1 INTRODUCTION

Kawasaki disease (KD), an autoimmune syndrome characterized by vasculitis, is prone to emerge in children under 5 years of age and was first detected in 1967.1 Currently, acquired heart disease is most likely caused by KD in numerous developed countries.2 Multiple complications of KD affect the cardiovascular and non-cardiovascular systems. As common complications in the cardiovascular system, coronary artery aneurysms are increasingly being studied along with coronary artery dilatation.3 According to some investigations, the annual incidence of KD has gradually increased in recent years in multiple places, such as Italy, Australia, South Korea, Japan, Inner Mongolia, and Jilin.4-9 Therefore, the incidence of KD is gradually rising in most regions, which is one of the reasons for studying this disease. The number of boys suffering from KD is approximately twice that of girls, and the mean age of onset in most regions is approximately 28 months.4, 5, 9-12 In individuals with KD, the occurrence rate of coronary artery lesions (CALs) was 23.5%, 32.6%, 40.2%, 41%, and 41.4% in Australia, Athens, Inner Mongolia, Jordan, and Jilin, respectively.4, 5, 8, 13, 14

Thus far, the pathogenesis of KD has not been fully elucidated. Single or multiple pathogens could stimulate an excessive immune response in susceptible individuals, easily inducing a systemic inflammatory response, which may give rise to KD.15-17 Through the analysis of bacteria and KD in the pharynx and serum, researchers found that streptococcus might be related to the onset of KD.18 The American Heart Association introduced criteria to distinguish the classic and incomplete forms of KD from other diseases. Classic KD is diagnosed in patients sustaining a fever for at least 4 days who have ≥4 chief clinical signs. Uncommon KD presents as a fever with an unexplained cause, <4 chief clinical signs, and corresponding echocardiographic and laboratory findings.2

MicroRNAs (miRNAs) are noncoding RNA molecules of approximately 20 nucleotides that can affect the expression of some genes.19, 20 More than 25 miRNAs have been identified for differentiating patients with KD from patients with fever using next-generation sequencing. Quantitative polymerase chain reaction was selected for further analysis of some of these miRNAs, but researchers did not find a connection between miRNA-149 and KD.21 In searching the literature, we found that miRNA-149 has a definite association with some cancers, such as lung cancer, colorectal cancer, laryngeal squamous cell carcinoma, hepatocellular carcinoma, and neuroblastoma.22-26 To a certain extent, the alteration of rs2292832 T>C in miRNA-149 may cause alterations in expression and susceptibility to diseases. For example, Sun et al27 reported that in a Korean population, some miRNAs and combinations of genotype polymorphisms, such as miRNA-149 rs2292832 T>C, could contribute to the occurrence of coronary artery disease, a major complication in KD. A study in a Chinese population might obtain similar results. A previous report revealed that the rs2292832 T>C polymorphism might have a potential connection with comorbid diseases, including allergic rhinitis and asthma and allergic rhinitis alone, and these allergic illnesses are caused by disorders in the immune system, such as the abnormal activation of T cells.28 The rs2292832 T allele could enhance the severity of inflammatory bowel disease, which is similar to KD, as it is caused by abnormal activation of the immune system by a pathogen.29

Nevertheless, no study has examined the association of the miRNA-149 rs2292832 T>C polymorphism with KD susceptibility. Based on data from our medical center, we examined 532 KD children and 623 controls to carry out a case-control study and evaluate the relationship between the miRNA-149 rs2292832 T>C polymorphism and KD susceptibility in a southern Chinese population.

2 MATERIALS AND METHODS

3 RESULTS

4 DISCUSSION

There are few studies on miRNAs and KD, and there is no research on the rs2292832 T>C polymorphism and KD susceptibility. In the first genome-wide association study (GWAS) for KD, variants of several genes (such as lnx1, CAMK2D, ZFHX3, CSMD1, and tcp1) were suggested to be associated with KD susceptibility.41 In addition, SNPs in rs2254546, rs2857151, rs4813003, rs16921209, rs7922552, rs17076896, rs12068753, rs4786091, and rs2833195 and some SNPs in BLK, CD40, and FCGR2A may be relevant to susceptibility, clinical presentations (such as CAA and CAL), laboratory data (such as CRP), treatment of KD, and gender in KD in GWASs.42-48

Therefore, we examined the relationship between the occurrence of KD and the miRNA-149 rs2292832 T>C polymorphism in this case-control trial. We failed to acquire meaningful positive results that could assist future experiments. KD-related allergic diseases, inflammatory bowel disease, and coronary artery disease may be related to the rs2292832 T>C polymorphism. A study of the relationship between the rs2292832 T>C polymorphism and KD is necessary. The negative results of this article will not only assist others in excluding the possibility of this association in a southern Chinese population but will also provide similar ideas for further studies, such as studying the nexus between the rs2292832 T>C polymorphism and KD susceptibility in other populations around the world.

As mentioned above, 168 (31.58%) children suffering from CAL were reported in southern China. In Inner Mongolia, Jilin, and Jordan, the incidence of CAL in KD was approximately 40%.4, 8, 13 In Australia, the incidence of CAL in KD was approximately 23%.5 The incidences of CAL in Western countries, such as Ireland, Italy, and Athens, Greece, were 2.9%, 15.6%, and 32.6%, respectively, which was close to that in southern China.14, 49, 50 The distinct occurrence of CAL in KD patients worldwide may be related to the frequency of rs2292832 genotypes due to differences in race based on diverse hereditary susceptibility, geography, time, definition of coronary artery injury, and other factors.

Studies have shown that genetic variants may increase the susceptibility to asthma and allergic rhinitis, and asthma was suggested to be connected with the miR-149 rs2292832 T>C polymorphism in a study by Hu et al28 Similar to KD, these are all inflammatory diseases, and correlations with these diseases are possible. From a laboratory and clinical perspective, according to the relevant literature and Harada score, age, gender, plasma albumin, CRP, WBC, and Hc, all could be risk factors for CAL in KD patients.51-53 Bai et al54 reported that increased CRP levels (≥30 mg/L), hepatomegaly, ESR acceleration (≥ 40 mm/h), and IVIG ineffectiveness had a significant effect on CAL. Particularly in patients aged <24 months, age-dependent increases in the LDH level, white blood cell count, erythrocyte sedimentation rate, and platelet count in Korean patients diagnosed with KD were caused by polymorphisms in two genes, ITPKC and SLC11A1.55 The diverse incidences of CAL may be due to different averages in various laboratory indices. According to epidemiology reports from Athens, 42.2% of sufferers with classic KD had CAL, but only 4.5% of sufferers with incomplete KD had CAL.14 We suspect that the ratio of typical KD to incomplete KD is also one of the factors contributing to the diverse incidence of CAL.

The miRNA-149 rs2292832 T>C polymorphism might not have an influence on the occurrence of KD in our current research. Nevertheless, our finding of no positive relationship is needed to assess further related aspects or exclude other interferential conditions. For instance, our study subjects were limited to children in southern China, an uncharacteristic Chinese population. The effect of low-penetrance hereditary variation on the result may not have been detected because of the small sample size and relatively high morbidity. In addition, some relevant mutation sites or genes exert a substantial effect on the final result. The functions of the rs2292832 T>C polymorphism might be concealed by interacting elements.56 The mechanism of KD caused by multiple factors is still unclear.57 Therefore, our research is not convincing without other useful data, such as disease history and living environment. Based on these results, we will try to address these issues in the future.

5 CONCLUSIONS

In conclusion, we found that the miRNA-149 rs2292832 T>C polymorphism did not affect KD susceptibility in southern Chinese patients, which needs to be further investigated in other populations.

AUTHOR CONTRIBUTIONS

All authors contributed significantly to this work. JL, ZJ, XR, XG, CJ, LZ, and HZ performed the research study and collected the samples and data; JL and XG analyzed the data; XG and MC designed the research study; JL and JW wrote the study; and JL and XS prepared all the Tables. All authors reviewed the study. In addition, all authors have read and approved the study.