−1154G/A and −2578C/A polymorphisms of the vascular endothelial growth factor gene in Tunisian Alzheimer patients in relation to β-amyloid (1–42) and total tau protein

Recent evidences indicate that polymorphisms within the promoter region of the vascular endothelial growth factor (VEGF) gene may elevate the risk for Alzheimer's disease (AD). To further investigate, we have analyzed association between promoter polymorphisms of the VEGF gene in 93 AD patients and age and sex matched 113 controls from Tunisian population. The distribution of genotype and allele frequencies of the VEGF (−2578C/A) and (−1154G/A) polymorphisms did not differ significantly between AD and control groups (p > 0.05). In the subgroup of ApoE ?4 carriers, the −2578A was observed to be significantly higher in the AD patients than in the control individuals. After adjusting the data by gender, age and the ApoE ?4 status using logistic regression, the −2578A allele was found to increase the risk for sporadic AD by 1.7-fold. The present study provides the evidence that the −2578A allele may be associated with the development of AD in the individuals with ApoE ?4 allele. In addition, AD patients carrying the −2578A allele had lower Aβ42 (p = 0.029) levels than those without this allele, particularly in subjects with ApoE ?4 allele.     

Lack of Association of the Vascular Endothelial Growth Factor Gene Polymorphisms with Kawasaki Disease in Taiwanese Children

INTRODUCTION: Kawasaki disease (KD) is an acute febrile vasculitis of unknown etiology that mainly occurs in infants and children. Clinical and histopathologic findings suggest that vascular endothelial growth factor (VEGF) is involved in the coronary artery lesions (CALs) development in KD. This study hypothesized that specific VEGF gene polymorphisms and their haplotypes are associated with KD susceptibility and CAL development in Taiwanese children. SUBJECTS AND METHODS: The VEGF -2578 A/C, -634 G/C, and +936 C/T single-nucleotide polymorphisms (SNPs) were genotyped in 156 children with KD and 672 ethnically matched healthy controls using the Pre-Developed TaqMan Allelic Discrimination Assay. RESULTS: No significant differences in genotype, allele, carrier, and haplotype frequencies of the three SNPs were found between healthy controls and children with KD or between patients with and without CAL. CONCLUSION: Our data suggest that VEGF -2578 A/C, -634 G/C, and +936 C/T SNPs do not confer increased susceptibility to KD or to CAL development.     

Association of vascular endothelial growth factor gene polymorphisms with behcet disease in a Korean population

Vascular endothelial growth factor (VEGF) is important for angiogenesis and inflammation, both of which are codependent and contribute to the pathophysiology of Behcet disease (BD). The increased expressions of VEGF have been observed in the active stage and in the ocular inflammation of BD. Polymorphisms of the VEGF gene have been associated with chronic inflammatory disease including rheumatoid arthritis. We sought to investigate whether polymorphisms on the regulatory region of the VEGF gene are associated with susceptibility of Korean patients with BD. One hundred one native Korean patients with BD and 138 healthy unrelated controls were recruited. Genotype and allele frequencies of the four selected polymorphisms (-2578, -1154, -634, and 936) were not different between the BD group and controls. Among the BD patients, the frequency of the -634 CC genotype decreased in patients with uveitis (2.6% vs. 20.6%, adjusted OR = 0.100, 95% CI 0.011-0.875, p = 0.037), although it became insignificant after correction for multiple comparisons. These results indicate that the VEGF gene polymorphisms are not associated with BD in the Korean population, but they may be involved in the development of the ocular inflammation of BD.     

Vascular endothelial growth factor genotypes and haplotypes are associated with pre-eclampsia but not with gestational hypertension

Vascular endothelial growth factor (VEGF) is relevant for normalpregnancy, and abnormalities in VEGF functions are associatedwith hypertensive disorders of pregnancy. Because there arefew studies on how VEGF genetic polymorphisms affect susceptibilityto pre-eclampsia (PE), and no studies on how they affect susceptibilityto gestational hypertension (GH), we compared VEGF genotypeand haplotype distributions in normotensive and hypertensivepregnancies. Genotypes and haplotypes for VEGF polymorphisms(C-2578A, G-1154A and G-634C) were determined in 303 pregnantwomen (108 healthy pregnant, HP; 101 with GH and 94 with PE).When white and non-white pregnant women were considered together,no significant differences were found in the distributions ofVEGF genotypes or haplotypes (P > 0.05) in the three groups.However, with only white subjects, significant differences werefound in genotypes distributions for two (C-2578A and G-634C)VEGF polymorphisms (both P < 0.05) between the HP and thePE groups. Importantly, the haplotype including the variantsC-2578, G-1154 and C-634, which is associated with higher VEGFgene expression, was less common in the PE group compared withthe HP group (4% versus 16%; P = 0.0047). However, we foundno significant differences in VEGF haplotypes distributionswhen the HP and GH groups were compared (P > 0.05). Thesefindings suggest a protective effect for the ‘C-2578,G-1154 and C-634’ haplotype against the development ofPE, but no major effects of VEGF gene variants on susceptibilityto GH.     

VEGF polymorphisms and serum VEGF levels in Parkinson's disease

Accumulated data within the recent years demonstrate that reduced levels of VEGF which is a well known angiogenic molecule might cause neurodegeneration in part by impairing neural tissue perfusion, vasoregulation and normal functioning of perivascular autonomic nerves. Additionally, VEGF has been reported to support neuroprotection in dopaminergic neurons by indirect and direct mechanisms and suppress apoptosis in dopaminergic neurons in vitro. The aim of the current study is first to demonstrate whether there is an association between the three common VEGF polymorphisms (−2578C/A, −634C/G and 936C/T) in the VEGF gene and idiopathic Parkinson's disease (IPD) which is a neurodegenerative disease caused by the progressive degeneration of nigrostriatal dopaminergic neurons, and second to see if the serum levels of VEGF is reduced in the patients with IPD. We screened the genotype and allele frequencies of three common functional polymorphisms of VEGF, namely −2578C/A, −634C/G and 936C/T in DNA samples of 126 patients with IPD and healthy control subjects and also we compared the median serum levels of VEGF between these two groups. No association was found between the inspected VEGF polymorphisms and IPD and also no difference was found between the serum VEGF levels of both groups. The current study failed to support the hypothesis that VEGF polymorphisms and/or reduced serum VEGF levels are likely contributors to the neurodegenerative process in IPD.     

Vascular endothelial growth factor gene polymorphisms and pre-eclampsia

Vascular endothelial growth factor (VEGF) plays a crucial role in physiological vasculogenesis and vascular permeability and has been implicated in the pathogenesis of pre-eclampsia. Our present study was undertaken to identify associations between three functional VEGF gene polymorphisms, linked with altered VEGF gene responsiveness, and pre-eclampsia. The study involved 42 pre-eclamptic and 73 healthy control women who were genotyped for the -2578C/A, -634G/C and 936C/T polymorphisms of the VEGF gene. No significant association between genotypic or allelic frequencies in women with pre-eclampsia relative to controls was found. A statistically significant difference was found for allelic frequencies of the 936C/T polymorphism between women with severe pre-eclampsia and controls (odds ratio: 2.70; 95% confidence interval: 1.09-6.63; P = 0.019). VEGF gene polymorphisms studied are unlikely to be major predisposing factors for pre-eclampsia. The presence of the 936T allele probably has a considerable effect on disease modification.     

VEGF C-634G polymorphism is associated with protection from isolated ventricular septal defect: case-control and TDT studies

The ventricular septal defect (VSD) is the most common congenital heart defect and no candidate susceptibility gene has been identified. Endocardial cushion and outflow septal morphogenesis, malalignment of which induces VSD, have been suggested to be mediated by the vascular endothelial growth factor (VEGF). Three single-nucleotide polymorphism (SNP) variants in promoter and 5'-UTR region of the VEGF gene, C-2578A (rs699947), G-1154A (rs1570360) and G-634C (rs2010963), were reported to alter its expression. We assessed the association in a Chinese population between these SNPs and VSD using a double approach: case-control and TDT designs. Among the three SNPs, only -634C allele was less frequently present in 222 patients compared to 352 controls (odds ratio: 0.76, 95% CI: 0.59-0.97, X(2)=5.06, P=0.024, not significant after a Bonferroni correction). This was significantly less transmitted to VSD patients (trios: 142) (odds ratio: 0.39, 95% CI: 0.25-0.62, X(2)=8.11, df=1, P=0.004, corrected P=0.024). A similar result was observed for haplotype -2578C/-1154G/-634C allele in both studies (in TDT: X(2)=7.51, df=1, P=0.006, corrected P=0.048). All these associations for the first time demonstrated that -634C allele was in a significant protective association against VSD, suggesting that VEGF dysregulation was involved in the pathological processes of VSD.     

Genetic polymorphisms of vascular endothelial growth factor in severe pre-eclampsia

Several lines of evidence support the hypothesis that vascular endothelial growth factor (VEGF) plays an important role in the pathogenesis of pre-eclampsia (PE). VEGF is a key component in the regulation of vascular remodelling and the survival of cytotrophoblasts in the placenta. In this case-control study, we aimed to test whether VEGF genetic polymorphisms are associated with the risk of severe PE. We enrolled 84 nulliparous pregnant women with severe PE (PE group). Their VEGF G(+405)C and VEGF C(-2578)A genotypes were determined by PCR-restriction fragment length polymorphism (PCR-RFLP) from venous blood samples and were compared with the corresponding VEGF genotypes of 96 nulliparous patients with uncomplicated pregnancies (control group). Carriers of the VEGF(+405)G allele occurred less frequently in PE than in the control group [P = 0.039; adjusted odds ratio (aOR) = 0.28, range: 0.08-0.93]. Hypertension and proteinuria were diagnosed earlier (by 1.6 weeks and 1.9 weeks, respectively) in PE patients with VEGF(-2578)A only after adjustment of this association for risk factors of PE. Our results suggest that carriers of VEGF(+405)G allele have a decreased susceptibility to PE and that the progression of PE may be modified by the presence of VEGF(-2578)A allele. Nevertheless, the clinical significance of these findings remains to be determined.     

Analysis of vascular endothelial growth factor (VEGF) functional variants in rheumatoid arthritis

The vascular endothelial growth factor (VEGF) is one of the most important pro-angiogenic mediators related to inflammation-associated synovial angiogenesis. The aim of this study was to asses the role of -1154 G-->A (rs1570360) and -634 G-->C (rs2010963) VEGF gene functional variants with rheumatoid arthritis (RA). The population under study was composed of a total of 753 unrelated RA patients and 801 healthy controls. The VEGF -1154 G-->A and -634 G-->C polymorphism genotyping was performed by real-time polymerase chain reaction technology, using TaqMan 5' allelic discrimination assay. No evidence of association was observed between the -1154 G-->A and the -634 G-->C VEGF polymorphisms, or inferred VEGF haplotypes with RA susceptibility or clinical manifestations. Our results suggest that the analyzed VEGF promoter polymorphisms may not play a relevant role in RA pathogenesis in our population.     

Association between promoter polymorphisms of vascular endothelial growth factor gene and sporadic Alzheimer's disease among Northern Chinese Han

Increasing evidences suggest that polymorphisms within the promoter region of the vascular endothelial growth factor (VEGF) gene may elevate the risk for Alzheimer's disease (AD). In Northern Chinese Han, we found three polymorphisms in the VEGF promoter: −2578C/A (rs699947), −2549I/D (rs35569394) and −1154G/A (rs1570360). A strong linkage disequilibrium was detected between −2578C/A and −2549I/D. After adjusting the data by gender, age and the APOE?4 status using logistic regression, the −1154G/G genotype was found to increase the risk for sporadic AD (SAD) by 1.4-folds. In the subgroup of APOE?4 non-carriers, the −1154G allele and −2549D/−1154G haplotype were observed to be significantly higher in the 279 SAD patients than in the 317 healthy individuals. The present study provides the evidence that the −1154G allele and the −2549D/−1154G haplotype may be associated with the development of SAD in the individuals without APOE?4 allele.     

Role of VEGF gene variability in longevity: a lesson from the Italian population

Vascular endothelial growth factor (VEGF) gene polymorphisms have been associated with an increased risk of developing a wide variety of disorders from diabetes to neurodegenerative diseases suggesting functions not confined to its vascular effects originally described. Based on the VEGF protective roles undisclosed in pathological conditions, we evaluate whether VEGF variability might be a determinant also for longevity. Four polymorphisms (−2578C/A, −1190G/A, −1154G/A and −634G/C) within the VEGF gene promoter region in 490 unrelated Italian healthy subjects have been analysed. Significant changes of allele, genotype (−2578/AA versus −2578/CC: OR = 2.08, p = 0.007; −1190/AA versus −1190/GG: OR = 2.01, p = 0.011) and haplotype (AAGG: 10.4% versus 14.9%, p = 0.03) frequency distributions were observed between young/elderly (25–84 years old) and long-lived (85–99 years old) subjects. These results suggest that VEGF gene variability can be inserted among the genetic factors influencing the lifespan.     

Vascular endothelial growth factor gene polymorphisms and vasculitis susceptibility: A meta-analysis

Objective

The aim of this study was to explore whether vascular endothelial growth factor (VEGF) polymorphisms are associated with susceptibility to vasculitis.

Methods

Meta-analyses were conducted on the associations between the −634 C/G, +936 C/T, −1154 A/G, and −2578 A/C polymorphisms of VEGF and vasculitis.

Results

Eight studies on VEGF polymorphisms and vasculitis involving 2740 subjects (vasculitis 834, controls 1906) were included in this meta-analysis. The meta-analysis showed no association between vasculitis and the VEGF −634 C allele (OR = 1.161, 95% CI = 0.921–1.464, p = 0.207) among study subjects. Meta-analysis showed no association between vasculitis and the VEGF + 936 T allele (OR = 1.121, 95% CI = 0.905–1.390, p = 0.295). However, stratification by ethnicity indicated a significant association between the VEGF + 936 T allele and vasculitis in Europeans, but not in Asians (OR = 1.486, 95% CI = 1.038–2.128, p = 0.030; OR = 0.958, 95% CI = 0.773–1.253, p = 0.755). Meta-analysis showed no association between vasculitis and the VEGF −1154 A/G and 2578 A/C polymorphisms.

Conclusions

This meta-analysis suggests that the VEGF + 936 T allele is associated with susceptibility to vasculitis in Europeans, but not in Asians.     

VEGF polymorphisms and severity of atherosclerosis

Introduction: Vascular endothelial growth factor (VEGF) is a potent angiogenic factor, and neovascularisation has been shown to be important in atherosclerotic plaque development. There is some disagreement as to whether VEGF acts as a pro-atherosclerotic or anti-atherosclerotic factor. In the present study we have sought to clarify this by determining genotypes and haplotypes for three reportedly functional VEGF SNPs in a large series of well documented coronary atherosclerosis patients. Methods: VEGF –2578, –1154, and –634 single nucleotide polymorphisms were genotyped in 984 subjects from the Southampton Atherosclerosis Study, using the 5'' nuclease assay for allelic discrimination (TaqMan). Results: VEGF –2578 genotypes showed a significantly different distribution in patients without myocardial infarction when stratified according to number of diseased arteries. VEGF –2578 was also associated with mean number of stenotic segments in the same patient group. The AA genotype was a risk factor and CC was protective. These associations were significant before and after adjustment for classic risk factors, and were reflected in associations between VEGF haplotypes and the number of diseased arteries and stenotic segments. As VEGF –2578 CC has been provisionally shown to be associated with higher VEGF expression than the AA genotype, these results are consistent with a protective effect for VEGF in atherosclerosis development. Some changes in VEGF –1154 genotype frequencies were also detected, but no significant associations were detected for any one particular genotype. Conclusions: This study provides preliminary evidence that VEGF polymorphism is associated with development of atherosclerosis, possibly via regulation of VEGF expression, supporting a protective effect for VEGF in atherosclerosis. These results require replication in an independent study group, combined with study of additional candidate polymorphisms in the VEGF gene.     

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.     

Association of vascular endothelial growth factor gene polymorphisms with susceptibility and clinicopathologic characteristics of colorectal cancer

Since vascular endothelial growth factor (VEGF) is known to be a potent pro-angiogenic factor, we evaluated the potential association of two VEGF gene polymorphisms (-634G>C and 936C>T) with the susceptibility and the clinicopathologic characteristics of colorectal cancer (CRC). The VEGF genotypes were determined using fresh colorectal tissue from 465 patients who had undergone a surgical resection and peripheral blood lymphocytes from 413 healthy controls by PCR/DHPLC assay. For the -634G>C polymorphism, the -634 GC or CC genotype was associated with a decreased risk of CRC (odds ratio [OR], 0.62; p=0.001) as a dominant model of C allele, whereas the 936 TT genotype correlated with advanced stage/ metastasis, a high serum level of CA19-9, and an higher grade in patients with CRC. In the haplotype analyses, haplotype -634C/936C and -634G/936T were associated with a decreased susceptibility of CRC (OR, 0.53 and 0.56; p<0.001, respectively). These observations imply that the VEGF gene polymorphisms may be associated with the susceptibility or clinicopathologic features of CRC. However, further studies of other VEGF sequence variants and their biological functions are needed to understand the role of the VEGF gene polymorphisms in the development and progression of CRC.     

A polymorphism in the CCL2 chemokine gene is associated with asthma risk: a case-control and a family study in Tunisia

Asthma is a complex genetic disorder characterized by chronic airway inflammation. We hypothesized that genetic polymorphisms in chemokines and their receptors alter leukocyte mobilization and may thus influence the risk and severity of childhood asthma. Distributions of the chemokine CCL2-2578G, CCL2-927C, CCR2-V64I, CX3CR1-V249I and CX3CR1-T280M receptor polymorphisms were examined in a case-control study of 121 children with asthma and 226 age-matched healthy controls and then replicated in a family study of 99 simplex families (297 individuals). The case-control study revealed that the CCL2-2578G allele was less frequent in children with than in those without asthma (P=0.0012). No association with asthma was found for the CCL2-927, CCR2 or CX3CR1 polymorphisms. The finding in the family study that the CCL2-2578G allele was transmitted less often by heterozygous parents to their children with asthma (P=0.0016) confirms the association of CCL2-2578G with asthma risk. Biochemical studies indicated that plasma CCL2 concentrations were higher in both patients (P=0.0214) and controls (P=0.001) carrying the G allele than in subjects with other polymorphisms. Both case-control and family-based studies suggest a protective effect of allele CCL2-2578G in Tunisian asthmatic children.     

Single nucleotide polymorphisms in VEGF gene are associated with an increased risk of osteosarcoma

We aimed to assess whether the five common SNPs can affect the risk of osteosarcoma, and its association with demographic characteristics of osteosarcoma. 165 osteosarcoma patients and 330 cancer-free controls were enrolled into our study. Five common SNPs in VEGF gene, -2578C/A (rs699947), -1156G/A (rs1570360), +1612G/A (rs10434), +936C/T (rs3025039) and -634G/C (rs2010963), were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Conditional logistic regression analyses found that individuals with AA genotype and A allele of rs699947 were associated with an increased risk of osteosarcoma. Individuals with GG genotype and G allele of rs2010963 were associated with an increased risk of osteosarcoma. By stratified analysis, AA genotype of rs699947 was associated with an increased risk of osteosarcoma in those with shorter age, males and a family history of cancer, and GG genotype of rs2010963 was correlated with an increased risk of osteosarcoma in those with shorter age, females and a family history of cancer. Our study suggests that rs699947 and rs2010963 polymorphisms may play a role in the pathogenesis of osteosarcoma.     

Association of ABCB1 and VEGFA gene polymorphisms with breast cancer susceptibility and prognosis

Breast cancer (BC) is the most common cause of cancer-related death in women worldwide. Several ABCB1 and VEGFA gene polymorphisms, such as ABCB1-G1199 T/A (rs2229109), VEGFA -634 G > C (rs2010963), VEGFA 2578 C > A (rs699947) and VEGFA 7 C > T (rs25648) have been associated with risk of BC and clinical outcomes. The purpose of this study was to evaluate the association between these gene polymorphisms and BC risk and prognosis.A retrospective case-control study was conducted, including 84 BC cases and 119 controls of Spanish (European, Caucasian) origin. ABCB1-G1199 T/A (rs2229109), VEGFA -634 G > C (rs2010963), VEGFA 2578 C > A (rs699947) and VEGFA 7 C > T (rs25648) gene polymorphisms were analysed by TaqMan®.The genotypic logistic regression model adjusted by aged revealed no association with any of the polymorphisms and BC risk, although the C-allele of VEGFA 2578 C > A showed a trend to higher BC risk in the allelic and recessive models (p = 0.055 and 0.054, respectively). There was no influence of these gene polymorphisms on overall survival (OS). The univariate Cox model showed that carriers of the A-allele for VEGFA 2578 C > A tended to have longer OS compared to CC patients (CC vs A-allele Hazard ratio (HR): 2.08; CI95 % = 0.96–4.49; p = 0.0587). There was no association between the gene polymorphisms analysed and disease-free survival (DFS). The univariate Cox model showed a trend toward a longer DFS in patients carrying ABCB1-G1199 T/A GG genotype compared to those with A-allele (GG vs A-allele HR: 0.43; CI95 % = 0.18–1.03; p = 0.0612).No influence of ABCB1-G1199 T/A (rs2229109), VEGFA -634 G > C (rs2010963), VEGFA 2578 C > A (rs699947) and VEGFA 7 C > T (rs25648) gene polymorphisms on risk of developing BC was found in our study. There was no association between the polymorphisms studied and DFS and OS.     

Vascular endothelial growth factor gene polymorphisms in spontaneously aborted fetuses

Citation Jeon YJ, Kim JH, Rah HC, Kim SY, Yoon TK, Choi DH, Cha SH, Shim SH, Kim NK. Vascular endothelial growth factor gene polymorphisms in spontaneously aborted fetuses. Am J Reprod Immunol 2011; 66: 544–553 Problems The VEGF?1154G>A polymorphism has been reported to be a genetic risk factor for recurrent spontaneous abortion in various studies; however, these studies have focused on genetic analyses of pregnant women rather than aborted fetuses. To evaluate and confirm the association between the VEGF?1154G>A polymorphism and spontaneous abortion, we focused on the relationship between four polymorphisms in the VEGF gene (?2578C>A, ?1154G>A, ?634G>C, and 936C>T) and spontaneously aborted fetuses (SAFs). Method of study The subjects included 118 SAFs at <20 weeks gestation and 380 normal controls consisting of children and adults. The polymorphisms were genotyped by polymerase chain reaction–restriction fragment length polymorphism analysis. Results Spontaneously aborted fetuses exhibited significantly different frequencies of the ?2578CA+AA/?634CC and ?1154GA+AA/?634CC combined genotypes compared with control subjects. The frequency of the ?2578A/?1154A/?634C/936C haplotype was significantly higher in SAFs. Conclusions VEGF genes ?2578CA+AA/?634CC and ?1154GA+AA/?634CC in the fetus are possible risk factors for spontaneous abortion.     

Novel polymorphisms in the promoter and 5' UTR regions of the human vascular endothelial growth factor gene

We have characterized 5 novel, single-nucleotide polymorphisms in the promoter and 5′ UTR regions of the human vascular endothelial growth factor (VEGF) gene. Transitions C → A at nucleotide position −2578 relative to the translation start site, T → C at position −1455, G → A at position −1154, G → C at position −1001, and C → T at position −7 were observed. In addition, individuals with the A allele at position −2578 also had an insertion of 18 nucleotides, whereas CC homozygotes did not contain this insertion. We have described the frequency distribution of the polymorphic alleles in the population of healthy volunteers and are investigating the functional significance of the 18-nucleotide insertion and of the single-nucleotide polymorphisms on VEGF gene expression.