A polymorphism in the promoter of the CD14 gene (CD14/-159) is associated with the development of coronary artery lesions in patients with Kawasaki disease

Nishimura, Satoshi; Zaitsu, Masafumi; Hara, Megumi; Yokota, Goro; Watanabe, Mamie; Ueda, Yoshiaki; Imayoshi, Miyoko; Ishii, Eiichi; Tasaki, Hakaru; Hamasaki, Yuhei

doi:10.1067/s0022-3476(03)00330-5

Cited by 53 publications

(27 citation statements)

References 42 publications

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“…In experimental studies of this syndrome, characterized by vasculitis resulting in coronary, as well as extracoronary, aneurysms, and stenosis, the attenuation of cytokine responses, especially IL-6, after infusions of IVIG may play an integral role in the rapid resolution of most of the symptoms in children with KD (6). In addition to these proinflammatory cytokines, VEGF, and markers of local inflammation of the family of damageassociated molecular pattern molecules (DAMPs) such as myeloid-related protein (MRP) 8/MRP14 and S100A12 have been reported to increase in acute KD and to play a crucial role in inflammation and are probably involved in the pathophysiology of acute vasculitis (7)(8)(9)(10)(11)(12)(13).…”

Section: K Awasaki Disease (Kd) Is the Most Common Systemicmentioning

confidence: 99%

Infliximab Reduces the Cytokine-Mediated Inflammation but Does Not Suppress Cellular Infiltration of the Vessel Wall in Refractory Kawasaki Disease

et al. 2009

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ABSTRACT:The aim of our study was to evaluate the efficacy of infliximab for the treatment of patients with refractory Kawasaki disease (KD) and investigate the dynamic changes of cytokines during infliximab treatment. We have performed a study of cytokine and proinflammatory molecule levels in 43 KD patients including 18 responders to IVIG, 14 nonresponders, and 11 patients treated with infliximab. We determined serum levels of soluble TNF receptor I (sTNFR I) and IL-6, as well as VEGF, damage associated molecular pattern (DAMP) molecules; myeloid-related protein (MRP)8/MRP14 and S100A12 sequentially. In eight patients, fever subsided immediately upon infliximab treatment. Four patients, who started infliximab after 12 d of illness, developed coronary artery lesions. Each of the cytokines was elevated before infliximab treatment in all patients. Although serum levels of proinflammatory cytokines decreased dramatically after infliximab treatment, DAMP molecules and VEGF and markers of local tissue damage were not suppressed. In contrast, in IVIG responders all cytokines decreased markedly after IVIG treatment. We show that infliximab is one of the adoptive therapies in refractory KD patients. Different behaviors of proinflammatory cytokines and DAMP molecules and VEGF after infliximab treatment suggest that infliximab is effective for suppression of cytokinemediated inflammation, but could not completely block local vasculitis. (Pediatr Res 65: 696-701, 2009) K awasaki disease (KD) is the most common systemic vasculitis syndrome primarily affecting small and medium-sized arteries, particularly the coronary artery. Although timely treatment with high-dose i.v. immune globulin (IVIG) is now accepted as reducing the incidence of coronary artery lesions (CAL), approximately 15% of the patients do not respond to IVIG treatment and have persistent fever as a manifestation of ongoing inflammation. These patients are at highest risk for development of CAL (1). The current practice for patients with KD and persistent or recrudescent fever after IVIG is to institute additional therapies, which may include one or more repeat doses of IVIG, high-dose pulse methylprednisoline, cyclophosphamide, methotrexate, ulinastatin, cyclosporine A (CyA), or plasmapheresis (2,3). Recently, potential new therapeutic approaches with infliximab (Remicade), a chimeric mouse-human MAb against tumor necrosis factor (TNF)-␣, have been reported in refractory KD patients (4).During the acute phase of KD, serum levels of proinflammatory cytokines such as TNF-␣ are elevated (5). In experimental studies of this syndrome, characterized by vasculitis resulting in coronary, as well as extracoronary, aneurysms, and stenosis, the attenuation of cytokine responses, especially IL-6, after infusions of IVIG may play an integral role in the rapid resolution of most of the symptoms in children with KD (6). In addition to these proinflammatory cytokines, VEGF, and markers of local inflammation of the family of damageassociated molecular pattern molecules (DAMP...

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Section: K Awasaki Disease (Kd) Is the Most Common Systemicmentioning

confidence: 99%

Infliximab Reduces the Cytokine-Mediated Inflammation but Does Not Suppress Cellular Infiltration of the Vessel Wall in Refractory Kawasaki Disease

et al. 2009

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“…In previous reports, several genetic polymorphisms, such as tumor necrosis factor-␣ gene and CD14 gene, were associated with KD occurrence and/or the development of CALs (15,16). However, these studies did not include functional assays or multivariate analysis with clinical data.…”

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confidence: 99%

Association of Vascular Endothelial Growth Factor (VEGF) and VEGF Receptor Gene Polymorphisms with Coronary Artery Lesions of Kawasaki Disease

et al. 2004

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We analyzed the genetic polymorphisms of vascular endothelial growth factor (VEGF) and its receptors [Fms-related tyrosine kinase-1, kinase insert domain receptor (KDR)] in Japanese patients with Kawasaki disease (KD) and normal control subjects to examine whether these genes would contribute to the KD occurrence and/or the development of coronary artery lesion (CAL) in KD. We found that the frequency of G allele of VEGF g.Ϫ634 GϾC single-nucleotide polymorphism in the promoter region was significantly higher in KD patients with CAL than in those without CAL (p ϭ 0.012) or control subjects (p ϭ 0.021) because of a significantly higher frequency of the GG genotype in KD patients with CAL. In addition, the frequency of the A1 allele with 11 AC repeats of KDR g.ϩ4422(AC)11-14 dinucleotide repeat polymorphism in intron 2 was significantly higher in KD patients with CAL than in those without CAL (p ϭ 0.013) or control subjects (p ϭ 0.040) as a result of a significantly higher frequency of the A1A1 genotype in KD with CAL patients. The multivariate analysis of clinical features and genotypes of the two polymorphisms showed that the A1A1 genotype of KDR g.ϩ4422(AC)11-14 polymorphism was an independent risk factor for the development of CAL with the highest odds ratio among several clinical parameters (odds ratio 6.76; 95% confidence interval 1. 05-43.48). Dual luciferase assay demonstrated that the A1 allele with KDR g.ϩ4422(AC)11 repeats showed a weaker silencer function than the A2 allele with 12 AC repeats. These findings suggested that VEGF and its receptor, KDR, genes contributed to the development of CAL in KD patients. Kawasaki disease (KD) is an acute febrile vasculitis of infants and children and is accompanied by the coronary artery lesions (CALs) that occur in~5-16% of patients (1,2). Even after the introduction of high-dose i.v. immunoglobulin (IVIG) therapy, CAL occurs in a small proportion of KD patients and leads to life-threatening complications, including myocardial infarction, as well as acquired heart diseases such as myocardial dysfunction, valvular diseases, and arrhythmias (3,4). Therefore, it is important to identify as early as possible KD patients who are at risk for the development of CAL.During the acute stage of KD, activation of the immune system with increased serum cytokines such as tumor necrosis factor-␣, interferon-␥, IL-1, IL-2, IL-6, and IL-8 may play important roles in the occurrence of endothelial cell injury (5-7). The pathologic findings of vascular tissues in KD patients include subendothelial edema, vascular damage, gap formation, and fenestration of endothelial cells (8,9

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“…In addition, other gene polymorphisms have been associated with an important common complication of KD, coronary artery aneurysm. These include polymorphisms in the genes encoding mannose-binding lectin, vascular endothelial growth factor, and CD14, as well as in the promoter region of the gene encoding metalloproteinase-3 (11)(12)(13)(14).…”

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confidence: 99%

The IL-10 (-627 A/C) Promoter Polymorphism May Be Associated With Coronary Aneurysms and Low Serum Albumin in Korean Children With Kawasaki Disease

Jin¹,

Kim

Kim³

et al. 2007

Pediatr Res

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Kawasaki disease (KD) is an acute febrile vasculitic syndrome of unknown etiology that preferentially affects the coronary artery. Interleukin-10 (IL-10) is a key proinflammatory cytokine, and a polymorphism near the major transcriptional start site of the IL-10 gene was shown to influence IL-10 production in vitro. This study investigated the association of the IL-10 promoter polymorphism with KD and its clinical parameters in Korean children. A total of 194 children with congenital heart disease (CHD) and 95 children with KD were included in this study. IL-10 (-627 A/C) polymorphism genotypes were determined using the single-base extension method. There was no difference in the allele frequencies of IL-10 (-627 A/C) polymorphism between CHD children and KD children. KD children with one or two copies of the IL-10 (-627C) allele showed significantly lower albumin levels (p ϭ 0.020) and higher frequencies of early coronary artery aneurysm [62.22% versus 37.78%, adjusted odds ratio (aOR) ϭ 3.50, 95% confidence interval (CI): 1.50 -8.16] compared with KD children with the common IL-10 (-627A) allele. These findings suggest that the IL-10 (-627 A/C) promoter polymorphism might be a genetic marker for the risk of early coronary artery complication in KD. (Pediatr Res 61: 584-587, 2007) K D is an acute, self-limiting vasculitis of unknown etiology that occurs predominantly in infants and young children. KD is characterized by widespread vascular inflammation of the coronary artery and other medium-sized arteries (1,2). Coronary artery lesions, including coronary artery dilatation or aneurysm, are the most common complications and develop in approximately 20%-25% of untreated children with KD (3). Even after high-dose intravenous immunoglobulin (IVIG) therapy, coronary artery lesions occur in a small percentage of KD patients, occasionally leading to lifethreatening complications (e.g. myocardial infarction) and/or acquired heart diseases such as myocardial dysfunction, valvular diseases, and arrhythmias (4,5).

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A polymorphism in the promoter of the CD14 gene (CD14/-159) is associated with the development of coronary artery lesions in patients with Kawasaki disease

Cited by 53 publications

References 42 publications

Infliximab Reduces the Cytokine-Mediated Inflammation but Does Not Suppress Cellular Infiltration of the Vessel Wall in Refractory Kawasaki Disease

Infliximab Reduces the Cytokine-Mediated Inflammation but Does Not Suppress Cellular Infiltration of the Vessel Wall in Refractory Kawasaki Disease

Association of Vascular Endothelial Growth Factor (VEGF) and VEGF Receptor Gene Polymorphisms with Coronary Artery Lesions of Kawasaki Disease

The IL-10 (-627 A/C) Promoter Polymorphism May Be Associated With Coronary Aneurysms and Low Serum Albumin in Korean Children With Kawasaki Disease

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