Association Of Vascular Endothelial Growth Factor Gene Polymorphisms Research Articles

Association of VEGF Gene Polymorphisms with Susceptibility to Diabetic Retinopathy: A Systematic Review and Meta-Analysis.

The associations between vascular endothelial growth factor (VEGF) gene polymorphisms and risk of type 2 diabetic retinopathy (DR) - proliferative diabetic retinopathy (PDR), and nonproliferative diabetic retinopathy (NPDR) - remain unclear. A systematic search and meta-analysis using odds ratio (OR) with 95% confidence interval (CI) was performed to evaluate the association. Our study concluded 26 studies containing 10 single nucleotide polymorphisms (SNPs). In Asian populations, rs3025039 polymorphism was associated with DR risk, while in overall populations and Caucasians, the DR risk was increased by association with rs2010963. There was a significant association between rs25648 and rs833061 and DR risk in Caucasians. DR risks were found to be significantly associated between rs3025021, rs13207351, and rs2146323 in either overall populations, Caucasians or Asians. Besides, in overall and Asian populations, rs699947 and rs3025039 were associated with PDR risk. rs1570360, rs3025039, and rs833061 played a key role in PDR etiology in Caucasians. rs2010963 was associated with increased risk of PDR in overall populations. A significant association between rs699947, rs3025039, and rs833061 and NPDR risk in overall populations and Asians was found. A significant association was observed between rs2010963 and increased NPDR risk in overall and Caucasian populations. This study provides a new insight into the parthenogenesis of diabetic retinopathy. Targeting VEGF SNPs may be a potential of therapeutic approach for the treatment of DR, PDR, and NPDR.

Vascular endothelial growth factor (VEGF) gene polymorphisms (rs699947, rs833061, and rs2010963) and psoriatic risk in South Indian Tamils

BackgroundPsoriasis is a chronic inflammatory disease of the skin. Vascular endothelial growth factor (VEGF), a pro-angiogenic factor, is involved in the pathogenesis of psoriasis. Being highly polymorphic, several SNPs of VEGF have been reported to be associated with increased risk of psoriasis. ObjectivesWe determined the association of VEGF gene polymorphisms with risk of psoriasis in South Indian Tamils. Methods300 cases of psoriasis and 300 controls were recruited in this case-control study. Genotyping of SNPs of VEGF gene was done using Taqman 5′ allele discrimination assay. Estimation of VEGF levels in plasma was done by ELISA. ResultsVEGF (rs2010963) polymorphism and the CTC haplotype were found to confer an increased risk of psoriasis. However, two other VEGF SNPs, rs833061, and rs699947, showed no association with psoriasis susceptibility. VEGF levels were higher in patients with psoriasis, as compared with controls and significantly correlated with disease severity. ConclusionsOur results indicate that VEGF (rs2010963) polymorphism and CTC haplotype of the VEGF SNPs (rs699947, rs833061, and rs2010963) confer an increased risk of psoriasis in the South Indian Tamil population. Plasma VEGF levels are higher in patients with psoriasis, as compared with controls and are significantly correlated with disease severity.

Association of VEGF gene polymorphisms with sporadic Parkinson's disease in Chinese Han population.

Recent evidence indicates that vascular endothelial growth factor (VEGF) is capable of protecting dopaminergic (DA) neurons. Parkinson's disease (PD) is a progressive neurodegenerative disease caused by the degeneration of nigrostriatal dopaminergic neurons. To evaluate the role of VEGF single nucleotide polymorphisms (SNPs) and haplotypes in PD, we performed a case-control study including 400 PD patients and 400 healthy-matched controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis and DNA sequencing were used to detect the rs699947, rs2010963 and rs3025039 polymorphisms of the VEGF gene in cases and controls. Our study revealed that T allelic frequency of rs3025039 polymorphism was significantly higher in PD subjects (OR 1.497, 95% CI 1.099-2.040, P=0.013) than that in controls. Significant association for rs3025039 could be found in additive model (TT vs. CT vs. CC: OR 1.489, 95% CI 1.018-2.177, P=0.040) and dominant model (TT+CT vs. CC: OR 1.538, 95% CI 1.068-2.216, P=0.021). Subgroup analyses performed by gender suggested that this association could be found in male, but not in female. Moreover, it also demonstrated a significant association in the subgroup of late-onset PD (LOPD). However, for rs699947 and rs2010963 polymorphisms, genotype or allele frequencies did not differ between groups. No significant association could be found between rs699947 and rs2010963 polymorphism and PD risk. None of the observed haplotypes showed significant association with PD. Therefore, these results suggested that the VEGF gene might be associated with risk of developing sporadic PD in Han Chinese and the rs3025039 polymorphism may be a risk factor for sporadic PD.

Genetic variation in vascular endothelial growth factor gene and its association with recurrent spontaneous abortion.

Vascular endothelial growth factor (VEGF) plays a main role in fetal and placental angiogenesis and is secreted by different cells of endometrium and placenta. In the present study we investigated the association of VEGF gene polymorphisms with recurrent spontaneous abortion (RSA). A case-control study of 100 women with at least two consecutive pregnancy losses before 20 weeks of gestational age and 100 fertile controls was performed to evaluate four VEGF gene polymorphisms including +936C/T (rs3025039), -154G>A (rs1570360), rs3025010 and +5092A/C (rs2146323). Genotyping was performed by PCR based restriction fragment length polymorphism (PCR-RFLP) analysis. Haplotype frequency was estimated for three SNPs' genotypes. Analysis of genetic STRUCTURE and K means clustering were performed to estimate genetic variation. We found an association between -154G/A heterozygous genotype (GA) and RSA. The VEGF single nucleotide polymorphism (SNP) in intron region (rs3025010) in different inheritance models was also associated with RSA. Linkage disequilibrium analysis revealed that VEGF SNP in intron 5 (rs3025010) was linked to promoter region SNP (rs1570360). Cluster analysis including Neighbor Joining and K-means clustering supported genetic differentiation of women with RSA and controls. Allelic polymorphisms in common VEGF SNPs was associated with RSA samples and haplotypes with at least one minor allele showing an association with RSA pathogenesis (Tab. 8, Fig. 2, Ref. 35).

Association of VEGF Gene Polymorphisms with Diabetic Retinopathy: A Meta-Analysis

BackgroundStudies on the association of vascular endothelial growth factor (VEGF) gene -460T/C and -2578C/A polymorphisms with diabetic retinopathy (DR) have reported conflicting results. The aim of the present study was to assess the association by using meta-analysis.MethodsA systematic search of electronic databases (PubMed, EMBASE, Elsevier Science Direct, ISI Web of Science, CBM, CNKI and VIP) was carried out until Sept 18, 2013. The pooled odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were used to assess the strength of the association.ResultsEleven studies (-460T/C: 6 studies including 932 cases and 722 controls; -2578C/A: 6 studies including 1,071 cases and 1,137 controls) were involved in this meta-analysis. Significant association was found for -460T/C polymorphism (C versus T: OR=1.48, 95%CI=1.07–2.05, P=0.02; TC+CC versus TT: OR=1.78, 95%CI=1.02–3.12, P=0.04; CC versus TT+TC: OR=1.76, 95%CI=1.10–2.81, P=0.02), but not for -2578C/A polymorphism (P>0.05). Similar results were found in the subgroup analysis.ConclusionsThis meta-analysis demonstrates that DR is associated with VEGF gene -460T/C polymorphism, but not -2578C/A polymorphism. Further case-control studies based on larger sample size are still needed, especially for -2578C/A polymorphism.

Association of VEGF gene polymorphisms with advanced retinopathy of prematurity: a meta-analysis

Published data on the association of vascular endothelial growth factor (VEGF) gene polymorphisms with retinopathy of prematurity (ROP) are inconclusive. The aim of the study was to assess the association by using meta-analysis. Data were collected from the following electronic databases: PubMed, Elsevier Science Direct, Excerpta Medica Database, Cochrane Library and China National Knowledge Infrastructure, with the last report up to 30 April, 2012. The odds ratio (OR) and its 95 % confidence interval (95 %CI) were used to assess the strength of the association. Meta-analysis was performed in a fixed/random effect model by using the software Review Manager 4.2. A total of 7 studies based on the search criteria were involved in this meta-analysis. Meta-analysis was performed for four VEGF gene polymorphisms (-634G/C, -460T/C, -2578C/A and 936C/T). Significant association was found for -460T/C polymorphism (C vs T: OR = 0.74, 95 %CI = 0.57-0.95, P = 0.02; TC+CC vs TT: OR = 0.75, 95 %CI = 0.47-1.21, P = 0.24; CC vs TT+TC: OR = 0.45, 95 %CI = 0.26-0.76, P = 0.003; CC vs TT: OR = 0.45, 95 %CI = 0.24-0.84, P = 0.01; TC vs TT: OR = 0.96, 95 %CI = 0.59-1.57, P = 0.87) in the VEGF gene, but not for other polymorphisms (-634G/C, -2578C/A and 936C/T). This meta-analysis demonstrates that advanced ROP is associated with VEGF gene -460T/C polymorphism, but not -634G/C, -2578C/A and 936C/T.

Impact of VEGF gene polymorphisms and haplotypes on radiation-induced late toxicity in prostate cancer patients

Vascular endothelial growth factor (VEGF) is an important determinant of microvascular permeability and angiogenesis and has been shown to be up-regulated during the late phase of radiation injury. The present prospective study was performed to evaluate the role of VEGF gene polymorphisms and haplotypes in the development of radiation-induced late side effects in prostate cancer patients. The association of VEGF gene polymorphisms and haplotypes with high-grade late rectal or urinary toxicity (defined as late toxicity EORTC/RTOG ≥ 2) was analyzed using 493 prostate cancer patients from the Austrian PROCAGENE study treated with definitive radiotherapy. Seven candidate polymorphisms in the VEGF gene were selected and determined by 5'-nuclease (TaqMan) assays. Within a median follow-up time of 48 months, 42 patients (8.6%) developed high-grade late rectal and 47 patients (9.6%) urinary toxicity, respectively. In a Kaplan-Meier analysis, carriers of the VEGF -7C > T polymorphism were at increased risk of high-grade late rectal toxicity (p = 0.003) and in a multivariate analysis including clinical and dosimetric parameters as potential confounders the VEGF -7C > T polymorphism remained a significant predictor (HR = 2.8, 95% CI 1.349-5.813; p = 0.006). Furthermore, the ATTGT haplotype formed by five polymorphisms upstream of the coding sequence demonstrated a significant association with late rectal toxicity grade ≥ 2 (p = 0.001). No significant associations were found for the remaining polymorphisms and haplotypes. We conclude that genetic variants in the VEGF gene may influence the risk of high-grade late rectal toxicity after definitive radiotherapy for prostate cancer.

Association of VEGF Gene Polymorphisms with the Development of Heart Failure in Patients after Myocardial Infarction

Objectives: Vascular endothelial growth factor (VEGF) is upregulated in vivoin the ischemic human myocardium. Since several polymorphisms have been shown to influence VEGF expression, we evaluated the contribution of such polymorphisms to the clinical outcome of patients after an acute myocardial infarction (AMI). Methods: PCR and restriction fragment length polymorphism analysis was performed to genotype 10 VEGF polymorphisms in 102 patients who had suffered an AMI and in 98 age- and sex-matched healthy individuals. Distribution of these polymorphisms was assessed by logistic regression analysis. Results: No significant differences were found between patients and normal individuals. However, when patients were subdivided into 2 groups based on the development of heart failure after their AMI judged by heart ultrasound measurements (ejection fraction <40%), the distribution of the –634 polymorphism differed significantly (p = 0.016). Specifically, patients with a CC genotype had 7 times higher risk of developing heart failure. Additionally, the co-inheritance of –634 with other VEGF polymorphisms was found to be significant for the development of heart failure between these 2 groups. Conclusions: Our data indicate that the –634 polymorphism and its co-inheritance with genotypes of other VEGF polymorphisms might be considered as risk factors playing a role in the clinical outcome of AMI patients.

The clinical role of vascular endothelial growth factor (VEGF) system in the pathogenesis of retinopathy of prematurity

Recent experimental studies suggest that vascular endothelial growth factor (VEGF) can play an important role in the development of retinopathy of prematurity (ROP). There are interesting observations of VEGF concentration in the serum, depending on its gene polymorphism which can have an impact on abnormal vessel development in the retina. Analysis of: (1) association of VEGF gene polymorphisms and the incidence of ROP, (2) correlation between serum concentration of VEGF and soluble VEGF receptor 1 (sVEGFR-1) during the 1st month of life and the risk of ROP, and (3) correlation between VEGF gene polymorphisms and VEGF serum concentrations. A sample of 181 newborns with mean birthweight 1054 g (range: 500-1500 g) was prospectively evaluated. Molecular analysis of VEGF -460T>C and 405G>C polymorphisms were performed in the whole studied population, and concentrations of VEGF and sVEGFR-1 were measured by Elisa assay in the 2nd, 3rd and 4th weeks of life in the group of 128 children. The infants were divided into 3 groups: A) no ROP (n = 101), B) ROP not requiring treatment (n = 20), and C) ROP requiring laser or cryotherapy (n = 60). The frequency of VEGF 405G>C polymorphism was similar in all studied groups. The carriage of polymorphic allele -460 T was significantly overrepresented in ROP newborns who required treatment as compared to the no ROP group (54.2% vs 42.6%; OR: 1.63; 95% CI: 1.03-2.55). VEGF serum concentrations in the patients ascribed to different groups depending on the 405G>C or -460 T>C polymorphisms were similar. VEGF and sVEGFR-1 concentration on the 10th day of life did not differ significantly between the studied groups. Consecutive measurements showed a gradual increase in VEGF serum concentration in children without ROP, whereas in children with ROP requiring treatment the levels remained low. Based on our observations and previously published data, the association of the VEGF gene promoter polymorphisms and the risk of advanced ROP is weak. VEGF serum concentration assessment as early as on the 20th day of life appears to be a promising approach to recognize newborns at risk of the development of advanced ROP.

Association of VEGF Gene Polymorphisms with Diabetic Retinopathy in a South Indian Cohort

Background: Polymorphisms in vascular endothelial growth factor (VEGF) gene have been associated with diabetic retinopathy (DR) in various populations. A promoter polymorphism and a 3′UTR variation are studied for association with DR. Materials and Methods: Type 2 diabetic patients with and without retinopathy were recruited. The −634C/G and 936C/T polymorphisms were genotyped by direct sequencing and their frequencies were analyzed using relevant statistical tests. Results: No significant association was observed between genotypes, alleles and haplotypes of −634C/G and 936C/T polymorphisms and DR or its severity. However, C(−634)G genotype was found to increase the risk for DR in patients with microalbuminuria (OR: 8.9, 95% CI: 1.4, 58.3). Conclusion: Our study broadly suggests lack of association of VEGF gene polymorphisms with DR.

Promoter polymorphisms of the vascular endothelial growth factor gene is associated with an osteonecrosis of the femoral head in the Korean population

Disruption of the vascular supply to the bone and subsequent hypoxia has been implicated in the pathogenesis of osteonecrosis of the femoral head (ONFH). Vascular endothelial growth factor (VEGF), a major inducer of angiogenesis, has been correlated with several pathological conditions, from inflammation to ischemic processes. A number of polymorphisms in the VEGF gene have been described as being associated with several diseases, such as diabetic retinopathy, prostate cancer and breast cancer. The aim of this study was to evaluate the association of VEGF gene polymorphisms with ONFH in a case--control study. Three polymorphisms (-2578C>A, -634G>C and +936C>T) in VEGF were genotyped in 317 ONFH patients and 497 control subjects, using the TaqMan 5' allelic discrimination assay. We performed the association analysis of genotyped single nucleotide polymorphisms (SNPs) and haplotypes with ONFH. The -634G>C genotype was significantly associated with an increased risk for ONFH in dominant model with odds ratio (OR) of 1.47, 95% confidence intervals (CIs) 1.08-2.01 with P value 0.015. Further analysis stratified by sex showed that the -634G>C genotype was also significantly associated with a high risk for male patients considering the dominant model with OR of 1.60, 95% CI 1.13-2.26 with P value 0.008. Haplotype association analysis did not provide a further delineation of the risk allele. Our study is, to our knowledge, the first report that shows the -634G>C polymorphism in the VEGF promoter was associated with an increased susceptibility of ONFH in the Korean population.

Association of polymorphisms in vascular endothelial growth factor gene with the age of onset of amyotrophic lateral sclerosis

This study investigated the association between polymorphisms in vascular endothelial growth factor (VEGF) gene (-1558C-T, -1190A-G and -1154A-G) and age at onset of amyotrophic lateral sclerosis (ALS). Between July 2000 and June 2004 we conducted a clinical genetic study at Peking University Third Hospital, China. The analyses included a total of 93 ALS patients. Genotyping was performed by using the 5'-nuclease assay technology (Applied Biosystems) with TaqMan allele-specific fluorogenic oligonucleotide probes. We used multivariate linear regression modelling and haplotype-based association test to analyse the association of VEGF gene polymorphisms with the age of onset, adjusting for initial symptoms and sex. The results indicated that patients with the -1190A/G and -1190G/G genotypes exhibited about a 4.1- and 9.4-years earlier onset of ALS than the patients with the -1190A/A genotype. A similar pattern emerged when the VEGF -1154A-G gene was considered: the beta was -7.9(p<0.001) years and -11.7(p<0.001) years for -1154A/G and -1154G/G genotypes, respectively. The VEGF -1558C-T had a positive effect in the -1558C/T group (p = 0.007, beta = 7.0) and -1558T/T (p<0.001, beta = 9.6) compared to the -1558C/C group. We neither observed an interaction nor haplotype association with age onset among -1558C-T, -1190A-G and -1154A-G. In conclusion, our results indicate, for the first time, that there was an important association between the polymorphism of the VEGF gene and age of ALS onset. This suggests a possible role for VEGF variability in the aetiology of individual differences in ALS onset.