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Inflammatory Gene Polymorphisms and Susceptibility to Kawasaki Disease and Its Arterial Sequelae

^a Department of Pediatrics and Adolescent Medicine, University of Hong Kong, Hong Kong SAR, China
^b Pediatric Cardiovascular Center, Children's Hospital, Fudan University, Shanghai, China
^c Shanghai Children Medical Center, Jiao Tong University, Shanghai, China

	ABSTRACT

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OBJECTIVE. We tested the hypothesis that single-nucleotide polymorphisms of inflammatory genes C-reactive protein (CRP) and tumor necrosis factor (TNF-) may exert influence on susceptibility to Kawasaki disease and its arterial sequelae.

METHODS. We analyzed the CRP +1444 CT and TNF- –308 GA polymorphisms in 167 patients aged 8.9 ± 4.1 years with a history of Kawasaki disease (73 with and 94 without coronary aneurysms) and 124 healthy control subjects. For patients with Kawasaki disease, we further determined whether these single-nucleotide polymorphisms were associated with coronary aneurysms, carotid arterial stiffening, and intima-media thickness.

RESULTS. Genotypic and allelic frequencies of CRP +1444 for T carrier and TNF- –308 for A carrier were significantly higher in patients than in control subjects. The genotypic and allelic distributions did not differ between patients with and those without coronary aneurysms; however, patients with CRP +1444 CT/TT genotype compared with those with a CC genotype and patients with TNF- –308 GA/AA genotype compared with those with a GG genotype had significantly greater carotid arterial stiffness and intima-media thickness. Carriers of both CRP +1444 T allele and TNF- –308 A allele had the highest susceptibility to Kawasaki disease and a significant trend of increased arterial stiffness and intima-media thickness compared with those who carried either 1 or none of the rare alleles. Multiple linear regression analysis identified CRP +1444 allele carrier as a significant determinant of both carotid stiffness and carotid intima-media thickness and TNF- –308 A allele carrier as a determinant of only intima-media thickness.

CONCLUSIONS. Our findings suggest that CRP +1444 CT and TNF- –308 GA polymorphisms are associated with predisposition to Kawasaki disease and, in patients with Kawasaki disease, increased carotid arterial stiffness and intima-media thickness in the long-term.

Key Words: gene polymorphisms • Kawasaki disease • arteries

Abbreviations: KD—Kawasaki disease • IMT—intima-media thickness • CRP—C-reactive protein • TNF-—tumor necrosis factor • SNP—single-nucleotide polymorphism • HDL—high-density lipoprotein • LDL—low-density lipoprotein • SBP—systolic blood pressure • DBP—diastolic blood pressure • PCR—polymerase chain reaction • OR—odds ratio • CI—confidence interval

Arterial sequelae constitute the most important cause of morbidity and mortality in Kawasaki disease (KD). Structural¹ and functional² alterations of coronary arteries are well documented. We and others have further unveiled the impact of diffuse vasculitis on late systemic arterial dysfunction, which is characterized by arterial stiffening,^3–5 endothelial dysfunction,⁶ and increased intima-media thickness (IMT).^5,7,8 Although the cause of KD remains elusive, epidemiologic and clinical data suggest that an infectious agent is probably the inciting factor⁹ that triggers the acute inflammatory process.

Studies have underlined the importance of gene polymorphisms of inflammatory molecules in modulating disease susceptibility, outcome, progression, and complications.^10–14 The C-reactive protein (CRP) and tumor necrosis factor (TNF-) genes are of particular relevance in KD given their role in inflammation and implicated associations with vascular damage.^12,15 Although several CRP gene polymorphisms have been reported to associate with blood CRP level,¹⁶ the CRP +1444 CT single-nucleotide polymorphism (SNP) has been shown to influence not only basal but also stimulated CRP levels.^15,17,18 Importantly, recent evidence suggests that CRP may contribute directly to a proinflammatory state and vascular damage.¹⁹ Conversely, TNF- has been shown to play an important role in the pathogenesis of acute vascular injury in KD.^20,21 The finding of an association between TNF- –308 GA SNP and increased TNF- production on stimulation²² may hence be of significance with regard to arterial complications in patients with KD.

In this multicenter study, we tested the hypothesis that SNPs at the CRP +1444 and TNF- –308 loci may exert influence on susceptibility to KD and occurrence of arterial sequelae. In a large cohort of patients who had KD and were recruited from 3 cardiovascular centers in China, we determined whether SNPs at the CRP +1444 and TNF- –308 loci are associated with KD and assessed their associations with early coronary arterial damage, late systemic arterial stiffening, and carotid IMT.

	METHODS

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Subjects
Patients who had a history of KD and were followed up for >12 months since disease onset were recruited from 2 pediatric cardiac centers in Shanghai and 1 in Hong Kong, China. From the medical charts, the following data were retrieved: age at disease onset, use of intravenous immunoglobulin, interval from disease onset to time of study, coronary complications, and medications at the time of study. Coronary aneurysms were documented by echocardiography and defined according to the Japanese Ministry of Health criteria.²³ Healthy children with functional heart murmur and their healthy siblings and those who attended for health checkups were recruited as control subjects. The institutional ethics committee approved the study, and parents of all subjects gave written, informed consent.

The weight and height of the children were measured, and the BMI was calculated accordingly. All children rested for at least 15 minutes before blood pressure and arterial measurements. The blood pressure in the right arm was measured twice using an automatic oscillometric device (Dinamap [Critikon, Inc, Tampa, FL]), and the average of the 2 readings was taken. Assessment of carotid arterial stiffness and IMT was performed as described in the next section. The principal investigator (Dr Cheung) standardized the equipment, software, and ultrasound method in all 3 sites. Venous blood was then withdrawn for measurement of fasting total cholesterol, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol levels and CRP and TNF- genotyping.

Assessment of Carotid Arterial Stiffness
The carotid artery stiffness was assessed by determination of the stiffness index.²⁴ Briefly, a 7- to 15-MHz linear array transducer, interfaced to a Hewlett-Packard (Hewlett Packard, Andover, MA) Sonos 5500 ultrasound machine, was used to image the right carotid artery at 1 cm proximal to the carotid bifurcation. The systolic and diastolic diameters, measured between the intima of the near and far walls, were measured. Three measurements were averaged for calculation of the stiffness index using the formula ln (SBP/DBP)/(D/D), where ln is natural logarithm, SBP is systolic blood pressure, DBP is diastolic blood pressure, D is difference between systolic and diastolic diameters, and D is the mean diameter.

Measurement of IMT
The right common carotid artery was similarly imaged using the linear array transducer. The IMT of the right common carotid artery far wall was measured offline using the QLAB analysis software (Philips, Bothell, WA). The QLAB IMT plug-in detects automatically the intima-media pixel pairs along the far wall of the carotid artery and provides a spatially averaged measurement of IMT over a preset of 10-mm region of interest. The average of 3 measurements was used for subsequent analysis.

Genotyping
Genomic DNA was isolated from peripheral blood collected in EDTA tubes according to Miller et al.²⁵ Genotyping of CRP +1444C/T and TNF- –308G/A was performed by polymerase chain reaction (PCR) followed either by direct-sequencing or restriction fragment-length polymorphism (RFLP).

For direct sequencing, PCR products that were amplified using primer pairs (5'-CAC TGC ATG GTT CCC ACG TCT-3'/5'-CTT CCT TCT CAG CTC TTG CCT T-3' for CRP +1444C/T, 5'-TCT CCC TCA AGG ACT CAG CTT-3'/5'-CAT CCT CCC TGC TCC GAT TC-3' for TNF- –308G/A) were sequenced with BigDye Terminator 3.1 Cycle Sequencing Kit (Applied Biosystems, Foster City, CA). For restriction fragment-length polymorphism, genotyping was performed as described previously.^15,26 The CRP +1444C/T were genotyped by SduI (isoenzyme Bsp1286I) digestion of the PCR product that was amplified using primer pair 5'-AGC TCG TTA ACT ATG CTG GGG CA-3'/5'-CTT CTC AGC TCT TGC CTT ATG AGT-3'. The TNF- –308G/A was genotyped by NcoI digestion of PCR product amplified using primer pair 5'-AGG CAA TAG GTT TTG AGG GCC AT-3'/5'-ACA CTC CCC ATC CTC CCT GCT-3'.

Data Analysis
Data are presented as means ± SD unless otherwise stated. Comparisons of continuous variables between patients and control subjects were performed using Student's t test for normally distributed data. Consistency of genotype frequency with Hardy-Weinberg equilibrium was tested by using ² test. Frequencies of alleles in patients with KD and control subjects were compared using Fisher's exact test. Analyses were performed with heterozygous being grouped with the homozygous for the rare allele because of low frequency of the rare allele. Vascular parameters of children with different allelic combinations were compared using analysis of variance with posthoc Bonferroni adjustment. For patients with KD, correlates of carotid arterial stiffness and IMT were determined using univariate and multivariate linear regression. P < .05 was considered statistically significant. All statistical analyses were performed by using SPSS 11.5 (SPSS, Inc, Chicago, IL).

	RESULTS

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Subjects
A total of 291 ethnic Chinese children were studied, including 167 children with a history of KD and 124 control subjects. Of the 167 patients with KD, 73 had coronary aneurysms. All but 20 patients had received intravenous immunoglobulin therapy during the acute phase of illness. The patients were studied at a median of 5.0 years (interquartile range: 3.2–8.0; range: 0.5–21.0 years) after KD, all of whom remained asymptomatic and did not require coronary arterial interventions.

The demographic data, systemic blood pressure, and lipid profile of patients and control subjects are summarized in Table 1. There were no significant differences in age, gender, distribution, BMI, and SBP between the 2 groups. Compared with control subjects, patients had higher DBP (P = .014) and total to HDL cholesterol ratio (P = .029). Their total (P = .059) and LDL cholesterol (P = .063) levels also tended to be higher.

TNF-

View this table: [in this window] [in a new window]   TABLE 2 Genotypic and Allelic Frequencies at the CRP +1444 and TNF- –308 Loci in Patients and Control Subjects

The power of the study was calculated using the genetic power calculator by Purcell et al.²⁹ With an OR of 2 and a high-risk allele frequency of 13.8% (see Table 2), the power of this study was at least 80% when 106 children were recruited in each of the groups.

Inflammatory Gene Polymorphisms and Arterial Sequelae
No associations were found between genotypic or allelic frequencies at the CRP +1444 and TNF- –308 sites and coronary aneurysm formation (Table 3). The associations were similarly absent after exclusion of patients who did not receive immunoglobulin therapy (all P > .05).

View this table: [in this window] [in a new window]   TABLE 3 Genotypic and Allelic Frequencies at the CRP +1444 and TNF- –308 Loci in Patients With and Without Coronary Aneurysms

TNF-

The carotid IMT was significantly greater in patients than in control subjects (0.44 ± 0.04 vs 0.43 ± 0.02 mm; P = .007). Patients with a CRP +1444 CT/TT genotype had significantly greater IMT than those with a CC genotype (0.46 ± 0.05 vs 0.43 ± 0.03 mm; P < .001). Conversely, the IMT was similar between control subjects with a CT/TT genotype and those with a CC genotype (0.43 ± 0.02 vs 0.43 ± 0.02 mm; P = .76). Patients with the TNF- –308 GA/AA genotype similarly had greater IMT than those with a GG genotype (0.45 ± 0.05 vs 0.43 ± 0.03; P = .002). The difference was again not observed in control subjects (0.43 ± 0.02 vs 0.43 ± 0.02 mm; P = .68).

The possibility of a linear trend of the arterial parameters was explored using linear regression in relation to 3 different allelic combinations: (1) carrier of CRP +1444 T allele and TNF- –308 A allele, (2) carrier of either CRP +1444 T allele or TNF- –308 A allele, and (3) carrier of neither CRP +1444 T allele nor TNF- –308 A allele. A significant trend was observed in patients but not control subjects for both stiffness index (P = .004) and IMT (P < .001). Analysis of variance further revealed significant differences in these parameters among the various allelic combinations (Fig 1).

View larger version (13K): [in this window] [in a new window]   FIGURE 1 Effects of allelic combinations on stiffness index (A) and carotid IMT (B) in patients and control subjects. The allelic combinations are (1) CRP +1444 T allele + TNF- –308 A allele carrier (), (2) carrier of either CRP +1444 T allele or TNF- –308 A allele (), and (3) carrier of neither CRP +1444 T allele nor TNF- –308 A allele (). a P < .05 versus allelic combination 3 by posthoc Bonferroni test.

	DISCUSSION

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The CRP +1444 CT polymorphism has been reported to influence stimulated CRP levels.^15,17,18 In adults with periodontitis, those homozygous for the +1444 T allele have been shown to have significantly increased CRP concentrations after intensive periodontal therapy.¹⁷ In humans, the CRP concentration showed an upward tendency at 24 hours after intravenous administration of endotoxin in those with a TT genotype as compared with those with CT and CC genotypes.¹⁸ The heterozygous individuals exhibited an intermediate response, which supports a gene dosage effect. To our knowledge, this is the first report of an increased frequency of CRP +1444 CT polymorphism in patients with KD. Hence, the magnitude of the CRP response of the host in response to the hitherto unknown inciting factor that triggers an acute inflammatory process may have significant implication for development of KD. Indeed, during the acute phase of KD, CRP has been shown to be 1 of the significant predictors of resistance to intravenous immunoglobulin therapy.^30,31

Although CRP has traditionally been regarded as a marker of inflammation, evidence suggests that it may contribute directly to a proinflammatory state and vascular damage¹⁹ through stimulation of monocyte release of inflammatory cytokines and complement activation. Although we failed to demonstrate an association between the CRP +1444 CT polymorphism and early coronary aneurysm formation, it is intriguing to find that this polymorphism is associated with carotid arterial stiffness and IMT late after the acute illness. In the recently reported Cardiovascular Risk in Young Finns Study,³² men who carried the +1444 T allele were found to have reduced carotid artery compliance. A gene dosage effect was also evident: heterozygous individuals were found to have an intermediate level of carotid artery compliance. In patients with KD, we previously showed elevated high-sensitivity CRP concentration in those with coronary aneurysms in long-term follow-up⁴ and a positive association between CRP concentration and carotid arterial stiffness.⁷ Although CRP gene polymorphism may exert its vascular effect through influencing basal CRP levels, albeit available data being controversial,^15–18 it has also been proposed to modulate local CRP concentration and CRP isoforms in the vasculature.^32–34 Carotid IMT has been regarded as a surrogate marker of atherosclerosis.³⁵ In the context of KD, increased carotid IMT may represent myointimal proliferation and fibrous scarring of the arterial wall. Previous population-based studies failed to demonstrate an association between CRP genetic variance and carotid IMT.^32,36 Conversely, the positive association in KD might be explained by an exaggerated CRP response that may increase vascular damage in the acute phase in individuals with a CRP +1444 CT/TT genotype. Alternatively, the observed association might reflect the relationship between carotid stiffness and IMT in patients with KD.⁷

Notwithstanding the controversies, the majority of data suggest a physiologic role of TNF- –308 GA polymorphism in regulating TNF- gene expression.³⁷ The presence of the A allele at this locus further seems to influence clinical outcomes of diseases in which inflammation plays a predominant role.^38–40 In KD, TNF- may play an important role in the pathogenesis of vascular injury. Its level during the acute phase is highest in children in whom coronary aneurysms develop.²⁰ In vitro studies have demonstrated that TNF- renders cultured endothelial cells susceptible to lysis by circulating antibodies during KD.²¹ Furthermore, the TNF- –308 GA genotype has been shown to be overrepresented among white patients with KD and coronary artery abnormalities.¹² We failed to replicate the latter finding in our Chinese cohort. Nonetheless, we have documented for the first time that the OR for KD is significantly higher in individuals who carry the –308 A allele, a finding not revealed in previous studies with relatively small patient cohorts.^12,41,42

We have further shown that the TNF- –308 GA/AA genotype is associated with worse arterial function and increased carotid IMT in the long-term in patients with KD. Although plasma TNF- concentration has been reported to be associated with carotid IMT in healthy middle-aged men,⁴³ TNF- –308 GA polymorphism has not been shown to correlate with circulating levels of TNF-.⁴⁴ Hence, chronic elevation of plasma TNF- level is an unlikely explanation of increased IMT in our patients. Nonetheless, a key role of TNF- in inflammatory processes that may have an impact on arterial dysfunction is illustrated by reports of efficacy of anti–TNF- therapy in reducing aortic stiffness⁴⁵ and carotid IMT⁴⁶ in patients with rheumatoid arthritis.

There is further evidence of synergistic modulating effects of the CRP +1444 T allele and TNF- –308 A allele on susceptibility to KD and late arterial dysfunction. Individuals who are genetically predisposed to have a more vigorous inflammatory response may hence be predisposed to KD and its arterial sequelae. Indeed, polymorphisms in chemokine receptor genes⁴⁷ and the key lectin pathway molecule mannose-binding lectin¹¹ have been shown to influence susceptibility to KD and the latter also to modulate arterial stiffness in the long-term.⁴⁸ That arterial parameters are different between patients but similar between control subjects with different CRP and TNF- genotypes supports the proposition that genetic effects may act via KD. Our findings may hence suggest interactions between genetic programming of the dynamic response to inflammatory stimuli and the exogenous vasculitic stress in KD.

Despite recruitment of a relatively large cohort of patients and control subjects from 3 centers, the specific effects of the homozygous state for the rare alleles in both the CRP +1444 and TNF- –308 loci cannot be fully addressed in this study because of the small number of homozygous individuals. With the new data provided by the International Hapmap Project,⁴⁹ haplotypic analyses of these 2 genes and genotyping of haplotype tag SNPs would enhance the success of detecting more KD-associated variants. Furthermore, issues generated, for example, by genotyping error, copy number, and rare SNPs may also be addressed.

	CONCLUSIONS

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Our findings suggest that CRP +1444 CT and TNF- –308 GA polymorphisms are associated with predisposition of KD and, in patients with KD, increased carotid arterial stiffness and IMT in the long-term; however, the association between these SNPs and KD susceptibility and vascular outcomes can be regarded only as a preliminary observation until it is established in an independent cohort.

	FOOTNOTES

 
Accepted Apr 18, 2008.

Address correspondence to Yiu-fai Cheung, MD, Grantham Hospital, University of Hong Kong, Division of Pediatric Cardiology, Department of Pediatrics and Adolescent Medicine, 125 Wong Chuk Hang Rd, Hong Kong, China. E-mail: xfcheung{at}hkucc.hku.hk

The authors have indicated they have no financial relationships relevant to this article to disclose.

What's Known on This Subject The CRP and TNF- genes are of particular relevance in Kawasaki disease, given their role in inflammation and implicated associations with vascular damage.

 

What This Study Adds This study suggests that CRP +1444 CT and TNF- –308 GA polymorphisms are associated with a predisposition to KD and, in patients with KD, increased carotid arterial stiffness and IMT in the long term.

 

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