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Clin Exp Immunol. Oct 2007; 150(1): 83–90.
PMCID: PMC2219275

Polymorphisms in chemokine receptor genes and susceptibility to Kawasaki disease


Kawasaki disease (KD) is an acute vasculitis occurring in young children. Its aetiology is unknown, but an infectious agent is assumed. Increased levels of proinflammatory cytokines and chemokines have been reported in KD. Genetic variation in these genes and the receptors for these genes could influence the regulation of cytokines and chemokines. In a case–control study of 170 Dutch Caucasian KD patients and 300 healthy Dutch Caucasian controls, common genetic variants in chemokine receptor genes CCR3, CCR2, CCR5, CX3CR1, CXCR1 and CXCR2 were analysed. Of the eight studied single nucleotide polymorphisms (SNPs) in the CCR3–CCR2–CCR5 gene cluster, four showed a significant association with susceptibility to KD. Moreover the CCR5-Δ32 was observed with an allele frequency of 10·7% in the control population compared to 6·5% in the KD patients (P = 0·04). Two haplotypes of the CCR3–CCR2–CCR5 gene-cluster appear to be at risk haplotypes for KD and one a protective haplotype. No association was observed with the studied SNPs in CX3CR1, CXCR1 and CXCR2. In conclusion, in a Dutch cohort of KD patients an association of KD occurrence with common genetic variants in the chemokine receptor gene-cluster CCR3–CCR2–CCR5 was observed.

Keywords: chemokine receptor, chemokines, Kawasaki disease, single nucleotide polymorphism


Kawasaki disease (KD) is an acute systemic vasculitis occurring in young children. The diagnosis is based on clinical symptoms, including fever for at least 5 days, cervical lymphadenopathy, bilateral conjunctivitis, rash, inflammation of the mucous membranes and peripheral oedema. Although the disease is self-limiting, in 20–25% of the cases coronary artery lesions (CAL) develop when no treatment is given. Currently, KD is the leading cause of acquired heart disease in children in North America and Europe [13]. Risk factors for the development of CAL are young age at diagnosis, late onset of treatment and male sex [4]. Although the aetiology of KD is enigmatic, most clinical and epidemiological data suggest an association with an infectious agent. The striking differences in annual incidence between Japan (135–150 per 100 000) and America and Europe (5–20 per 100 000) suggest that there is a genetic component as well, particularly as an increased risk has been observed in siblings and twins [1].

In children with KD, increased levels of proinflammatory cytokines [interleukin (IL)-6, tumour necrosis factor (TNF)-α] [58] and chemokines [IL-8, monocyte chemoattractant protein (MCP)-1, regulated upon activation normal T cell expressed and secreted (RANTES)] have been reported [911]. Genetic variations, i.e. single nucleotide polymorphisms (SNPs), in these genes and the receptors for these genes could influence the regulation of cytokines and chemokines. Hence, it is plausible that common genetic variants in these genes could contribute to susceptibility to KD, similar to human immunodeficiency virus (HIV) infection and autoimmune disorders.

The genes coding for chemokine receptors (CCR) 2, 3 and 5 are located in a gene cluster (CCR3–CCR2–CCR5) spanning 285 Kb on chromosome 3p21.3 [12]. The CCR5 gene encodes a receptor for the chemokines macrophage inflammatory protein (MIP)-1α, MIP-1β and RANTES. A 32-base pairs (bp) deletion in the gene (CCR5-Δ32), resulting in a frameshift and premature termination of translation of the transcript, affords protection against human immunodeficiency virus (HIV) infection. Moreover, individuals heterozygous for CCR5-Δ32 show a delayed progression of HIV disease [13]. Population studies have shown significant differences in the minor allele frequency by geographical region. For instance, in European populations the average allele frequency is estimated to be 10%, whereas in Asian populations the 32-bp deletion is rare [14]. Moreover, Burns et al. report about a striking, inverse relationship between the worldwide distribution of the CCR5-Δ32 allele and the incidence of KD [15]. They state that genetic variation in CCR5 plays an influential role in KD susceptibility but that the results need to be confirmed in an independent cohort. A common non-synonymous SNP in the CCR2 gene results in the substitution of valine with isoleucine at position 64 (V64I), and has also been associated with delayed progression of HIV. CCR2 encodes a chemokine receptor for MCP-1. CCR3 is a receptor for various chemokines, i.e eotaxin, RANTES and MCP-2, and is expressed predominantly on eosinophils, basophils and T helper 2 (Th2) lymphocytes. A synonymous SNP in exon 3, at amino acid position 17 (Y17Y), of the CCR3 gene has been associated with asthma in a British population and not in a Japanese population. In Japanese the observed allele frequency of this SNP was low (0·03) [16].

The receptor for fractalkine is CX3CR1 (3pter-p21). Fractalkine is a transmembrane chemokine, which induces both adhesion and migration of leucocytes. Two common SNPs have been identified in the CX3CR1 gene, V249I and T280M, with allele frequencies of 25·7% and 13·5%, respectively, in Caucasians [17]. The haplotype 249I/280M is associated with rapid HIV progression; moreover, 249I has been shown to be an independent risk factor for coronary artery disease [17,18]. Finally, the neutrophil-chemokine, IL-8, has two receptors, IL-8 receptor alpha (CXCR1) and beta (CXCR2), both located on chromosome 2q35. CXCR2 also binds alternative ligands such as GRO-α, -β, and -γ and NAP-2.

The aim of this study was to determine if common genetic variants in the chemokine receptors CCR2, CCR3, CCR5, CX3CR1, CXCR1 and CXCR2 are associated with susceptibility to KD.

Subjects, materials and methods

The study population included 170 Caucasian KD patients, who were referred by paediatricians and paediatric cardiologists from the hospitals in the Amsterdam area between January 1992 and January 2004. The diagnosis of KD was confirmed if fever persisted for more than 5 days and four of the five ‘classical’ clinical criteria had occurred [1]. CAL was defined as coronary arteries with a diameter of 3 mm or greater for children up to 5 years of age. A diameter of 4 mm was used in children over 5 years of age [19]. Evaluation was carried out with echocardiography in all KD patients. The KD group consisted of 108 boys and 62 girls. The median age of KD patients was 23 months (range 1·1–188·3). Therapy consisted of i.v. high-dose immunoglobulin infusion (2 g/kg) and oral aspirin, according to standard procedures [3]. Pulsed methylprednisolone was administered in 10 KD patients (15–30 mg/kg as bolus infusion, 3 consecutive days). CAL had occurred in 43 cases (25%).

As a control population DNA of 300 healthy Dutch Caucasian controls was evaluated. The study was approved by the Medical Ethical Committee of the Academic Medical Center Amsterdam, the Netherlands. Informed consent of the parents of the KD patients had been obtained before DNA was collected.

Genomic DNA was isolated with the Puregene DNA purification kit (Gentra Systems, Venlo, the Netherlands). Genotypes of three SNPs of the CCR3 gene, IVS2-509G > T, Y17Y (alias T51C) and 754 bp 3′ of STP A > T, two SNPs in exon 2 of the CCR2 gene, V64I and N260N, three SNPs in the promoter of the CCR5 gene, + 208G > T, + 303C > T and +927C > T, two SNPs in exon 2 of the CX3CR1 gene, V249I and T280M, one SNP in exon 2 of CXCR1, S276T and two in the 3′ untranslated area of exon 3 in CXCR2, +1208C/T and +1440G > A, were analysed by 5′ nuclease Taqman™ assays. The 32-bp deletion in exon 4 of CCR5 was also analysed by 5′ nuclease Taqman™ assay. A third synonymous SNP in exon 3 of CXCR2, L262L, was analysed by MGB Eclipse assay (https://snp500cancer.nci.nih.gov) [20].

Statistical analysis was performed with GraphPad Instat version 3·00 for Windows 95 (GraphPad Software, San Diego, CA, USA). For each SNP genotype and allele, distributions were compared between KD patients and controls using Fisher's exact tests. For odds ratios (OR) and 95% confidence intervals (95% CI) wild-type alleles/genotypes were taken as reference. Within the KD group, patients with and without CAL were analysed. A P-value of < 0·05 was considered as statistically significant. The Benjamini–Hochberg method was used to control for false discovery rate (FDR) [21], because multiple tests within the same data set were conducted. The FDR is defined as the expected ratio of erroneous rejections of the null hypothesis to the total number of rejected hypotheses. Haplotypes were inferred from unphased genotype data with the Baysian statistical method in phase 2·1 [22,23]. With Haplo. Stats software (version 1·1.1. written for r 1·7.1) a global and haplotype-specific test was performed to study the differences in haplotype frequencies of healthy controls and KD patients [24].


In a case–control study of 170 Caucasian KD patients and 300 healthy Caucasian controls, common genetic variants in the chemokine receptor genes CCR3, CCR2, CCR5, CX3CR1, CXCR1 and CXCR2 were analysed. The study population is not representative for the true incidence of KD, nor of CAL in the Netherlands, as the KD patients enrolled in the study on a voluntary basis.

Tables 13 shows the genotype and allele frequencies of the studied SNPs in the CCR3, CCR2 and CCR5 genes. In CCR3 a significant difference in genotype and allele frequency was observed for the G > T substitution at position IVS2-509 and for the SNP located in the 3 UTR (754 bp 3′ of STP A > T) of the gene. No difference was observed for the Y17Y (T51C) SNP. Also, a significant difference in genotype and allele frequency was observed for the CCR2-V64I variant. The allele frequency of CCR2-64I was 6·2% in the controls compared to 11·9% in the KD patients (P = 0·004), whereas no association was observed for the CCR2-N260N variant. In CCR5, a significant difference in allele and genotype distribution was observed for the 32-bp deletion. The CCR5-Δ32 was observed in 62 (10·7%) controls compared to 21 (6·5%) KD patients (P = 0·04). Heterozygous individuals were more common in the control group (18·6% controls versus 9·3% KD). For the SNP at position +927C > T a significant difference in distribution of allele and genotype frequency was also observed. The P-values from the 15 tests (i.e. for the total number of SNPs studied) were adjusted according to the FDR method [21]. After accounting for multiple comparisons, the four SNPs in the CCR3–CCR2–CCR5 gene cluster remained associated significantly with susceptibility to KD. However, the association observed for CCR5-Δ32 no longer showed any significance (uncorrected P-value 0·04, corrected P-value 0·12).

Table 1
CCR3 genotype and allele frequencies in Dutch Kawasaki disease patients and Dutch Caucasian controls.
Table 3
CCR5 genotype and allele frequencies in Dutch Kawasaki disease patients and Dutch Caucasian controls.
Table 2
CCR2 genotype and allele frequencies in Dutch Kawasaki disease patients and Dutch Caucasian controls.

No significant differences in genotype and allele frequencies were observed for any of the studied SNPs in the genes for CX3CR1, CXCR1 and CXCR2(Table 4). In a preliminary analysis of CAL in the children with KD, there were no observed associations for the genes studied (data not shown).

Table 4
CX3CR1, CXCR1 (IL-8RA), CXCR2 (IL-8RB) genotype and allele frequencies in Dutch Kawasaki disease patients and Dutch Caucasian controls.

As CCR3, CCR2 and CCR5 lie in close proximity on chromosome 3p21 (Fig. 1), haplotypes could be inferred based on the common genetic variants in the CCR3, CCR2 and CCR5 genes (Table 5). Six of the observed haplotypes were seen in both Caucasian controls and KD patients, with a frequency ≥5%. The haplotype GTTGTGACW (W = wild-type and D = deletion) was observed with the highest frequency in both groups. The haplotypes TTAGTTGCW and TTAATGATW were observed more frequently in KD patients compared to controls and therefore appear to be ‘at-risk’ haplotypes, whereas the haplotype GTTGTGACW appears to be a protective haplotype (P = 0·03, P = 0·04 and P = 0·02, respectively) (Table 5). The only haplotype carrying the CCR5-Δ32 was observed with a frequency of 0·10 in the controls compared to 0·07 in the KD patients (n.s.). Haplotypes of the SNPs in the CXCR2 gene, on chromosome 2q32, were inferred and analysed for differences in frequencies in both groups but no significant differences were observed (data not shown).

Fig. 1
Schematic representation of chromosome 3. Schematic representation of the location of the chemokine receptors CX3CR1, CCR3, CCR2 and CCR5 on chromosome 3. The distance between CX3CR1 and the CCR3CCR2CCR5 gene-cluster is approximately ...
Table 5
Haplotype frequencies of CCR3CCR2CCR5 cluster in controls and KD patients.


The aetiology of KD is complex and probably includes genetic risk factors coupled with an exposure, such as an infectious agent. Previous studies have suggested that activated monocytes and macrophages also contribute to the pathogenesis of KD. Thus, common genetic variation in chemokine receptors could influence host response, and perhaps contribute to KD. In this case–control study in a Dutch Caucasian cohort of 170 KD patients we observed an association with SNPs in the CCR3–CCR2–CCR5 gene cluster and susceptibility to KD, including the functionally characterized and relevant genetic variants CCR2-V64I and CCR5-Δ32. No association was observed with any of the SNPs studied in CX3CR1 gene, which is located on the same chromosome at a distance of approximately 8 Mb (Fig. 1).

In the literature, the CCR2-64I variant has been associated with delayed progression of HIV and lower risk of acute rejection of renal transplants [25,26]. In our study, the CCR2-64I allele appeared to be an ‘at-risk’ variant for susceptibility to KD. In a CCR2–/– gene knock-out mouse model, the absence of CCR2 leads to diminished recruitment of macrophages and dendritic cells to the site of inflammation in response to bacterial and viral infections [2729]. A role for CCR2 may be present in KD, although it is not clear whether the valine-to-isoleucine substitution alters CCR2 function or expression. From our results, it is not possible to conclude whether the ‘at-risk’ effect observed is caused by CCR2-64I itself or that alternative SNP(s) residing on the haplotype TTAATGATW are responsible.

In our Caucasian KD population, we observed a frequency of 6·5% for the CCR5-Δ32 compared to 10·7% in controls. The average frequency in Europe is 10%. In Asia, where KD occurs with a higher incidence, the 32-bp deletion is almost absent whereas in northern Europe this deletion is more common and KD is rare. Our results are intriguing because they suggest that the deletion could be protective. The deletion has been postulated to occur at high frequency in select populations as a consequence of prior infectious challenges (e.g. plague and smallpox) [30].

Burns et al. [15] have also reported about genetic variation in CCR5 and susceptibility to KD, demonstrating an inverse relationship between the worldwide distribution of CCR5-Δ32 allele and the incidence of KD. In a large family-based study using transmission disequilibrium test (TDT) analyses, an asymmetric transmission of the CCR5-Δ32 allele from 46 heterozygous parents to their affected children is observed, supporting the hypothesis that the CCR5-Δ32 allele might protect against development of KD. Our results confirm this observation using a different genetic approach of a case–control study selected for racial background (i.e. Caucasian only). The frequency of the CCR5-Δ32 allele observed in our control population is comparable with the frequency mentioned in the article by Burns et al. for the United Kingdom (10·7% versus 11·5%). Burns et al. observed a trend towards an association between the presence of the CCR5-HHG*2 haplotype (including the CCR5-Δ32 allele) and a reduced risk of CAL. We could not confirm this trend. While both studies are relatively small, population genetic differences could play a role.

Of all the known chemokine receptors, CCR3 seems to play the major role in allergic diseases, which is supported by the detection of this receptor on the cell types found in the inflamed tissue due to the attraction of chemokines: Th2 cells, mast cells, basophils and eosinophils. In patients with Kawasaki disease, an increased risk of allergy has been noted by several groups [3133], supported by a possible skewing into a Th2 profile by mRNA expression [34,35]. Moreover, in blood as well as urine, eosinophils can be detected compared to febrile control patients [36,37]. Finally, in autopsy material the coronary lesions obtained from deceased patients show infiltration of CCR3-positive cells such as eosinophils and macrophages [37]. This was a reason to study the impact of SNPs in the CCR3 gene located at chromosome 3p21 in close proximity to the CCR2–CCR5 gene cluster (Fig. 1).

Fukunga et al. [16] observed an association with CCR3 Y17Y (alias T51C) with asthma in a British population; we did not observe an association with this SNP in the CCR3 gene but instead with two other SNPs in the gene. To our knowledge the three CCR3 SNPs investigated in our study have not yet shown to have any direct functional consequence. Therefore, another SNP in or close to the CCR3 gene may be responsible for the observed association with KD. Such SNPs could reside in candidate chemokine receptor genes involved in immunity and located nearby, such as CCR9, XCR1 or, more particularly, CCR1, which is directly adjacent to the CCR3 gene [38]. CCR1 plays important roles in leucocyte trafficking, pathogen clearance and type 1/type 2 cytokine balance, acting − similarly to CCR5 − as a major receptor for the chemokines MIP-1α and RANTES [3941]. However, functional SNPs have not yet been described in the CCR1 gene.

Kawasaki disease is a vasculitis preferentially affecting the coronary arteries. Terai et al. [11] observed that the early coronary lesions were infiltrated by large numbers of mononuclear cells, predominantly macrophages, implying the recruitment of monocytes from the circulation in response to chemotactic stimuli. In the literature, chemokines have been mentioned to play an important role in the pathogenesis of coronary artery disease (i.e. arteriosclerosis, hypertension, myocardial infection) [18,42,43]. In our study population we did not observe an association with the investigated SNPs and the development of CAL. This could, however, be due to our small sample size (i.e. 43 patients developed CAL) and therefore these findings need to be validated in a larger group of patients.

In our haplotype analysis we observed one haplotype that appears to be protective (reduced risk) for KD. The haplotype that appears to be protective in our analysis does not contain the CCR5-Δ32 allele. Burns et al. also observed three haplotypes that were associated with a reduced risk of KD, two not containing CCR5-Δ32. These observations together make it more probable that not (only) CCR5-Δ32 itself is involved in the protection against disease but a SNP residing on the haplotypes GTTGTGACW is.

In conclusion, an association of KD occurrence with common genetic variants in the chemokine receptor genes CCR3, CCR2 and CCR5 was observed in a Dutch KD cohort. Moreover, such an association was not observed with CX3CR1, CXCR1 and CX3CR1.


The authors thank Michiel Tanck for his statistical advice. B. Breunis was funded by the Ter Meulen Fund, Royal Netherlands Academy of Arts and Sciences, and by ZonMw (g20_03_3gl). M. H. Biezeveld and J. Geissler were funded by the Dutch Heart Association (NHS 99·189).


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