Published online August 18, 2008
PEDIATRICS (doi:10.1542/peds.2008-0646)
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cheung, Y.-f.
Right arrow Articles by Lau, Y.-l.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cheung, Y.-f.
Right arrow Articles by Lau, Y.-l.
Related Collections
Right arrow Infectious Disease & Immunity
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

ARTICLE

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

Yiu-fai Cheung, MDa, Guo-ying Huang, MDb, Shu-bao Chen, MDc, Xiao-qin Liu, MDb, Li Xi, MDb, Xue-cun Liang, MDb, Mei-rong Huang, MDc, Sun Chen, MDc, Li-su Huang, MDc, Xiao-qing Liu, MDc, Koon-wing Chan, MPhila and Yu-lung Lau, MDa

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
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. We tested the hypothesis that single-nucleotide polymorphisms of inflammatory genes C-reactive protein (CRP) and tumor necrosis factor {alpha} (TNF-{alpha}) may exert influence on susceptibility to Kawasaki disease and its arterial sequelae.

METHODS. We analyzed the CRP +1444 C->T and TNF-{alpha} –308 G->A 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-{alpha} –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-{alpha} –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-{alpha} –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-{alpha} –308 A allele carrier as a determinant of only intima-media thickness.

CONCLUSIONS. Our findings suggest that CRP +1444 C->T and TNF-{alpha} –308 G->A 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-{alpha}—tumor necrosis factor {alpha} • 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


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
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 {alpha} (TNF-{alpha}) 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 C->T 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-{alpha} 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-{alpha} –308 G->A SNP and increased TNF-{alpha} 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-{alpha} –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-{alpha} –308 loci are associated with KD and assessed their associations with early coronary arterial damage, late systemic arterial stiffening, and carotid IMT.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
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-{alpha} 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)/({delta}D/D), where ln is natural logarithm, SBP is systolic blood pressure, DBP is diastolic blood pressure, {delta}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-{alpha} –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-{alpha} –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-{alpha} –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 {chi}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
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
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.


View this table:
[in this window]
[in a new window]

  		TABLE 1 Comparisons of Demographic Data, Blood Pressure, and Lipid Profile Between Patients and Control Subjects

 
Genotypic and Allelic Frequencies
The distributions of the CRP +1444 and TNF-{alpha} –308 were in Hardy-Weinberg equilibrium in patients and control subjects. Table 2 shows the genotypic and allelic frequencies at the CRP +1444 polymorphic site in patients and control subjects. The frequency of CT/TT genotype in patients with KD was higher than that in healthy control subjects (odds ratio [OR]: 2.3 [95% confidence interval (CI): 1.2–4.2]). Furthermore, compared with control subjects who had allelic frequencies similar to previous published findings in Chinese,27 patients had significantly higher frequency of the T allele (OR: 2.2 [95% CI: 1.2–3.9]).


View this table:
[in this window]
[in a new window]

  		TABLE 2 Genotypic and Allelic Frequencies at the CRP +1444 and TNF-{alpha} –308 Loci in Patients and Control Subjects

 
The genotypic and allelic frequencies at the TNF-{alpha} –308 site in patients and control subjects are also shown in Table 2. The frequency of GA/AA genotype was significantly higher in patients than in control subjects (OR: 2.1 [95% CI: 1.1–3.9]). Similarly, the frequency of the A allele was significantly higher in patients (OR: 2.1 [95% CI: 1.2–3.8]). The allelic frequencies of control subjects were similar to those reported in Chinese previously.28 A TNF-{alpha} –308 A allele in combination with a CRP +1444 T allele conferred the greatest susceptibility to KD (OR: 7.2 [95% CI: 2.1–24.5]), compared with the combination of common alleles or presence of only 1 rare allele at the 2 loci (Table 2).

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-{alpha} –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-{alpha} –308 Loci in Patients With and Without Coronary Aneurysms

 
The carotid arterial stiffness index was significantly greater in patients than in control subjects (3.94 ± 0.87 vs 3.48 ± 0.59; P < .001). For determination of the influence of CRP +1444 and TNF-{alpha} –308 genotypes on arterial stiffness, the cohort was stratified into the following groups: CC versus CT/TT for CRP +1444 locus and GG versus GA/AA genotype for TNF-{alpha} –308 locus. Patients with a CRP +1444 CT/TT genotype had significantly stiffer carotid arteries than those with a CC genotype (4.29 ± 0.93 vs 3.85 ± 0.83; P = .01). Conversely, control subjects with a CT/TT genotype had arterial stiffness similar to those with a CC genotype (3.65 ± 0.71 vs 3.45 ± 0.56; P = .19). Patients with a TNF-{alpha} –308 GA/AA genotype had significantly stiffer carotid arteries than those with a GG genotype (4.21± 0.90 vs 3.87± 0.85; P = .037). This difference was not observed in control subjects (3.38 ± 0.65 vs 3.49 ± 0.58; P = .47).

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-{alpha} –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-{alpha} –308 A allele, (2) carrier of either CRP +1444 T allele or TNF-{alpha} –308 A allele, and (3) carrier of neither CRP +1444 T allele nor TNF-{alpha} –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).


Figure 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-{alpha} –308 A allele carrier ({blacksquare}), (2) carrier of either CRP +1444 T allele or TNF-{alpha} –308 A allele ({square}), and (3) carrier of neither CRP +1444 T allele nor TNF-{alpha} –308 A allele ({square}). a P < .05 versus allelic combination 3 by posthoc Bonferroni test.

 
Univariate and multivariate linear regression models of carotid arterial stiffness and IMT in patients are shown in Table 4. Significant determinants of carotid stiffness as identified by the adjusted multivariate model were SBP (P < .001), DBP (P < .001), carrier of CRP +1444 allele (P = .004), and carrier of TNF-{alpha} –308 allele (P = .049). The only identifiable significant determinant of carotid IMT was carrier of CRP +1444 allele (P < .001).


View this table:
[in this window]
[in a new window]

  		TABLE 4 Univariate and Multivariate Adjusted Linear Regression Model of Carotid Artery Stiffness and IMT in Patients

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
This study demonstrated that patients with KD were more likely to have a CT/TT genotype and T allele at the CRP +1444 site and a GA/AA genotype and A allele at the TNF-{alpha} –308 site. The genomic and allelic frequencies did not, however, differ between patients with and those without coronary artery aneurysms. Nonetheless, carriage of the CRP +1444 T allele and/or TNF-{alpha} –308 A allele was associated with increased carotid arterial stiffness and IMT late after the acute illness, implicating a genotype-modulating effect on late systemic arterial function in KD.

The CRP +1444 C->T 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 C->T 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 C->T 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-{alpha} –308 G->A polymorphism in regulating TNF-{alpha} 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-{alpha} 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-{alpha} renders cultured endothelial cells susceptible to lysis by circulating antibodies during KD.21 Furthermore, the TNF-{alpha} –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-{alpha} –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-{alpha} concentration has been reported to be associated with carotid IMT in healthy middle-aged men,43 TNF-{alpha} –308 G->A polymorphism has not been shown to correlate with circulating levels of TNF-{alpha}.44 Hence, chronic elevation of plasma TNF-{alpha} level is an unlikely explanation of increased IMT in our patients. Nonetheless, a key role of TNF-{alpha} in inflammatory processes that may have an impact on arterial dysfunction is illustrated by reports of efficacy of anti–TNF-{alpha} 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-{alpha} –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-{alpha} 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-{alpha} –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
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Our findings suggest that CRP +1444 C->T and TNF-{alpha} –308 G->A 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-{alpha} 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 C->T and TNF-{alpha} –308 G->A polymorphisms are associated with a predisposition to KD and, in patients with KD, increased carotid arterial stiffness and IMT in the long term.

 


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

  1. Kato H, Sugimura T, Akagi T, et al. Long-term consequences of Kawasaki disease: a 10- to 21-year follow-up study of 594 patients. Circulation. 1996;94 (6):1379 –1385[Abstract/Free Full Text]
  2. Sugimura T, Kato H, Inoue O, Takagi J, Fududa T, Sato N. Vasodilatory response of the coronary arteries after Kawasaki disease: evaluation by intracoronary injection of isosorbide dinitrate. J Pediatr. 1992;121 (5 pt 1):684 –688[CrossRef][Web of Science][Medline]
  3. Cheung YF, Yung TC, Tam SC, Ho MH, Chau AK. Novel and traditional cardiovascular risk factors in children after Kawasaki disease: implications for premature atherosclerosis. J Am Coll Cardiol. 2004;43 (1):120 –124[Abstract/Free Full Text]
  4. Cheung YF, Ho MH, Tam SC, Yung TC. Increased high sensitivity C reactive protein concentrations and increased arterial stiffness in children with a history of Kawasaki disease. Heart. 2004;90 (11):1281 –1285[Abstract/Free Full Text]
  5. Noto N, Okada T, Yamasuge M, et al. Noninvasive assessment of the early progression of atherosclerosis in adolescents with Kawasaki disease and coronary artery lesions. Pediatrics. 2001;107 (5):1095 –1099[Abstract/Free Full Text]
  6. Dhillon R, Clarkson P, Donald AE, et al. Endothelial dysfunction late after Kawasaki disease. Circulation. 1996;94 (9):2103 –2106[Abstract/Free Full Text]
  7. Cheung YF, Wong SJ, Ho MH. Relationship between carotid intima-media thickness and arterial stiffness in children after Kawasaki disease. Arch Dis Child. 2007;92 (1):43 –47[Abstract/Free Full Text]
  8. Dalla Pozza R, Bechtold S, Urschel S, Kozlik-Feldmann R, Netz H. Subclinical atherosclerosis, but normal autonomic function after Kawasaki disease. J Pediatr. 2007;151 (3):239 –243[CrossRef][Web of Science][Medline]
  9. Rowley AH, Shulman ST. Kawasaki syndrome. Pediatr Clin North Am. 1999;46 (2):313 –329[CrossRef][Web of Science][Medline]
  10. Madsen HO, Videm V, Svejgaard A, Svennevig JL, Garred P. Association of mannose-binding-lectin deficiency with severe atherosclerosis. Lancet. 1998;352 (9132):959 –960[CrossRef][Web of Science][Medline]
  11. Biezeveld MH, Kuipers IM, Geissler J, et al. Association of mannose-binding lectin genotype with cardiovascular abnormalities in Kawasaki disease. Lancet. 2003;361 (9365):1268 –1270[CrossRef][Web of Science][Medline]
  12. Quasney MW, Bronstein DE, Cantor RM, et al. Increased frequency of alleles associated with elevated tumour necrosis factor-{alpha} levels in children with Kawasaki disease. Pediatr Res. 2001;49 (5):686 –690[Web of Science][Medline]
  13. Rocha V, Franco RF, Porcher R, et al. Host defence and inflammatory gene polymorphisms are associated with outcomes after HLA-identical sibling bone marrow transplantation. Blood. 2002;100 (12):3908 –3918[Abstract/Free Full Text]
  14. Foster CB, Lehrnbecher T, Mol F, et al. Host defense molecule polymorphisms influence the risk of immune-mediated complications in chronic granulomatous disease. J Clin Invest. 1998;102 (12):2146 –2155[Web of Science][Medline]
  15. Brull DJ, Serrano N, Zito F, et al. Human CRP gene polymorphism influences CRP levels: implications for the prediction and pathogenesis of coronary heart disease. Arterioscler Thromb Vasc Biol. 2003;23 (11):2063 –2069[Abstract/Free Full Text]
  16. Hage FG, Szalai AJ. C-reactive protein gene polymorphisms, C-reactive protein blood levels, and cardiovascular disease risk. J Am Coll Cardiol. 2007;50 (12):1115 –1122[Abstract/Free Full Text]
  17. D'Aiuto F, Casas JP, Shah T, Humphries SE, Hingorani AD, Tonetti MS. C-reactive protein (+1444C->T) polymorphism influences CRP response following a moderate inflammatory stimulus. Atherosclerosis. 2005;179 (2):413 –417[CrossRef][Web of Science][Medline]
  18. Marsik C, Sunder-Plassmann R, Jilma B, et al. The C-reactive protein +1444C/T alteration modulates the inflammation and coagulation response in human endotoxemia. Clin Chem. 2006;52 (10):1952 –1957[Abstract/Free Full Text]
  19. Blake GJ, Ridker PM. Novel clinical markers of vascular wall inflammation. Circ Res. 2001;89 (9):763 –771[Abstract/Free Full Text]
  20. Matsubara T, Furukawa S, Yabuta K. Serum levels of tumor necrosis factor, interleukin 2 receptor, and interferon-gamma in Kawasaki disease involved coronary-artery lesions. Clin Immunol Immunopathol. 1990;56 (1):29 –36[CrossRef][Web of Science][Medline]
  21. Leung DY, Geha RS, Newburger JW, et al. Two monokines, interleukin 1 and tumor necrosis factor, render cultured vascular endothelial cells susceptible to lysis by antibodies circulating during Kawasaki syndrome. J Exp Med. 1986;164 (6):1958 –1972[Abstract/Free Full Text]
  22. Louis E, Franchimont D, Piron A, et al. Tumour necrosis factor (TNF) gene polymorphism influences TNF-{alpha} production in lipopolysaccharide (LPS)-stimulated whole blood cell culture in healthy humans. Clin Exp Immunol. 1998;113 (3):401 –406[CrossRef][Web of Science][Medline]
  23. Research Committee on Kawasaki Disease. Report of Subcommittee on Standardization of Diagnostic Criteria and Reporting of Coronary Artery Lesions in Kawasaki Disease. Tokyo, Japan: Ministry of Health and Welfare; 1984
  24. Kawasaki T, Sasayama S, Yagi S, Asakawa T, Hirai T. Non-invasive assessment of the age related changes in stiffness of major branches of the human arteries. Cardiovasc Res. 1987;21 (9):678 –687[Abstract/Free Full Text]
  25. Miller SA, Dykes DD, Polesky HF. A sample salting procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16 (3):1215[Free Full Text]
  26. Wilson AG, di Giovine FS, Blakemore AI, Duff GW. Single base polymorphism in the human tumour necrosis factor alpha (TNF alpha) gene detectable by NcoI restriction of PCR product. Hum Mol Genet. 1992;1 (5):353
  27. Yan M, Zhao L, Zheng F, Sun X, Zhang Y, Wang C. The relationship between gene polymorphism and CRP level in a Chinese Han population. Biochem Genet. 2007;45 (1–2):1 –9[CrossRef][Web of Science][Medline]
  28. Chen R, Fang M, Cai Q, et al. Tumor necrosis factor alpha –308 polymorphism is associated with rheumatoid arthritis in Han population of Eastern China. Rheumatol Int. 2007;28 (2):121 –126[CrossRef][Web of Science][Medline]
  29. Purcell S, Cherny SS, Sham PC. Genetic power calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics. 2003;19 (1):149 –150[Abstract/Free Full Text]
  30. Kobayashi T, Inoue Y, Takeuchi K, et al. Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease. Circulation. 2006;113 (22):2606 –2612[Abstract/Free Full Text]
  31. Egami K, Muta H, Ishii M, et al. Prediction of resistance to intravenous immunoglobulin treatment in patients with Kawasaki disease. J Pediatr. 2006;149 (2):237 –240[CrossRef][Web of Science][Medline]
  32. Eklund C, Kivimaki M, Islam MS, et al. C-reactive protein genetics is associated with carotid artery compliance in men in the Cardiovascular Risk in Young Finns Study. Atherosclerosis. 2008;196 (2):841 –848[Medline]
  33. Yasojima K, Schwab C, McGeer EG, McGeer PL. Generation of C-reactive protein and complement components in atherosclerotic plaques. Am J Pathol. 2001;158 (3):1039 –1051[Abstract/Free Full Text]
  34. Wang HW, Sui SF. Dissociation and submit rearrangement of membrane-bound human C-reactive proteins. Biochem Biophys Res Commun. 2001;288 (1):75 –79[CrossRef][Web of Science][Medline]
  35. Slyper AH. What vascular ultrasound testing has revealed about pediatric atherogenesis, and a potential clinical role for ultrasound in pediatric risk assessment. J Clin Endocrinol Metab. 2004;89 (7):3089 –3095[Abstract/Free Full Text]
  36. Lange LA, Carlson CS, Hindorff LA, et al. Association of polymorphisms in the CRP gene with circulating C-reactive protein levels and cardiovascular events. JAMA. 2006;296 (22):2703 –2711[Abstract/Free Full Text]
  37. Abraham LJ, Kroeger KM. Impact of the –308 TNF promoter polymorphism on the transcriptional regulation of the TNF gene: relevance to disease. J Leukoc Biol. 1999;66 (4):562 –566[Abstract]
  38. McGuire W, Hill AV, Kwjatkowski D. Variation in the TNF-{alpha} promoter region associated with susceptibility to cerebral malaria. Nature. 1994;371 (6497):508 –511[CrossRef][Web of Science][Medline]
  39. Warzocha K, Ribero P, Bienvenu J, et al. Genetic polymorphisms in the tumor necrosis factor locus influence non-Hodgkin's lymphoma outcome. Blood. 1998;91 (10):3574 –3581[Abstract/Free Full Text]
  40. Sykora J, Subrt I, Dìdek P, et al. Cytokine tumour necrosis factor-alpha: a promoter gene polymorphism at position –308 G->A and pediatric inflammatory bowel disease—implications in ulcerative colitis and Crohn's disease. J Pediatr Gastroenterol Nutr. 2006;42 (5):479 –487[CrossRef][Web of Science][Medline]
  41. Kamizono S, Yamada A, Higuchi T, Kato H, Itoh K. Analysis of tumour necrosis factor-{alpha} production and polymorphisms of the tumour necrosis factor-{alpha} gene in individuals with a history of Kawasaki disease. Pediatr Int. 1999;41 (4):341 –345[CrossRef][Web of Science][Medline]
  42. Chien YH, Chang KW, Yang YH, Lu MY, Lin YT, Chiang BL. Association between levels of TNF-alpha and TNF-alpha promoter –308 A/A polymorphism in children with Kawasaki disease. J Formos Med Assoc. 2003;102 (3):147 –150[Web of Science][Medline]
  43. Skoog T, Dichtl W, Boquist S, et al. Plasma tumour necrosis factor-{alpha} and early carotid atherosclerosis in healthy middle-aged men. Eur Heart J. 2002;23 (5):376 –383[Abstract/Free Full Text]
  44. Skoog T, van't Hooft FM, Kallin B, et al. A common functional polymorphism (C->A substitution at position –863) in the promoter region of the tumour necrosis factor-{alpha} (TNF-{alpha}) gene associated with reduced circulating levels of TNF-{alpha}. Hum Mol Genet. 1999;8 (8):1443 –1449[Abstract/Free Full Text]
  45. Mäki-Petäjä KM, Hall FC, Booth AD, et al. Rheumatoid arthritis is associated with increased aortic pulse-wave velocity, which is reduced by anti-tumor necrosis factor-{alpha} therapy. Circulation. 2006;114 (11):1185 –1192[Abstract/Free Full Text]
  46. Del Porto F, Laganà B, Lai S, et al. Response to anti-tumour necrosis factor alpha blockade is associated with reduction of carotid intima-media thickness in patients with active rheumatoid arthritis. Rheumatology (Oxford). 2007;46 :1111 –1115[CrossRef][Medline]
  47. Breunis WB, Biezeveld MH, Geissler J, et al. Polymorphisms in chemokine receptor genes and susceptibility to Kawasaki disease. Clin Exp Immunol. 2007;150 (1):83 –90[Web of Science][Medline]
  48. Cheung YF, Ho MH, Ip WK, Fok SF, Yung TC, Lau YL. Modulating effects of mannose binding lectin genotype on arterial stiffness in children after Kawasaki disease. Pediatr Res. 2004;56 (4):591 –596[CrossRef][Web of Science][Medline]
  49. The International HapMap Consortium. A haplotype map of the human genome. Nature. 2005;437 (7063):1299 –1320[CrossRef][Web of Science][Medline]
PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Facebook Facebook   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:


Home page
 Cardiovasc ResHome page
P. Lacolley, P. Challande, M. Osborne-Pellegrin, and V. Regnault
Genetics and pathophysiology of arterial stiffness
Cardiovasc Res, March 1, 2009; 81(4): 637 - 648.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cheung, Y.-f.
Right arrow Articles by Lau, Y.-l.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cheung, Y.-f.
Right arrow Articles by Lau, Y.-l.
Related Collections
Right arrow Infectious Disease & Immunity
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?