KD, TNF-α, IL-6, TNFR, and other cytokines exist, and these cytokines lead to vascular endothelial cell damage in KD patients, and eventually causing vasculitis (Furukawa et al., 1994; Wang et al., 2011; Kumrah et al., 2020). Tumor necrosis factor (TNF) can bind to TNFR and initiate inflammatory response and physiological functions (Halim et al., 2021). TNFR family is composed of TNFRSF8, OPG, DCR3, etc., and is a growing superfamily with extracellular homologous sequences (Darnay and Aggarwal, 1999; Inoue et al., 2000; Aggarwal, 2003). As an activator of NF-κB receptor, TNFRSF11A is also a member of the tumor necrosis factor receptor superfamily (Yang et al., 2019; Glasnovic et al., 2020). Yang et al. (2019) indicated that RANKL (a specific ligand of TNFRSF11A) rs2277438 polymorphism increased the risk of rheumatoid disease. Petean et al. (2019) showed that TNFRSF11A (rs3826620) and its ligand RANKL (rs9594738) gene polymorphisms were associated with Persistent Apical Periodontitis. Wu et al. (2019) deemed that TNFRSF11B (rs2073617) gene polymorphism may increase chronic infection with HCV. In a study on osteoporosis, Richards et al. (2009) showed that polymorphism at the TNFRSF11A SNP site was significantly associated with fracture risk. Omar et al. (2015) suggested that the rs2073618 gene locus polymorphism of OPG, a key protein downstream of RANK-RANKL signaling pathway, was associated with the development of breast cancer to some degree. These studies suggested that TNFRSF11A gene polymorphism may play a role in the occurrence and development of different diseases.

With the development of molecular genetic methods, it is possible to identify susceptibility genes of complex diseases using GWAS and candidate gene methods (Kumrah et al., 2020). Numerous studies have shown that many candidate genes, including FCGR2A (Kuo et al., 2015), ITPKC (Onouchi et al., 2008), VEGF (Ohno et al., 2000), IL-1B (Fu et al., 2019), and ABCC4 (Che et al., 2018a), have been identified as susceptibility genes that increase the risk of KD or coronary complications from KD. However, there is a lack of research on TNFRSF11A gene polymorphism and its relationship with KD. In our case-control study, we found that TNFRSF11A rs7239667C allele is a protective factor for CAL of KD. To our knowledge, this is the first study to validate the association between rs7239667 C allele and KD coronary complications in a population of southern China. We considered that rs7239667 C allele may play a significant role in the pathogenesis of CAL of KD.

Although this is the first study to evaluate the association between TNFRSF11A gene polymorphism and the risk of KD in children in southern China, there are some limitations that should be noted. First, we focus only on the allele associated with rs7239667 G > C of TNFRSF11A. Polymorphisms at other loci of TNFRSF11A gene were ignored. Secondly, due to the nature of the retrospective study design, we only collected cases and controls consistent with race, geography, age and gender, ignoring other factors such as the environment of parents and the presence or absence of infection in eating habits. Third, the sample size of this study is limited and this study lacks functional studies on TNFRSF11A (rs7239667). Future studies require larger sample sizes to confirm the role of TNFRSF11A in susceptibility to KD and relevant functional studies also will be included in our research plan in the follow-up work.

In conclusion, although the current study suggested an association between TNFRSF11A gene rs7239667 and the severity of coronary artery damage in KD. We still need to conduct big data, multi-center studies on the polypeptide properties of TNFRSF11A gene to further confirm our current results.

The original data supporting the relevant research in this article is in the supplementary material. For further inquiries, please contact the corresponding authors of this article directly.

This study was approved by the Medical Ethics Committee of Guangzhou Women and Children’s Medical Center (2014073009). Informed written consent was obtained from the guardians of patients.

LZ, KL, YW, and XG designed and organized the study and supervised the whole project. LP, HM, JL, ZJ, and BW contributed to field survey, data collection, laboratory detection, and quality control. DC, LF, YX, and HY performed the data cleansing and statistical analysis. XG, HY, DC, and LZ wrote and critically revised the manuscript. All authors contributed constructively to the editing and drafting of the manuscript and read and approved the final manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.