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.     

Vascular Endothelial Growth Factor Gene Polymorphisms May Predict the Risk of Acute Graft-versus-Host Disease following Allogeneic Transplantation: Preventive Effect of Vascular Endothelial Growth Factor Gene on Acute Graft-versus-Host Disease

Microvessel injury is associated with the development of graft-versus-host disease (GVHD), whereas high levels of posttransplantation vascular endothelial growth factor (VEGF) have a protective effect on severe acute GVHD (aGVHD) and transplantation-related mortality. The current study aimed to determine the impact of VEGFA gene single-nucleotide polymorphisms (SNPs) on the risk of aGVHD after allogeneic stem cell transplantation (SCT). Using polymerase chain reaction and restriction fragment length polymorphism, 4 VEGFA SNPs— -2578 C>A (rs699947), -460 T>C (rs833061), +405 G>C (rs2010963), and +936 C>T (rs3025039)—were analyzed in 98 recipients. Strong linkage disequilibrium was noted among loci -2578, -460, and +405, but not among these loci and locus +936. Accordingly, 4 haplotypes were generated based on the genotypes of -2578, -460, and +405: CTC (47.9%), CTG (26.7%), ACG (24.2%), and CCC (1.0%). The group with low VEGF production (ie, +936CT genotype and 2 copies of the ACG haplotype) had a higher incidence of aGVHD. Significant associations were found between the risk of grade 2-4 aGVHD and the +936 CT (P = .006), -2578 AA (P = .003), and -460 CC (P = .002) genotypes and the ACG haplotype (P = .003). No association between the VEGFA SNPs and chronic GVHD was observed. The VEGFA SNPs might predict a lower risk of aGVHD. Our findings suggest that VEGF may have a protective role in the pathogenesis of aGVHD.     

Impact of VEGF polymorphisms on the severity of peripheral artery disease in diabetic patients

Objective. To determine the potential genotype vascular endothelial growth factor (VEGF) gene differences in diabetic patients with peripheral arterial disease (PAD), which might be associated with different stages of the vascular disease. Methods. A study was conducted with type 2 diabetic patients with PAD [n = 70; 32 intermittent claudication and 38 critical limb ischaemia (CLI)]. Genotyping of the VEGF gene insertion/deletion ? 2549, ? 2578 C/A and +405 G/C polymorphisms was done in both groups and correlated them with the severity of PAD. We compared serum VEGF levels in both groups. Results. There was a higher frequency of +405 CC and ? 2578 CC genotypes in claudication group [(31.3% vs. 5.4%, p = 0.01) and (37.5% vs. 15.8%, p = 0.05), respectively]. The presence of +405 GG and ? 2578 AA genotypes was more common among CLI patients [(57.8% vs. 37.5%, p = 0.01) and (42.1% vs. 18.8%, p = 0.05), respectively]. There were higher serum VEGF levels in patients with CLI (p = 0.029). Conclusions. We found preliminary evidence regarding the association between VEGF polymorphisms and different stages of PAD in diabetic patients.     

Case-control study of vascular endothelial growth factor (VEGF) genetic variability in Alzheimer's disease

Vascular endothelial growth factor (VEGF) is a major regulator of angiogenesis and blood vessel function. Recent evidence indicates that VEGF facilitates memory and learning through stimulating angiogenesis and neurogenesis in the rat hippocampal dendate gyrus. Abnormal regulation of VEGF expression has been reported in the pathogenesis of both atherosclerosis and motoneuron degeneration in amyotrophic lateral sclerosis, with low VEGF-producing polymorphisms (-2578 allele A and -634 allele G) conferring increased susceptibility for the development of the disorders. We tested whether these polymorphisms downregulating expression of VEGF might increase the risk of developing Alzheimer's disease (AD). So, we performed a case-control study in 362 Spanish AD patients and 428 healthy controls. The current study does not demonstrate an association between VEGF (-2578) and VEGF (-634) genotypes or haplotypes and AD.     

Vascular endothelial growth factor gene +405 C/G polymorphism is associated with susceptibility to advanced stage endometriosis

BACKGROUND: Vascular endothelial growth factor (VEGF) is known to play a pivotal role in the development of endometriosis. This study was performed to investigate whether the VEGF gene 5'-untranslated region polymorphism is associated with susceptibility to advanced stage endometriosis. METHODS: This study comprised 215 women with advanced stage endometriosis, 219 control women without endometriosis, and 70 fertile women. Following extraction of genomic DNA, genotyping of the -460 C/T and +405 C/G polymorphisms of the VEGF gene were performed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. RESULTS: The distribution of genotypes and allele frequencies of the -460 C/T polymorphism in the endometriosis group did not differ from those in the control group and the fertile women group. However, genotype distribution of the +405 C/G polymorphism was significantly different between patients with and without endometriosis (P = 0.01) and between patients with endometriosis and the fertile women (P = 0.02). Patients with endometriosis showed a higher incidence of the +405 CC genotype compared with the controls and the fertile women (P = 0.007 and 0.016 respectively). CONCLUSIONS: These findings suggest that the VEGF +405 C/G polymorphism may be associated with the risk of advanced stage endometriosis in the Korean population.     

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.     

−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.     

Vascular endothelial growth factor +405 G/C,−460 T/C and −2578 A/C polymorphisms are not associated with insulin resistance in polycystic ovary syndrome

Insulin resistance (IR) and pancreatic β-cell dysfunction are usual comorbidities in polycystic ovary syndrome (PCOS). Vascular endothelial growth factor (VEGF) is known to play an important role in the pathogenesis of PCOS. This study examined firstly the possible association of common +405 G/C,−460 T/C and −2578 A/C polymorphisms of VEGF gene with fasting glucose, fasting insulin and the indices of IR [glucose/insulin ratio (GIR), homoeostasis model assessment (HOMA) and quantitative insulin sensitivity check index (QUICKI)] in 137 patients with PCOS. None of the studied polymorphisms were found to affect IR indices significantly. However, there was a trend towards higher HOMA in +405 G and −460 T allele carriers in comparison with homozygotes +405 CC and −460 CC, respectively. With regard to −2578 A/C polymorphism, although not significant, in −2578 C carriers HOMA was lower, and GIR was higher in comparison with −2578 AA genotype. Alteration of QUICKI between genotypes was minimal and varied from 4% to 7%. Because of the relatively small sample size, more studies with greater number of cases are necessary to confirm our observations before any statement can be made about the relationship between VEGF gene polymorphism and IR parameters in PCOS.     

Vascular endothelial growth factor gene +813CC polymorphism of foetus is associated with preterm labour but not with pre-eclampsia in Turkish pregnant women

We investigated the effect of polymorphism at +813 locus of vascular endothelial growth factor (VEGF) gene on predisposition to preterm labour and pre-eclampsia (PE). We examined polymorphism of the VEGF +813 gene of foetuses from umbilical cord blood in 31 cases of preterm labour, 34 pre-eclamptic and 58 healthy term labour. VEGF +813 gene polymorphisms were studied using a polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. In preterm group, foetal CC genotype was found at 80.6%, and CT genotype was seen at 19.4%. No any TT genotype was detected in preterm group. CC genotype of VEGF 813 gene was significantly more frequent than CT genotype (P = 0.04). Foetuses with CC genotype VEGF+813 gene have an increased risk for preterm labour. C allele frequency was 90.3 and 76.7% in preterm and control groups, respectively. T allele frequency was 9.7 and 23.3% in preterm and control groups, respectively. C allele was significantly associated with preterm labour (P = 0.02). OR of C and T alleles for preterm labour was 2.8 (CI: 1.1-7.2). In PE group, foetal CC genotype of +813 locus was found in 67.6%, and CT genotype was seen in 29.4%. Only one TT genotype was detected in 2.9% of PE group. There was no association between PE and VEGF gene genotypes and alleles at +813 locus. These results suggest that foetal VEGF gene polymorphism of +813 CC seems to be highly associated with preterm labour, whereas in PE, foetal VEGF gene polymorphism at +813 locus is not related. Especially, C allele was significantly associated with preterm labour. Carriage of the +813C allele of the VEGF gene has been found 2.8 times increased susceptibility to the development of preterm labour in Turkish women and may be an independent risk factor for prematurity. There was no association between PE and VEGF gene genotypes and alleles at +813 locus. We suggest to search for foetal aetiologies or genetic susceptibility in preterm labour, whereas in PE, not foetal, but maternal susceptibility is to be investigated.     

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.     

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.     

Meta-analysis of vascular endothelial growth factor variations in amyotrophic lateral sclerosis: increased susceptibility in male carriers of the -2578AA genotype

BACKGROUND: Targeted delivery of the angiogenic factor, vascular endothelial growth factor (VEGF), to motor neurons prolongs survival in rodent models of amyotrophic lateral sclerosis (ALS), while mice expressing reduced VEGF concentrations develop motor neuron degeneration reminiscent of ALS, raising the question whether VEGF contributes to the pathogenesis of ALS. An initial association study reported that VEGF haplotypes conferred increased susceptibility to ALS in humans, but later studies challenged this initial finding. Methods and findings: A meta-analysis was undertaken to critically reappraise whether any of the three common VEGF gene variations (-2578C/A, -1154G/A and -634G/C) increase the risk of ALS. Over 7000 subjects from eight European and three American populations were included in the analysis. Pooled odds ratios were calculated using fixed-effects and random-effects models, and four potential sources of heterogeneity (location of disease onset, gender, age at disease onset and disease duration) were assessed. After correction, none of the genotypes or haplotypes was significantly associated with ALS. Subgroup analysis by gender revealed, however, that the -2578AA genotype, which lowers VEGF expression, increased the risk of ALS in males (OR = 1.46 males vs females; 95% CI = 1.19 to 1.80; p = 7.8 10E-5), even after correction for publication bias and multiple testing. CONCLUSIONS: This meta-analysis does not support the original conclusion that VEGF haplotypes increase the risk of ALS in humans, but the significant association of the low-VEGF -2578AA genotype with increased susceptibility to ALS in males reappraises the link between reduced VEGF concentrations and ALS, as originally revealed by the fortuitous mouse genetic studies.     

The vascular endothelial growth factor (VEGF) +405G>C 5'-untranslated region polymorphism and increased risk of endometriosis in South Indian women: a case control study

BACKGROUND: Vascular endothelial growth factor (VEGF), a major mediator of angiogenesis and vascular permeability, is known to play a key role in the pathophysiology of endometriosis. METHODS AND RESULTS: The single nucleotide polymorphisms, -460C>T and +405G>C, in the 5'-untranslated region of the VEGF gene were tested for association in a case-control study of 215 affected women and 210 women with no evidence of disease. All the women were of South Indian origin and ascertained from the same infertility clinic. The genotype and allele frequencies of the -460C>T polymorphism did not differ significantly between cases and controls. In contrast, the genotype (P = 0.002) and allele (P = 0.001) frequencies of the +405G>C polymorphism showed a significant difference between cases and controls. The +405 GG genotype was found more often in patients with an endometrioma >3 cm compared to controls. The frequency of the -460T/+405C haplotype (P = 0.016) was significantly lower in affected women compared to controls. CONCLUSIONS: The -460T/+405C haplotype in the VEGF gene, which is associated with lower promoter activity, was significantly less common in women with endometriosis than in controls. These data suggest that the +405G allele may influence the likelihood of a woman developing the disease.     

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.     

Haplotype analysis of single nucleotide polymorphisms in VEGF gene for vascular dementia.

A case-control study was performed to identify single nucleotide variants of vascular endothelial growth factor (VEGF) gene associated with vascular dementia. Seven SNPs in promoter, 5'-UTR, 3'-UTR, and introns of VEGF gene were identified in 24 Koreans. Three of them, -1154G/A, -7C/T, and 13553C/T, were selected based on allele frequency and linkage disequilibrium (LD), and genotyped in 207 vascular dementia patients and 207 control subjects. Significant association with vascular dementia was not shown (P > 0.05) in the alleles and genotypes of single locus. Subsequent analysis of composing VEGF risk haplotypes associated with vascular dementia was performed with maximum likelihood estimates of their possible haplotypes employing the expectation-maximization (EM) algorithm. Of three-locus haplotypes, only GTC was significantly associated with vascular dementia, conferring a risk of 1.87 (P < 0.05). Of two-locus haplotypes, the risk was observed with the nested forms of the risk haplotype GTC, that is, GT at the loci -1154G/A and -7C/T and TC at the loci -7C/T and 13553C/T (P < 0.05). Our findings suggested some interaction among -1154G/A, -7C/T, and 13553C/T variants in the determination of risk for vascular dementia.     

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.     

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.     

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.