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

Abstract

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

Role of +405C>G and +936C>T Polymorphisms of the Vascular Endothelial Growth Factor Gene and Risk of Esophageal Cancer in the Kashmiri Population

“…Similar to our findings, significant association of +405GG genotype has been reported with increased risk for pancreatic adenocarcinoma (Sivaprasad et al, 2013). Correlation of+405G allele has also been reported with increased risk for the coronary artery lesions in the Kawasaki disease (Kariyazono et al, 2004) and progressive retinopathy of prematurity (Cooke et al, 2004). The +405G allele has been shown to increase transcriptional activity and lipopolysacharide stimulated VEGF production in peripheral blood mononuclear cells (Watson et al, 2000); (Stevens et al, 2003).…”

Bevacizumab

“…These SNPs result in decreased VEGF production or increased promoter activity. In addition, there are several nonsynonymous SNPs in the coding region of KDR [32] and HIF-1␣ [18], which are responsible for their greater expression.…”

Susceptibility genes for Kawasaki disease: toward implementation of personalized medicine

“…30 Although several other groups have studied other combinations of HLA subtypes, no consistent association has been detected so far. Considering that no significant linkage was detected near the 6p region in our genome-wide linkage analysis, 31 34 and MCP-1 35 ), hematopoietins (interleukin-4 (IL-4) [36][37][38] and IL-6 39 ), IL-1 family (IL-1b, 37 IL-18, 40 and IL-1Ra 37 ), IL-10 family (IL-10 41 ), platelet-derived growth factor family (vascular endothelial growth factor (VEGF) [42][43][44][45] and VEGFR2 42 ), and tumor necrosis factor (TNF) family (TNF-a, 46-50 lipoteichoic acid, 47 and CD40L 51,52 ). Other candidates include plasma proteins (C-reactive protein [53][54][55] and MBL2 53,55,56 ), matrix metalloproteinase (MMP) and their inhibitors (MMP2, 58 MMP3, 57,58 MMP-9, 58 MMP-12, 58 MMP-13, 58 and tissue inhibitors of metalloproteinase-2 59 ), enzymes related to atherosclerosis (methylenetetrahydrofolate reductase (MTHFR), 60 endothelial nitric oxide synthase, 61 and inducible nitric oxide synthase 61 ), components of the renin-angiotensin system (angiotensin-converting enzyme [62][63][64][65] and AGTR1 64 ), and an unclassified group (CD14, 66 FCGR2A, 67,68 SLC11A1, 69 PLA2G7, 70 UGT1A1, 71 MICA, 72 and HMOX1 71 ).…”