Vascular Endothelial Growth Factor Genotypes Research Articles

The 936C>T polymorphism of the gene for vascular endothelial growth factor is associated with 18F-fluorodeoxyglucose uptake

Positron emission tomography (PET) is a an important technology for detection and staging of breast cancer. The method is based upon assessment of glucose metabolism using the 18F-fluorodeoxyglucose (18F-FDG) as glucose analog. A strong variability of 18F-FDG uptake by breast cancer tissue has been reported, the reason for which is not fully understood but may involve vascular density and integrity. A 936C>T polymorphism in the gene for the vascular endothelial growth factor (VEGF) has been associated with VEGF plasma levels and breast cancer risk. To analyze the role of this polymorphism for 18F-FDG uptake in breast cancer patients, we determined the VEGF genotype in 37 patients in whom PET was performed for detection of metastases. An 18F-FDG uptake score of 1 (low uptake), 2 (medium uptake) or 3 (high uptake) was assigned to each patient. VEGF CC, CT and TT genotypes were found in 28, 8 and 1 patient. Uptake score of 1 was found in three patients, score 2 in 12 patients and score 3 in 22 patients. VEGF genotype was significantly associated with FDG uptake score (chi2 test, p=0.007). The number of 936-T alleles correlated with a lower 18F-FDG uptake score (Spearman correlation test, p=0.032). In the present study the common VEGF 936C>T polymorphisms had a major impact on 18F-FDG uptake in breast cancer patients. If this result can be confirmed in following studies, it might have strong relevance for the use of PET as diagnostic tool.

Association of VEGF genotype with mRNA level in colorectal adenocarcinomas

The mRNA expression of vascular endothelial growth factor (VEGF) was evaluated in colorectal adenocarcinomas and adjacent noncancerous colorectal tissues in 18 Japanese patients. The expression was confirmed to be up-regulated in the colorectal adenocarcinomas, when compared with the noncancerous tissues. Twelve genotypes of VEGF: six positions in the promoter region, two in the 5′UTR, and four in the 3′UTR, and their association with the expression of VEGF mRNA were evaluated. While G-1877A, T-1455C, G-1154A, C702T, and G1612A were not detected, C-2578A, T-1498C, G-1190A, C-634G, C-7T, C936T, and C1451T were found at allele frequencies of 4/36, 15/36, 15/36, 20/36, 8/36, 6/36, and 6/36, respectively, suggesting that C-2578A, G-1154A, and G1612A were associated with a decreased risk for colorectal adenocarcinoma. T-1498C (G-1190A) and C-7T were found to be associated with higher levels of VEGF mRNA, and may be a risk factor for the development of liver metastasis and/or prognosis of colorectal adenocarcinoma.

Genetic polymorphism of VEGF: Impact on longitudinal change of peritoneal transport and survival of peritoneal dialysis patients

Vascular endothelial growth factor (VEGF) plays a pivotal role in the peritoneal angiogenesis and hyperpermeability in patients on peritoneal dialysis. We hypothesis that VEGF genetic polymorphism may affect the longitudinal change of peritoneal transport and clinical outcome of peritoneal dialysis patients. We studied 135 consecutive new peritoneal dialysis patients. VEGF genetic polymorphism at -1154 and -2578 positions were determined by polymerase chain reaction (PCR) methodologies. Standard peritoneal test and dialysis adequacy and transport test (DATT) were performed at the initiation of peritoneal dialysis. After 12 months, DATT was repeated in 83 patients. In 35 patients, VEGF production in vivo was determined by its levels in serum and peritoneal dialysis effluent, and mRNA expression in peritoneal dialysis effluent. Patients were followed for 19.4 +/- 8.5 months for survival study. There was no relation between VEGF genotype and baseline peritoneal transport group. The changes in 24-hour dialysate-to-plasma (D/P) creatinine after 12 months were 0.028 +/- 0.159, -0.013 +/- 0.137, and 0.141 +/- 0.231 for CC, CA, and AA genotype at -2578 position, respectively [one-way analysis of variance (ANOVA), P= 0.028]. The AA genotype had significantly higher increase in 24-hour D/P creatinine than the other genotypes. Similar results were found with the genotype at -1154 position, which had marked linkage disequilibrium with the genotype at -2578 position. Actuarial patient survival was 90.3% and 74.9% at 24 months for CC and CA/AA genotypes at -2578 position, respectively (P= 0.036). After correcting for confounding covariates, the adjusted hazard ratio of death was 3.04 (95% CI, 1.10 to 8.36) for the CA/AA group as compared to CC group. Although baseline serum VEGF level was higher in patients with CC genotype than those with CA/AA genotype at -2578 position (541.5 +/- 322.8 pg/mL vs. 298.8 +/- 209.4 pg/mL, P= 0.012), VEGF mRNA expression in peritoneal dialysis effluent was significantly lower in patients with CC genotype (1.82 +/- 2.77 vs 4.48 +/- 3.28, P= 0.021). VEGF protein level in peritoneal dialysis effluent was also marginally lower in patients with CC genotype, although the difference was not significant. Genotype at -1154 position was not associated with VEGF production in vivo or patient survival. We conclude that in peritoneal dialysis patients, the AA genotype of VEGF promoter at -2578 position was associated with progressive increase in peritoneal transport. The CA/AA genotype at -2578 position was also associated with an excess mortality. Our finding also suggests that systemic and local peritoneal VEGF production may be differentially regulated.

Maximal Oxygen Consumption is Associated with VEGF Sequence Variation

0711 As the delivery of oxygen to working skeletal muscle can impose a limit on maximal oxygen consumption (OV2max), factors that can affect the supply of oxygen to exercising skeletal muscle may impact maximal oxygen consumption before or after exercise training. Vascular endothelial growth factor (VEGF) is one such agent as its expression is regulated by hypoxia and it is involved in the process of angiogenesis. Several polymorphisms in the DNA sequence of VEGF have been identified, and two (C-2578A & C936T) have been chosen for study here based on previous reports of associations with plasma VEGF levels. PURPOSE: To determine if sequence variation in VEGF is associated with Vo 2max before and after aerobic exercise training. METHODS: Genomic DNA was extracted from peripheral lymphocytes and RFLP genotyping was performed on the C-2578A and C936T variants in VEGF. Indirect calorimetry during a graded treadmill exercise test was used to assess OV2max. Subjects (50–75 years of age) underwent 24 weeks of aerobic exercise training, with an initial training volume of 20 minutes at 50% of HR reserve that was increased over 10 weeks to 40 minutes at 70% of HRreserve, a level maintained for 14 weeks. ANCOVA was used to test for associations between VEGF genotype and Vo 2max, with age, sex, and baseline OV2max included as covariates where appropriate. RESULTS: No significant differences were observed in OV2max among genotype groups for the C936T variant. Significant differences in OV2max were observed among C-2578A genotype groups such that carriers of the A-allele (CA & AA groups) exhibited higher OV2maxafter aerobic exercise training (27.7 ± 0.59 vs. 25.1 ± 0.80 ml/kg·min, p = 0.02) and greater change in OV2max in response to aerobic exercise training (2.66 ± 0.59 vs. 0 ± 0.80 ml/kg·min, p = 0.02) than those homozygous for the C-allele. CONCLUSION: Variation in the DNA sequence of VEGF appears to be associated with Vo 2max after aerobic exercise training. Supported by NIH AG17474, AG15389, & AG22791.

Steroid-sensitive nephrotic syndrome and vascular endothelial growth factor gene polymorphisms.

Genetic polymorphisms have been recognized as important determinants of gene expression. Three common single nucleotide polymorphisms have been identified in the promoter and 5' untranslated region of the vascular endothelial growth factor (VEGF) gene: -460 C --> T, -141 A --> C and +405 G --> C. As VEGF has been postulated to play a role in the pathogenesis of childhood steroid-sensitive nephrotic syndrome (SSNS), this study tested the hypothesis that VEGF genotype may be associated with susceptibility to SSNS. We examined the genotype frequencies of these polymorphisms in a total of 116 children with SSNS and 150 control subjects, using polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP). There were no statistically significant differences in any of the genotype frequencies between SSNS patients and controls. We conclude that VEGF -460, -141 and +405 genotypes are not associated with susceptibility to childhood SSNS.

Influence of vascular endothelial growth factor single nucleotide polymorphisms on tumour development in cutaneous malignant melanoma.

Vascular endothelial growth factor (VEGF) is a potent regulator of vasculogenesis and tumour angiogenesis. We have investigated whether the VEGF -2578, -1154, +405 and +936 SNPs and associated haplotypes confer susceptibility to and/or influence prognosis in cutaneous malignant melanoma (CMM) skin cancer. A total of 152 CMM patients and 266 controls were genotyped for VEGF promoter SNPs by ARMS-PCR. Strong linkage disequilibrium between the -2578, -1154 and +405 SNPs was detected (association, rho = 0.488-0.965), but not between these SNPs and SNP +936 (association, rho = 0.004-0.130). No SNPs or three SNP haplotypes (-2578, -1154, +405) were significantly associated with CMM, although a number of non-significant trends were observed. However, the VEGF -1154 AA genotype and -2578, -1154, +405 CAC haplotype were both significantly associated with less advanced (Stage 1) disease (P = 0.03). In addition, the VEGF -1154 AA genotype was associated with thinner primary vertical growth phase tumours (P = 0.002), while VEGF -1154 GG was associated with thicker primary tumours (P = 0.02). These preliminary results indicate that VEGF genotype may influence tumour growth in CMM, possibly via the effects of differential VEGF expression on tumour angiogenesis.

IDENTIFICATION OF POLYMORPHISMS WITHIN THE VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) GENE: CORRELATION WITH VARIATION IN VEGF PROTEIN PRODUCTION

Dysregulated vascular endothelial growth factor (VEGF) expression has been implicated as a major contributor to the development of a number of common disease pathologies. The aim of this study was to establish the extent of genetic variability within the VEGF gene and to determine whether this genetic variation influenced levels of VEGF protein expression. The promoter region and exon 1 of the VEGF gene were screened for polymorphisms using single-stranded conformation (SSCP) polymorphism analysis and direct PCR-sequencing. We identified 15 novel sequence polymorphisms most of which were rare. Eleven of these polymorphisms were single base substitutions, three were single base insertions and one was a two base deletion. Thirteen of the polymorphisms were located within the promoter and two in the 5′ untranslated region (5′UTR) of the gene. We established PCR-RFLP typing systems for ten of the polymorphisms. For the two common polymorphisms at −460 and +405, we developed a combined sequence specific priming (SSP) PCR typing system to determine thecis /trans orientation of each allele and hence, ascertain haplotypes. A significant correlation was observed between lipopolysaccharide (LPS) stimulated peripheral blood mononuclear cell (PBMC) VEGF protein production and genotype for the +405 polymorphism.