Vascular Endothelial Growth Factor Haplotypes Research Articles

Vascular endothelial growth factor haplotypes are associated with severe ischaemic complications in giant cell arteritis regardless of the disease phenotype.

To determine whether functional vascular endothelial growth factor (VEGF) polymorphisms influence the expression of the clinical phenotype of giant cell arteritis (GCA). We also evaluated whether VEGF polymorphism is associated with the development of severe ischaemic manifestations in patients with GCA regardless of the clinical phenotype, classic cranial GCA or predominantly extracranial GCA large vessel vasculitis (LVV). VEGF rs833061 T/C, rs2010963 G/C and rs3025039 C/T polymorphisms were genotyped in 185 patients with biopsy-proven cranial GCA, 105 with extracranial LVV-GCA and 490 healthy controls. Allelic combinations (haplotypes) of VEGF were carried out. Comparisons were performed between patients with GCA and healthy controls as well as between patients with GCA stratified according to the clinical phenotype and the presence of severe ischaemic manifestations. No significant differences in genotype, allele, and haplotype frequencies of VEGF were found between patients with GCA and healthy controls as well as between GCA patients with the classic cranial pattern and the extracranial LVV-GCA pattern of the disease. However, the VEGF CGC haplotype (OR= 1.63 [1.05-2.53]) and the CGT haplotype (OR= 2.55 [1.10-5.91]) were significantly more frequent in GCA patients with severe ischaemic complications compared to those patients without these complications. VEGF haplotypes seem to play a role in the development of severe ischaemic manifestations in GCA patients, regardless of the clinical phenotype of expression of the disease.

Vascular Endothelial Growth Factor (VEGF) Polymorphisms and Serum VEGF Levels in Women With Epithelial Ovarian Cancer, Benign Tumors, and Healthy Ovaries.

This study analyzed the relation of 5 single-nucleotide polymorphisms (SNPs) in the VEGF (vascular endothelial growth factor) gene in patients with epithelial ovarian cancer (EOC), compared with patients carrying benign tumors or healthy ovaries. We studied serum VEGF levels and the relation with SNPs and association between VEGF SNPs and haplotypes with progression-free survival (PFS) in patients with cancer. The genotyping of VEGF gene polymorphisms (-2578 C/A, -1154 G/A, -460 T/C, +405 G/C, +936 C/T) was performed in DNA isolated from blood samples of 100 women. The different genotypes were evaluated by quantitative real-time polymerase chain reaction. Vascular endothelial growth factor protein concentration was assessed in serum using solid-phase sandwich enzyme-linked immunosorbent assay. We found statistically significant differences in the distribution of VEGF genotypes among the 3 groups of patients: -2578 C/A between those with EOC and healthy ovary (P = 0.04), -460 T/C between those with EOC and healthy ovary (P = 0.03), and -460 T/C between those with benign tumors and healthy ovary (P = 0.02). Vascular endothelial growth factor serum levels were analyzed in patients with EOC. Higher levels were found in patients with clear cell carcinoma compared with those with serous, mucinous, or endometrioid tumors (P < 0.05). No clear association was observed between VEGF SNPs and serum VEGF levels. There was no significant correlation between VEGF SNPs and PFS. In haplotype analysis, CGTCT and CGTGT showed worse prognosis without reaching the statistical significance. CGCGC and AGTGC haplotypes had statistically significant differences among patients with EOC, benign tumors, and healthy ovaries (Ps = 0.046 and 0.041, respectively). The distribution of VEGF genotypes was different in patients with EOC, compared with those with benign tumors or women with healthy ovaries. Vascular endothelial growth factor serum levels were higher in patients with clear cell carcinoma. No correlation was found with improved PFS, but CGTCT and CGTGT haplotypes showed worse prognosis.

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.

Relationship of common vascular endothelial growth factor polymorphisms and haplotypes with the risk of cervical cancer in Tunisians

ObjectiveWe investigated the association between common vascular endothelial growth factor (VEGF) single nucleotide polymorphisms (SNPs) and the risk of cervical cancer (CC) in Tunisian patients and control women. MethodsStudy subjects comprised 86 CC cases and 124 control women. Genotyping of VEGF rs699947, rs833061, rs1570360, rs2010963, rs25648, rs833068, rs833070, rs3025039 SNPs was done by real-time PCR. ResultsHigher minor allele frequencies (MAF) of rs699947 (−2578C/A) [P=0.04; OR (95% CI)=1.52 (1.02–2.29)], and rs1570360 (−1154G/A) [P=0.04; OR (95% CI)=1.58 (1.01–2.47)] were seen in CC cases compared to control women. Marked differences in the distribution of rs699947 (P=9×10−4) and rs1570360 (P=0.03) genotypes were seen between CC cases and control groups; the distribution of the remaining SNPs was comparable between CC cases and control women. The association of rs699947 and rs1570360 with heightened CC risk with was seen in the heterozygous, and more so in the homozygous states. Haploview analysis revealed high LD between rs699947, rs833061, rs1570360, rs2010963, rs25648, rs833068 and rs833070 but weak or no LD between rs3025039 and the other SNPs. Seven-locus (rs699947/rs833061/rs1570360/rs2010963/rs25648/rs833068/ rs833070) haploview analysis identified only CTGCCAG haplotype to be positively associated with CC [P=0.022; OR(95% CI)=1.74 (1.08–2.79)]. ConclusionSpecific VEGF variants (rs699947, rs1570360) and haplotype (CTGCCAG) may contribute to the development of CC among Tunisian women.

Genetic polymorphisms of vascular endothelial growth factor and risk for retinopathy of prematurity in South of Iran

Retinopathy of prematurity (ROP) is a multifactorial disease, that cause visual impairment in premature children. The exact pathogenesis and etiology of ROP is unknown and genetic susceptibility is considered as risk factor. Vascular endothelial growth factor (VEGF) plays a major role in retinal neovascularization and subsequently retinal detachment. VEGF polymorphism is associated with proliferative ROP in some studies. We examined the possible association of the VEGF gene polymorphisms with ROP in preterm infants in south of Iran. A total of 111 preterm infants were examined by ophthalmologist and after that were genotyped. Genotyping of the VEGF +405 (rs2010963) and VEGF +936 (rs3025039) was done by the polymerase chain reaction and restriction fragment length polymorphism methods. The frequency of VEGF alleles, genotypes and haplotype distribution were compared between groups. The patients were divided in three groups: 66 to the normal group (normal fundoscopy), and 45 to the ROP group; 30 infants were not treated with Lasertherapy (Regressive group) and 15 treated with Lasertherapy. The frequency of VEGF +405 and VEGF +936 G/C genotypes as well as allele frequencies was not different between groups. No significant difference was found between ROP with treatment and ROP without lasertherapy. Our report indicate that there is no association between the carrier states of gene polymorphisms VEGF +405, VEGF +936 and progression or spontaneous regression of ROP in preterm infants in Iranian population. However, it should be considered that angiogenesis is a complex process and genetic factors in addition to environmental factors are contributed in this pathway.

Association of VEGF and KDR single nucleotide polymorphisms with colorectal cancer susceptibility in Koreans

Vascular endothelial growth factor (VEGF) and its receptor kinase insert domain-containing receptor (KDR) play crucial roles in angiogenesis, which contributes to the development and progression of solid tumors. The aim of this study was to investigate the associations of VEGF (-2578C > A, -1154G > A, -634G > C, and 936C > T) and KDR (-604T > C and 1192G > A) polymorphisms with the development of colorectal cancer (CRC). A total of 882 participants (390 CRC patients and 492 controls) were enrolled in the study. The genotyping of VEGF and KDR polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism assay. We found that the CT and TT genotype of the 936C > T was associated with an increased risk of CRC compared with the CC genotype as the dominant model for the T allele. In addition, we also found a increased CRC risk with TC + CC genotype of KDR -604T > C compared with TT genotype in CRC patients and control subjects. Similarly, KDR 1192G > A also showed significant association between 1192G > A variants and risk of CRC. In the haplotype analyses, haplotype -2578A/-1154A/-634G/936T of VEGF polymorphisms and haplotype -604C/1192G and -604C/1192A of KDR polymorphisms were associated with an increased susceptibility of CRC. Our results suggest that the VEGF 936C > T, KDR -604T > C, and KDR 1192G > A polymorphisms may be contribute to CRC risk in the Korean population.

The relation of vascular endothelial growth factor (VEGF) gene polymorphisms on VEGF levels and the risk of vasoocclusive crisis in sickle cell disease

The association of vascular endothelial growth factor (VEGFA) variants and VEGF secretion with sickle cell disease (SCD) vasoocclusive crisis (VOC) was investigated in 210 VOC patients and 114 pain-free control patients. VEGFA -2578C/A (rs699947), -460T/C (rs833061), -1154G/A (rs15703060), -634G/C (rs2010963), 398G/A (rs833068), 497G/A (rs833070), -583T/C (rs3025020), and 936C/T (rs3025039) were carried out by real-time PCR. Higher frequency of rs2010963 C-allele, rs833068 A-allele, and rs3025020 C-allele and significant differences in rs2010963, rs833068, and rs3025020 genotype distribution were seen in VOC than steady-state patients. Increased VOC risk was seen with rs2010963 as heterozygous and more as homozygous, and in rs833068 and rs3025020 homozygous carriers. While there were no differences in VEGF levels between VOC and steady-state controls, there was a progressive decline in serum VEGF in rs2010963 and rs833068 heterozygous and homozygous genotypes, but an opposite trend was seen in VOC patients. Haploview analysis revealed high LD between rs699947, rs833061, rs1570360, rs2010963, rs833068, and rs833070, but weak or no LD between rs3025020 and rs3025039 and other SNPs. Six-locus (rs699947/rs833061/rs1570360/rs2010963/rs833068/rs833070) VEGFA haplotype analysis identified haplotype 111111 to be negatively (OR = 0.68) and haplotype 111222 to be positively (OR = 1.89) associated with VOC. rs2010963, rs833068, and rs3025020 were correlated with VOC type, while rs3025020 was correlated with hospitalization, VOC treatment, and duration. Specific VEGFA variants contribute to the pathogenesis of SCD VOC.

Haplotypes in candidate genes related to nitric oxide pathway and vascular permeability associated with migraine and aura

Dear Editor, In a recent article in Journal of Headache and Pain, Markus Schurks has reviewed current findings on migraine genetics identified by both candidate gene approaches and genome-wide association studies [1]. We would like to contribute to some candidate gene studies focused on endothelial function possibly involved in migraine pathophysiology, which reported associations of haplotypes with migraine with aura (MA) or with aura in migraine patients [2–4]. This common condition has gained much attention because it is now recognized as an established risk factor for cardiovascular disease and ischemic stroke [5]. We have studied three clinically relevant SNPs in the vascular endothelial growth factor (VEGF) promoter region; C−2578A (rs699947), G−1154A (rs1570360), and G−634C (rs2010963) and found that haplotype “AGC” was more frequent in MA than controls (P = 0.0023) [2]. We have also examined three clinically relevant endothelial nitric oxide synthase (eNOS) polymorphisms; T−786C (rs2070744), an Intron 4 VNTR and Glu298Asp (rs1799983), and two tagSNPs rs3918226 and rs743506. Our findings suggest that haplotypes “CCaGluG” and “CCbGluG” are associated with increased susceptibility to the presence of aura in patients with migraine (both P < 0.001) [3]. Finally, we have also examined two functionally relevant polymorphisms of inducible nitric oxide synthase (iNOS); C−1026A (rs2779249) and G2087A (rs2297518). The haplotype “AA” was more commonly found in MA than in patients without aura (P = 0.0027) [4]. Gene–gene interaction studies among candidate genes are further required in order to better elucidate the genetic basis of migraine, as previously pointed out elsewhere [6]. Therefore, we are currently performing interaction analysis among the polymorphisms previously reported [2–4]. However, our findings on eNOS, iNOS and VEGF haplotypes must be replicated in populations with different genetic backgrounds, which will further validate the role of these candidate genes associated with migraine and aura and may provide clinically relevant information to migraine susceptibility.

Identification of specific vascular endothelial growth factor susceptible and protective haplotypes associated with recurrent spontaneous miscarriages

We investigated the association of vascular endothelial growth factor (VEGF) gene polymorphism with recurrent spontaneous miscarriage (RSM). VEGF -2578C/A, -1154G/A, -634G/C, +936C/T single nucleotide polymorphisms (SNPs) were assessed in 304 RSM patients, and 371 age-and body mass index-matched control subjects using real-time PCR. Higher minor allele frequency of -1154G/A (P < 0.001) and +936C/T (P < 0.001), but not -2578C/A (P = 0.55) or -634G/C (P = 0.87) SNPs, were seen in patients. Significant differences in the distribution of -1154G/A (P = 0.006) and +936C/T (P = 0.015), but not -2578C/A (P = 0.473) or -634G/C (P = 1.000) genotypes, were seen in cases compared with control women. Of the possible 16 VEGF haplotypes, 9 were found to be common, and were included. A significantly lower frequency of C G C C (P = 0.008), and A G G C (P < 0.001) haplotypes, and a higher frequency C G C T (P = 0.020), and C G T (P = 0.004) haplotypes were seen in patients. These results strongly support that VEGF polymorphisms, in particular-1154G/A and +936C/T, are significantly associated with RSM. Our results confirm, in the largest sample to date, previous works in other populations on VEGF polymorphism in RSM.

Functional VEGF haplotypes affect the susceptibility to hypertension

We examined whether vascular endothelial growth factor (VEGF) polymorphisms (C-2578A, G-1154A and G-634C) are associated with hypertension, response to antihypertensive therapy and nitric oxide (NO) formation. Substudy 1 compared the distribution of VEGF genotypes and haplotypes in 178 patients with arterial hypertension (100 whites and 78 blacks) and 186 healthy controls (115 whites and 71 blacks). Substudy 2 compared the distribution of VEGF markers in 82 patients with controlled hypertension, 89 patients with resistant hypertension and 101 normotensive (NT) patients. In substudy 3, plasma nitrite/nitrate (NOx) levels were determined (chemiluminescence assay) in 64 NT subjects and 48 hypertensive (HTN) subjects, and the distribution of VEGF markers was compared in subjects having low NOx with subjects having high NOx. Although the substudy 1 showed no differences in genotypes or allele distributions for the three VEGF polymorphisms between NT and HTN subjects, the 'C-A-G' haplotype was more common in white NT subjects than in the white HTN subjects, and the 'C-A-C' haplotype was more frequent in black and white HTN subjects than in black and white NT subjects. The substudy 2 showed similar results, with no differences between responsive and resistant HTN subjects. The substudy 3 showed that the 'C-A-G' haplotype, which had a protective effect against hypertension, was significantly more common in subjects with higher NOx concentrations than in subjects with lower NOx concentrations. VEGF haplotypes are associated with hypertension, and the haplotype associated with normotension was more common in subjects with increased NO formation, possibly offering a mechanistic clue for our findings.

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.

Contribution of VEGF polymorphisms to variation in VEGF serum levels in a healthy population

Vascular endothelial growth factor (VEGF) is a pro-angiogenic factor. Variability in VEGF expression, induced by specific VEGFA variants, are involved in angiogenesis-related disorders. This study examined the genotype distribution and functional role (VEGF expression) of rs699947, rs833061, rs1570360, rs2010963, rs833068, rs833070, rs3025020, and rs3025039 VEGFA variants and their haplotypes in 519 healthy Bahraini individuals of both genders. The distribution of the eight VEGFA polymorphisms screened was in Hardy-Weinberg equilibrium. The minor allele frequencies of rs699947 (0.42), rs833061 (0.32), rs1570360 (0.31), rs2010963 (0.33), rs833068 (0.37), rs833070 (0.42), rs3025020 (0.33), and rs3025039 (0.13) were generally compared to those established for Caucasians. Of the variants tested, rs3025020 was associated with increased VEGF serum levels (p=0.019), while rs3025039 was associated with decreased levels (p=0.038). Linkage analysis identified two VEGFA blocks, the first, spanning 16 kb, was not associated with altered VEGF levels, while the second, spanning 3 kb containing rs3025020 and rs3025039, was linked with higher VEGF expression, of which the (-583)T/(+936)T haplotype (p=0.008) was linked with higher VEGF levels compared to the (-583)C/(+936)C (all wild-type) haplotype. These results support the association of rs30250202 and rs3025039, and specific VEGF haplotypes, with altered VEGF serum levels, although the exact functional mechanisms remain to be elucidated.

Vascular endothelial growth factor polymorphisms in patients with steroid-induced femoral head osteonecrosis

To investigate an association between steroid-induced femoral head osteonecrosis (FHON) and functional vascular endothelial growth factor (VEGF) gene (-2578A/C, -1154A/G, -634C/G, and +405C/G) polymorphisms polymerase chain reaction-restriction fragment length polymorphism genotyping was performed in 160 patients (86 idiopathic FHON and 74 steroid-induced FHON) and 160 gender- and age-matched controls. The steroid-induced subgroup had a significantly lower prevalence of -1154A allele (7.4% vs. 18.1%, odds ratio (OR) = 0.363) and genotype carrying -1154A (14.9% vs. 32.5%, OR = 0.333 in a recessive model) than controls. In a dominant model, the frequency of genotype carrying +405G (74.3% vs. 84.4%, OR = 0.492) was significantly lower in steroid-induced FHON than in controls. The distribution of haplotypes was significantly different between controls and FHON patients (p = 0.00011). Especially, when haplotypes were classified into high (CGCG and AAGG) or low (CGGC and AGGC) VEGF inducing haplotypes, patients with steroid-induced FHON had a significantly lower prevalence of high inducing haplotypes (7.4% vs. 15.9%, OR = 0.424) and a significantly higher prevalence of low inducing haplotypes (4.7% vs. 0.6%, OR = 7.894) than controls. Low inducing VEGF haplotypes may confer an increased risk and high inducing haplotypes have a protective effect for the development of steroid-induced FHON in Korea.

Vascular Endothelial Growth Factor Haplotypes Associated with Childhood Obesity

Expansion of adipose tissue in obesity is associated with angiogenesis and adipose tissue mass depends on neovascularization. Vascular endothelial growth factor (VEGF) is the main angiogenic factor in the adipose tissue, and VEGF expression is tightly regulated at both transcriptional and translational levels. However, no previous study has tested the hypothesis that genetic polymorphisms in the VEGF gene could affect susceptibility to obesity. To test this hypothesis, we compared the distribution of genotypes and haplotypes including three VEGF genetic polymorphisms in obese children and adolescents with those found in healthy controls. We studied 172 healthy children and adolescents and 113 obese children and adolescents. Genotypes of three clinically relevant VEGF polymorphisms in the promoter region (C-2578A, G-1154A, and G-634C) of the VEGF gene were determined by TaqMan allele discrimination assay and real-time polymerase chain reaction. VEGF haplotypes were inferred using Haplo.stats and PHASE 2.1 programs. We found no differences in the distributions of VEGF genotypes and alleles (p > 0.05). However, the CAG haplotype was more frequent in the obese group than in the control group (4% versus 0%, respectively, in white subjects; p = 0.008; odds ratio = 10.148 (95% confidence interval: 1.098-93.788). Our findings suggest that VEGF haplotypes affect susceptibility to obesity in children and adolescents.

Genetics: 49. Polymorphism in the Promoter Region of the Vascular Endothelial Growth Factor Gene is Associated with Serum Vegf Level and Disease Activity in RA

Background: Previous studies have demonstrated that the vascular endothelial growth factor (VEGF) level is associated with disease activity and severity in rheumatoid arthritis (RA). Polymorphism in the VEGF gene has also been associated with susceptibility to RA, but the relationship of VEGF genetic variants with RA activity and severity measures is unclear. The aim of this study was to determine whether common VEGF polymorphisms (VEGF-2578/-460/+405/+936) are associated with serum levels of VEGF in patients with RA, and to assess whether these genetic variants are associated with disease activity and/or severity of RA. Methods: Serum levels of VEGF were measured using a fluorescent bead-based assay system in a cohort (n = 410) of consecutively recruited RA patients of Caucasian origin. Genotyping of the four VEGF SNPs in the same patients was carried out using PCR-RFLP methods. RA clinical variables such as IgM RF (+/-), anti-CCP (+/-), ESR, DAS-28, HAQ and serum levels of CRP, MMP-1 and −3 were obtained for each patient. Demographic characteristics were also recorded. Associations were first analyzed using univariate statistics. Thereafter, multivariate multiple regression was applied to assess the independence of associations and to adjust for possible confounding factors. Results: We confirmed in this patient group that serum VEGF level was correlated with various markers such as ESR (r = 0.12, p = 0.015), CRP (r = 0.14, p = 0.004), MMP-1 (r = 0.15, p = 0.003) and MMP-3 (r = 0.13, p = 0.009). It was also strongly associated with disease activity (as measured by DAS-28, p < 0.0001) and functional outcome (as measured by HAQ score, p = 0.001), independent of age, sex and disease duration. Serum VEGF levels were significantly lower in patients carrying the AA genotype of VEGF-2578, compared to that in subjects with a C allele (74.0 vs 85.7 pg/ml, p = 0.033). Other VEGF SNPs or haplotypes were not associated with serum VEGF levels. VEGF-2578 AA was found to be associated with lower DAS-28 (p = 0.046) after adjustment for age, sex, RA duration, and levels of VEGF, MMP-1 and −3. Haplotype analysis demonstrated that A-C-G (-2578/-460/+405), the most frequent haplotype (48.3%), was associated with lower DAS-28 (p = 0.017). Regression analyses suggested that VEGF-2578 SNP associations were independent of VEGF serum level associations. Conclusions: The VEGF-2578 SNP is associated with the serum VEGF level in RA, and may play an additional role in RA disease activity apart from its influence on VEGF expression. Disclosure statement: The authors have declared no conflicts of interest.

Association of vascular endothelial growth factor gene polymorphisms with osteoporotic vertebral compression fractures in postmenopausal women

Vascular endothelial growth factor (VEGF) is involved in bone formation through its role in angiogenesis. VEGF is also known to promote the healing of fractures. Thus, we determined whether or not VEGF −2578C>A, −1154G>A, −634G>C, and 936C>T polymorphisms and haplotypes are associated with osteoporotic vertebral compression fractures (OVCF) in postmenopausal Korean women. The study subjects consisted of 82 patients with osteoporotic vertebral compression fractures and 117 control postmenopausal Korean women. PCR-RFLP and real-time PCR were used to analyze the VEGF polymorphisms. Homocysteine levels were also measured to determine whether or not polymorphisms of the VEGFgene affect homocysteine/folate metabolism. The AA genotype of the −2578C>A polymorphism was significantly different between the stroke and control groups; no significant differences in the −1154G>A, −634G>C, and 936C>T genotype frequencies existed. However, the A-G-G-C haplotype had a tendency to be associated with OVCF in postmenopausal Korean women. Associations between the VEGF −2578C>A polymorphism and homocysteine levels were also noted. In summary, these results suggest that the VEGF −2578C>A polymorphisms and VEGF haplotypes may play an important role in the etiology of OVCF in postmenopausal Korean women.

VEGF Haplotypes are Associated with Increased Risk to Progressive Supranuclear Palsy and Corticobasal Syndrome

Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are in the spectrum of tauopathies and recognized to have a strong genetic background. It has been widely reported that MAPT tau haplotype H1 is a genetic risk factor in both conditions, but no other genetic determinants have so far been proposed. Recently, vascular endothelial growth factor (VEGF) haplotypes were reported to confer risk to frontotemporal dementia (FTD). The aim of this study was to evaluate the role of VEGF genetic determinants in PSP and CBS susceptibility. We evaluated a cohort of 687 unrelated Italian subjects, including 117 PSP, 108 CBS, 199 FTD, and 263 healthy controls. Genotype and allele frequencies of three well-known polymorphisms located within the VEGF promoter (-2578C/A, -1190G/A, and -1154G/A) were carried out. Genetic analysis revealed the presence of significant changes in terms of genotype and allele distributions in patients compared to healthy controls. A-G-G haplotype (-2578C/A, 1190G/A, -1154G/A) was overrepresented in both PSP (OR=6.64, 95% CI=2.3-19.6, P=0.0003, CGG=reference) and CBS (OR=5.20, 95% CI=1.70-15.9, P=0.003, CGG=reference) compared to healthy subjects. No differences between PSP and CBS and FTD were found, and the A-G-G haplotype was also overrepresented in FTD. Overall, these data suggest that VEGF gene variability represents a susceptibility factor for PSP and CBS. These data argue that additional genes may confer disease risk to PSP and CBS, and to FTD as well, beyond the MAPT tau haplotype. Further studies are warranted.

Vascular Endothelial Growth Factor Genetic Polymorphisms and Haplotypes in Women with Migraine

Vascular endothelial growth factor (VEGF) production is regulated by growth factors and inflammatory cytokines, and VEGF plays a role in migraine. We examined for the first time whether three functional polymorphisms in the promoter region of VEGF gene (C(-2578)A, G(-1154)A, and G(-634)C) and VEGF haplotypes are associated with migraine. We studied 114 healthy women without migraine and 175 women with migraine (129 without aura, and 46 with aura). We found no differences in the distributions of VEGF genotypes and alleles (p > 0.05). However, the CAC haplotype was more frequent in controls than in migraine patients, and the AGC haplotype was more frequent in patients with migraine with aura than in controls (both p < 0.05). These findings suggest that VEGF haplotypes affect susceptibility to migraine.

Association study of vascular endothelial growth factor polymorphisms with the risk of recurrent spontaneous abortion

To investigate the association of vascular endothelial growth factor (VEGF) polymorphisms (-2578C>A, -1154G>A, -634G>C, 936C>T) with idiopathic recurrent spontaneous abortion (RSA) in Koreans. Prospective case-control study. University-based hospital. Two hundred and fifteen patients with a history of two or more unexplained consecutive pregnancy losses and 113 healthy controls with at least one live birth and no history of pregnancy loss. None. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analyses were performed for the -2578C>A and 936C>T genotypes. Real-time PCR was also used to analyze the -1154G>A and -634G>C genotypes. The GA (adjusted odds ratio [AOR] 2.774; 95% confidence interval [CI] 1.512-5.092) genotype of the VEGF -1154G>A polymorphism was significantly different between women with idiopathic RSA and controls. The difference in overall (GA + AA) frequency was also marginally significant between the controls and patients with idiopathic RSA (AOR, 2.006; 95% CI, 1.158-3.473). The differences in frequencies of the A-A-G-T and C-A-G-T haplotypes of the VEGF polymorphisms (-2578C>A, -1154G>A, -634G>C, 936C>T) were marginally significant between the patient and control groups. This study suggests that VEGF polymorphisms and haplotypes are a genetic determinant for the risk of idiopathic RSA in Korean women.

The influence of genotype on vascular endothelial growth factor and regulation of myocardial collateral blood flow in patients with acute and chronic coronary heart disease

Objective: To test the hypothesis that mutations in the vascular endothelial growth factor (VEGF) gene are associated with plasma concentration of VEGF and subsequently the ability to influence coronary collateral arteries in patients with coronary heart disease (CHD). Methods: Blood samples from patients with chronic ischemic heart disease (n=53) and acute coronary syndrome (n=61) were analysed. Coronary collaterals were scored from diagnostic biplane coronary angiograms. Results: The plasma concentration of VEGF was increased in patients with acute compared to chronic CHD (p=0.01). The genotype frequencies differed significantly from Hardy-Weinberg equilibrium in three of 15 examined loci. Four new mutations in addition to the already described were identified. The VEGF haplotype did not seem to predict plasma VEGF concentration (p=0.5). There was an association between the genotype in locus VEGF-1154 and coronary collateral size (p=0.03) and a significant association between the VEGF plasma concentration and the collateral size (p=0.03). Conclusion: VEGF plasma concentration seems related to coronary collateral function in patients with CHD. The results did not support the hypothesis that polymorphisms in the untranslated region of the VEGF gene were associated with the concentration of circulating VEGF. Increased understanding of VEGF in the regulation of myocardial collateral flow may lead to new therapies in CHD.