Vascular Endothelial Growth Factor Alleles Research Articles

Association of polymorphisms of VEGF and VEGFR1 pathways related genes and risk of pre-eclampsia

To assess the association of single nucleotide polymorphisms (SNPs) of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 1 (VEGFR1) pathways-related genes and the risk of pre-eclampsia. In total 178 pregnant women with pre-eclampsia (case group) and 100 healthy pregnant women (control group) during the third trimester were enrolled. The SNPs of VEGF rs3025039, rs2010963 and VEGFR1 rs3812867, rs55875014 and rs722503 loci were determined by PCR-restriction fragment length polymorphism (PCR-RFLP) assay. The levels of serum VEGF and sVEGFR1 were also determined. And their association with pre-eclampsia was analyzed. The systolic blood pressure, diastolic blood pressure and sVEGFR1 of the case group were significantly higher than those of the control group, while the VEGF level was significantly lower than that in the control group (P<0.05). Allelic frequencies of the VEGF (rs3025039, rs2010963) and VEGFR1 (rs3812867, rs55875014, rs722503) have fit the Hardy-Weinberg equilibrium (P>0.05). The frequency of T allele of VEGF at rs3025039 locus in the case group was higher than that in the control group (P<0.05). There were significant differences in VEGF at rs3025039 locus under dominant and co-dominant models in case group (P<0.05). Compared with those with CC, the risk was higher in patients with CT or TT genotypes (P<0.05). The systolic and diastolic blood pressure and sVEGFR1 in pre-eclampsia pregnant women with CT or TT genotypes were significantly higher than those with the CC genotype, while their VEGF level was significantly lower (P<0.05). No significant difference was found in allelic frequencies of other four loci between the two groups (P>0.05). Polymorphisms of rs3025039 locus of VEGF gene is associated with the occurrence of pre-eclampsia. The variant at this locus may affect the activity of VEGF and influence the development of pre-eclampsia.

ASSOCIATION BETWEEN VASCULAR ENDOTHELIAL GROWTH FACTOR GENE POLYMORPHISMS AND THE RISK OF PREECLAMPSIA IN IRAQI PREGNANT WOMEN

Background: Vascular endothelial growth factor (VEGF) is an essential factor for angiogenesis and plays important role in placental development. Objective: To investigate the association between VEGF single nucleotide polymorphisms (SNPs) +936 Cytosine/Thymine (C/T) and -634 Guanine/Cytosine (G/C) and preeclampsia risk. Methods: A total of 50 cases of pregnant women with preeclampsia and 50 healthy pregnant women (as a control) were involved in this case control study. Blood samples were collected form each woman and the Deoxyribonucleic acid (DNA) was extracted. Amplification of VEGF gene was done by conventional polymerase chain reaction (PCR) and then detection of SNPs-634 G/C and +936 C/T were carried out by restriction fragment length polymorphism PCR (PCR-RFLP). Results: The frequency of different genotypes of VEGF SNPs +936 C/T &amp;-634 G/C are in accordance with Hardy Weinberg equilibrium. VEGF polymorphism +936 C/T appeared in 3 genotypes after digestion with restriction enzymes Cytosine Cytosine (CC), Cytosine Thymine (C/T) &amp; Thymine Thymine (TT). VEGF SNP -634 G/C appeared in 3 genotypes after digestion with restriction enzymes; those were Guanine Guanine (GG), Guanine Cytosine (GC) and CC. The heterozygous genotype CT of polymorphism +936 C/T was more frequent among preeclamptic patients than the controls (26% versus 16%). Likewise, TT genotype was more frequent among preeclamptic patients (8% versus 2%) with no significant differences. At the allelic level, the difference was more prominent. The frequency of mutant allele (T allele) was much more frequent in preeclamptic patients than controls (21% versus 10%) with a statistically significant difference (p=0.049). Although CC genotype of polymorphism -634 G/C was more frequent among preeclamptic patients than controls (14% versus 10%), the difference was not significant (p=0.704). Likewise, there were no significant differences in allele frequency. Conclusion: The study suggested that the mutant T allele of VEGF +936 C/T polymorphism was associated with increased preeclampsia risk and disease development. Keywords: Vascular endothelial growth factor, polymorphisms, preeclampsia Citation: Khaleel MF, Al-Moayad HA. Association between vascular endothelial growth factor gene polymorphisms and the risk of preeclampsia in Iraqi pregnant women. Iraqi JMS. 2022; 20(1): 106-112. doi: 10.22578/IJMS.20.1.14

Impact of VEGFA promoter polymorphisms on esophageal cancer risk in North-West Indians: a case-control study.

Angiogenesis play a critical role in the development and progression of tumors in solid tumors. Vascular endothelial growth factor (VEGF) is one of the most important endothelial cell mitogen which plays a critical role in normal physiological and tumor angiogenesis. The objective of this case-control study was to investigate the association of VEGF-2578C/A, -2549 I/D, and -460T/C promoter polymorphisms with esophageal cancer risk in North-West Indians. In this study, 200 sporadic esophageal cancer patients and 200 healthy, unrelated, age and gender matched controls were analyzed. The genomic DNA was extracted from blood samples using phenol chloroform method. Genotyping of VEGF- 2549I/D polymorphism was carried out by direct polymerase chain reaction (PCR) whereas VEGF -2578C/A and VEGF-460T/C) polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. AA genotype (p = 0.005) and A allele (p = 0.005) VEGF -2578 C/A, II genotype (p = 0.011) and I allele (p = 0.012) of VEGF - 2549 I/D and CC genotype (p = 0.013) and C allele of VEGF-460T/C polymorphisms were significantly associated with increased risk of esophageal cancer. Stratification of data on the basis of gender showed that VEGF -2578 AA genotype (p = 0.001) and A allele (p = 0.001); VEGF -2549 II genotype (p = 0.002) and I allele (p = 0.002) and VEGF- 460CC genotype (p = 0.001) and C allele (p = 0.002) was significantly associated with increased risk of esophageal cancer in female group. Haplotype analysis revealed that A-2578 I- 2549 C- 460 haplotype was significantly associated with increased risk for esophageal cancer in total samples (p = 0.008) as well as in female group (p = 0.001). The results of present study indicate that VEGF -2578C/A, - 2549I/D and -460T/C polymorphisms were significantly associated with increased risk of esophageal cancer in North-West Indians.

Study of the Association between VEGF Polymorphisms and the Risk of Coronary Artery Disease in Koreans.

Coronary artery disease (CAD), a leading cause of death worldwide, has a complex etiology comprising both traditional risk factors (type 2 diabetes, dyslipidemia, arterial hypertension, and cigarette smoking) and genetic factors. Vascular endothelial growth factor (VEGF) notably contributes to angiogenesis and endothelial homeostasis. However, little is known about the relationship between CAD and VEGF polymorphisms in Koreans. The aim of this study is to investigate the associations of 2 VEGF promoter region polymorphisms (−1154G>A [rs1570360], −1498T>C [rs833061]) and 4 VEGF 3′-UTR polymorphisms (+936C>T [rs3025039], +1451C>T [rs3025040], +1612G>A [rs10434], and +1725G>A [rs3025053]) with CAD susceptibility in Koreans. We studied 885 subjects: 463 CAD patients and 422 controls. Genotyping was conducted with polymerase chain reaction-restriction fragment length polymorphism analysis and TaqMan allelic discrimination assays, and the genotype frequencies were calculated. We then performed haplotype and genotype combination analyses and measured the associations between VEGF polymorphisms and clinical variables in both the CAD patients and control subjects. We detected statistically significant associations between CAD and certain VEGF allele combinations. In the haplotypes of 5 single-nucleotide polymorphisms, the VEGF allele combination −1154A/+936T was associated with a decreased prevalence of CAD (A-T-T-G-G of VEGF −1154G>A/−1498T>C/+936C>T/+1612G>A/+1725G>A, AOR = 0.077, p = 0.021). In contrast, the VEGF allele combinations −1498T/+1725A and −1498T/+1612A/+1725A were associated with an increased prevalence of CAD (G-T-C-C-A of VEGF −1154G>A/−1498T>C/+936C>T/+1451C>T/+1725G>A, AOR = 1.602, p = 0.047; T-C-C-A-A of VEGF −1498T>C/+936C>T/+1451C>T/+1612G>A/+1725G>A, AOR = 1.582, p = 0.045). Gene–environment combinatorial analysis showed that the combination of the VEGF +1725AA genotype and several clinical factors (e.g., body mass index, hemoglobin A1c, and low-density lipoprotein cholesterol) increased the risk of CAD. Therefore, we suggest that VEGF polymorphisms and clinical factors may impact CAD prevalence.

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.

Association of vascular endothelial growth factor gene polymorphism with psoriasis

Background Psoriasis is an immune-mediated complex cutaneous disorder. In its pathologic process, there is abnormal keratinocyte differentiation and proliferation, as well as inflammation, besides abnormal vascular expansion. Vascular endothelial growth factor (VEGF) acts as a potent mediator of inflammation and angiogenesis in psoriasis. Objective This work aimed to study the role of VEGF gene polymorphism (rs2010963) in psoriasis vulgaris. Patients and methods This case–control study covered 45 patients with psoriasis vulgaris and 45 age-matched and sex-matched healthy participants as a control group, and had been checked to discover C-G transition polymorphism at position +405 of the VEGF gene by a real-time PCR. Results There was a significant difference between cases and controls concerning the distribution of VEGF gene polymorphism (P = 0.046), and also, there was a statistically significant difference between cases and controls concerning VEGF alleles (P = 0.036). Conclusion There was a significant association between the genotypes of the VEGF gene polymorphism and psoriasis vulgaris, suggesting that the VEGF gene polymorphism may have a possible active role in the etiopathogenesis of psoriasis vulgaris.

Gene polymorphisms of VEGF and VEGFR2 are associated with the severity of Hashimoto's disease and the intractability of Graves' disease, respectively.

Vascular endothelial growth factor (VEGF) is one of main regulators of angiogenesis that functions by binding to its receptors, including VEGF receptor (VEGFR) 2. There are few data available regarding the association between VEGF and VEGFR polymorphisms and the susceptibility to and prognosis of autoimmune thyroid diseases (AITDs). To elucidate this association, we genotyped four functional VEGF and two VEGFR2 polymorphisms and measured serum VEGF levels. In the four functional VEGF polymorphisms, the frequencies of the I carrier and I allele of VEGF -2549 I/D, which has lower activity, were higher in patients with severe HD than in those with mild HD. In the two functional VEGFR2 polymorphisms, the frequency of the rs2071559 CC genotype, which has higher activity, was higher in patients with intractable GD than in controls, and the proportion of GD patients with larger goiters was higher in those with the CC genotype. Moreover, the frequency of the rs1870377 TT genotype with higher activity was higher in patients with intractable GD than in those with GD in remission. Combinations of VEGF and VEGFR2 polymorphisms with stronger interactions were associated with the intractability of GD. Serum VEGF levels were higher in HD and AITD patients than those in controls. In conclusion, VEGF polymorphisms with lower activity were associated with the severity of HD, while VEGFR2 polymorphisms and the combinations of VEGF and VEGFR2 polymorphisms, which have stronger interactions, were associated with the intractability of GD. VEGF and VEGFR2 polymorphisms were associated with HD severity and GD intractability, respectively.

Genetic variants of vascular endothelial growth factor gene polymorphism affect the risk and severity of ischemic stroke: a case–control study

<br><b>Background and objectives</b><br>Vascular endothelial growth factor (VEGF) is the key mediator of angiogenesis and atherosclerosis. Hence, it may play a major role in the pathogenic mechanisms underlying ischemic stroke (IS) progression. Thus, we conducted this case–control study to explore the genetic association of a single gene polymorphism of VEGF + 936C/T (rs3025039) with the risk and severity of IS and its relation with serum VEGF level.<br><b>Patients and methods</b><br>This study included a case series of 49 patients with IS with 41 controls. VEGF + 936C/T (rs3025039) variants were determined via Taqman allelic discrimination PCR. Serum VEGF level was estimated using enzyme-linked immunosorbent assay. The frequency of VEGF rs3025039 genotypes and alleles was calculated manually in both cases and controls. The risk ratio was estimated and represented by odds ratio (OR) and 95% confidence interval (CI) adjusted to the confounding variables via multinomial logistic regressions. The stroke severity was assessed by National Institute of Health Stroke Scale. Moreover, serum VEGF levels were compared between the studied groups and among different genotypes and alleles of IS cases.<br><b>Results</b><br>Our study detected significantly increased frequencies of TT genotype (<i>P</i> = 0.030) and T allele (<i>P</i> = 0.045) in IS cases when compared with the controls. TT genotype represents an increased adjusted risk for IS progression by 9.94 folds (OR: 9.938, 95% CI: 1.235–79.97) and T allele by 2.19 folds (OR: 2.191, 95% CI: 1.004–4.782) over the CC genotypes and C allele, respectively. Moreover, TT genotypes are associated with higher National Institute of Health Stroke Scale. The serum VEGF level was significantly lower in IS cases than controls, and a more decreased level was associated with the T allele carriers in IS cases groups.<br><b>Conclusions</b><br>VEGF rs3025039 gene polymorphism is associated with increased risk and severity of IS and decreased VEGF expression, which may play a major role in the pathogenesis of IS progression.<br>

Investigation of VEGF gene polymorphism rs35569394 in endometriosis

ABSTRACT Introduction: Endometriosis is a chronic gynecological condition characterized by the presence of endometrial tissue in locations outside the uterus. Its symptoms include dysmenorrhea, dyspareunia, chronic pelvic pain, infertility, dysuria, and dyschezia. Several studies have related the vascular endothelial growth factor (VEGF) gene polymorphisms as a factor for the development of endometriosis. Objectives: The aim of this study was to compare the frequency of the VEGF gene polymorphism rs35569394 in women with endometriosis and a control group, as well as to investigate the association of this polymorphism with the risk of endometriosis. Methods: This case-control study included 45 endometriosis patients (cases) and 78 controls. The molecular analysis was performed by polymerase chain reaction (PCR). The chi-square test was used to compare the genotype and allele frequencies, and the Hardy-Weinberg equilibrium was also tested using the chi-square test, considering the significance of p < 0.05. Results: The frequency of the II, ID and DD genotype was 24.4% versus 26.9%; 35.6% versus 37.2%; and 40% versus 35.9%, in patients and the control group, respectively. The allele frequencies were I: 0.42 (cases) and 0.45 (control); D: 0.58 (cases) and 0.55 (control). The allele and genotype frequency of VEGF -2549I/D polymorphism was not different between women with endometriosis and the control. Conclusion: In the present study, the frequency of the VEGF gene polymorphism rs35569394 is similar between cases and control. This genetic variant is not associated with endometriosis in the investigated population.

Genetic alterations of IDH1 and Vegf in brain tumors.

BackgroundThis study evaluates the presence of R132H mutation in isocitrate dehydrogenase (IDH1) gene and the vascular endothelial growth factor (VEGF) +936 C/T polymorphism in brain tumors. The impact of these genetic alterations on overall survival (OS) and progression free survival (PFS) was evaluated.MethodsA cohort of 80 patients surgically treated at Hospital Clínico San Carlos, Madrid, between March 2004 and November 2012, was analyzed. Tumors were distributed in 73 primary brain tumors (gliomas, meningiomas, hemangiopericytomas and hemangioblastomas) and seven secondary tumors evolved from a low grade glioma, thus providing a mixed sample.Results IDH1 R132H gene mutation was found in 12 patients (15%) and appears more frequently in secondary tumors (5 (71.4%) whereas in 7 (9.7%) primary tumors (p < .001)). The mutation is related to WHO grade II in primary tumors and a supratentorial location in secondary tumors. The OS analysis for IDH1 showed a tendency towards a better prognosis of the tumors containing the mutation (p = .059).The IDH1 R132H mutation confers a better PFS (p = .025) on primary tumors. The T allele of VEFG +936 C/T polymorphism was found in 16 patients (20%). No relation was found between this polymorphism and primary or secondary tumor, neither with OS or PFS.Conclusions IDH1 R132H gene mutation is exclusive in supratentorial tumors and more frequent in secondary ones, with a greater survival trend and better PFS in patients who carry it. The T allele of VEGF +936 C/T polymorphism is more common in primary tumors, although there is no statistical relation with survival.

Association of VEGF and VEGFR1 polymorphisms with breast cancer risk in North Indians.

The aim of present study was to evaluate the relationship between vascular endothelial growth factor (VEGF) -2578C/A, -2549I/D, -460T/C and -7C/T and VEGFR1 -710C/T polymorphisms with risk to breast cancer in North Indians. A total of 204 sporadic breast cancer patients and 204 controls were recruited for this case-control study. Significantly increased frequency of II genotype of -2549I/D polymorphism was observed in patients as compared to control individuals (odds ratio (OR) = 2.76, 95 % confidence interval (CI), 1.55-4.92; p = 0.0005). VEGF -2578AA genotype (OR = 2.87; 95 % CI, 1.61-5.10; p = 0.0003) and A allele (OR = 1.65, 95 % CI, 1.25-2.18; p = 0.0004) were found to be associated with increased risk for breast cancer. Individuals carrying CC genotype (OR = 2.23, 95 % CI, 1.25-3.97) and C allele (OR = 1.42, 95 % CI, 1.07-1.87) of VEGF -460T/C polymorphism were at higher risk of breast cancer. There was no significant difference in genotype and allele distribution of VEGF -7C/T and VEGFR1 -710C/T polymorphisms between cases and control individuals (p > 0.05). Linkage disequilibrium analysis showed a strong linkage between VEGF -2549I/D and -2578C/A polymorphisms (Lewontin's [Formula: see text] = 0.99; r (2) = 0.97), -2549I/D and -460T/C ([Formula: see text] = 0.94; r (2) = 0.84), and -2578C/A and -460T/C polymorphisms ([Formula: see text] = 0.93; r (2) = 0.83). In the present study, we concluded that VEGF -2549I/D, -2578C/A and -460T/C polymorphisms are associated with risk to breast cancer in Punjab, North India.

3'-UTR polymorphism (rs10434) in the VEGF gene is associated with B-CLL in a Chinese population.

We investigated the relationship between a VEGF genetic polymorphism and B cell chronic lymphocytic leukemia (B-CLL). A total of 102 patients with B-CLL and 124 healthy subjects were included in this study. All individuals were typed for the rs10434 in the vascular endothelial growth factor (VEGF) gene using the TaqMan technique. We found that the A allele and the AA genotype of rs10434 were more frequent in B-CLL patients than in control subjects (0.54 vs 0.34; 27 vs 13%; respectively). VEGF alleles and genotypes segregated similarly in patients at different disease stages according to Rai classification. These results suggest a possible association between the VEGF polymorphism and high-risk B-CLL.

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.

Genetic association of VEGF and PEDF polymorphisms with age-related macular degeneration in Korean

Age-related macular degeneration (AMD) causes progressive impairment of central vision and is the leading cause of vision loss in older individuals. Although the etiology of AMD has not been clearly elucidated, genetic and environmental factors have been implicated. Vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF), a major regulator of vascular permeability and angiogenesis, have been suggested to play an important role in the pathogenesis of AMD. This study was performed to determine whether VEGF and PEDF variations are associated with AMD in the Korean population. Four SNPs of both the VEGF gene the PEDF gene were used to screen for genetic variation. This analysis was performed using polymerase chain reaction–restriction fragment length polymorphism, direct sequencing and an allele-specific oligonucleotide analysis. The study investigated four SNPs in VEGF and PEDF in Korean patients with AMD. The frequency of the TT genotype of rs1413711 and the recessive VEGF allele significantly differed between the patient and control groups. The TT genotype of rs1136287 (M72T) in PEDF significantly differed between the patient and control groups. Six haplotypes in the VEGF gene and two haplotypes in the PEDF gene were significantly associated with AMD. In this study, rs1413711 of VEGF, rs1136287 of PEDF and haplotypes were identified as candidate variants associated with AMD in Korean patients.

VEGF and bFGF gene polymorphisms in Polish patients with B-CLL

Among a variety of angiogenic factors involved in the B cell chronic lymphocytic leukemia (B-CLL), vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were identified. Their levels have been regarded as prognostic markers of the progression of disease. The objective of the present study was to assess whether polymorphisms located within the genes coding for these key angiogenic activators contribute to disease susceptibility and/or progression in patients with B-CLL. For this purpose, 180 individuals were investigated, including 68 B-CLL patients and 112 healthy controls. All individuals were typed for the VEGF (936 C > T) and bFGF (−921 C > G) alleles using PCR–RFLP technique. Only a slight prevalence of the VEGF T variant was observed among patients as compared to healthy individuals (p = 0.095) with a significant difference when high risk (stage III/IV) patients were considered (OR = 3.81, p = 0.045). No other significant association was observed between the VEGF polymorphism and progression of the disease. The VEGF alleles and genotypes segregated similarly in patients with different stage of the disease according to Rai classification. No significant relationships were also observed for the bFGF polymorphism with either susceptibility to B-CLL (when compared to control group) or progression of the disease. These results suggest the possible association of the VEGF polymorphism with high risk B-CLL.

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.

Preeclampsia, a disease of the maternal endothelium: the role of antiangiogenic factors and implications for later cardiovascular disease.

Preeclampsia is a clinical syndrome defined as the new onset of hypertension and proteinuria during the second half of pregnancy.1 It afflicts 3% to 5% of pregnancies and is a leading cause of maternal mortality, especially in developing countries.2,3 Because the only known remedy is delivery of the placenta, in developed countries preeclampsia is an important cause of premature delivery, usually medically indicated for the benefit of the mother. This results in infant morbidity and substantial healthcare expenditure.4 Despite the considerable morbidity and mortality, the cause of preeclampsia has remained enigmatic. Both hypertension and proteinuria implicate the endothelium as the target of the disease. The hypertension of preeclampsia is characterized by peripheral vasoconstriction and decreased arterial compliance.5,6 The proteinuria of preeclampsia is associated with a pathognomonic renal lesion known as glomerular endotheliosis, in which the endothelial cells of the glomerulus swell and endothelial fenestrations are lost.7,8 Podocyturia has been recently associated with preeclampsia during clinical disease9; however, whether this is the cause or effect of proteinuria is unknown. The glomerular filtration rate is decreased compared with normotensive pregnant women; in rare cases, acute renal failure may develop. Preeclampsia is a systemic vascular disorder that may also affect the liver and the brain in the mothers. When the liver is involved, women may present with abdominal pain, nausea, vomiting, and elevated liver enzymes. Pathological examination of the liver reveals periportal and sinusoidal fibrin deposition and, in more extreme cases, hemorrhage and necrosis.10 The severe preeclampsia variant HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) occurs in ≈20% of women with severe preeclampsia,11 and is named not only for the liver involvement, but also for the disorder of the coagulation system that develops.12 Approximately 20% of …

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.

The role of vascular endothelial growth factor +405 G/C polymorphism and albuminuria in patients with type 2 diabetes mellitus

Observations on the association between the vascular endothelial growth factor (VEGF) gene polymorphism and nephropathy have been inconsistent, which might be due to ethnic and geographical variations. Furthermore, the relationship between +405 G/C polymorphism and albuminuria in the diabetic population has not been sufficiently studied. The aim of this study was to evaluate for the first time the possible association between +405 G/C polymorphism and albuminuria in an population from Tehran of Iran. A total of 255 consecutive patients with type 2 diabetes and microalbuminuria (Group A) and 235 patients with type 2 diabetes and normoalbuminuria (Group B) were included. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were used to detect the VEGF alleles. In univariate analysis, the groups were statistically similar in all variables except for HbA1c (8.53 ± 1.7 in Group A vs. 8.2 ± 1.73 in Group B; P = 0.034), 24-h urinary albumin (201.33 ± 84.8 in Group A vs. 22.88 ± 3.5 in Group B; P < 0.001), and the frequency of GG genotype (31% in Group A vs. 18.7% in Group B; P = 0.006). The GG genotype was the independent predictor of albuminuria [P = 0.014, OR = 1.771, 95% confidence interval (CI) = 1.124-2.790]. Our study showed that the G allele was not associated with albuminuria, but the GG genotype in the VEGF gene is independently associated with development of nephropathy in the our diabetic population.

Intracrine vascular endothelial growth factor signaling in survival and chemoresistance of human colorectal cancer cells

Although the effects of VEGF on angiogenesis and vascular function are well known, the effects of VEGF on tumor cell function remain to be elucidated. We studied phenotypic changes in human colorectal cancer (CRC) cells with homozygous deletion of VEGF alleles to determine the potential direct role of VEGF on tumor cell function. Loss of VEGF expression led to significantly decreased cell growth and increased spontaneous apoptosis in CRC cells (p<0.01). Loss of VEGF also increased the in vitro sensitivity of cells to the cytotoxic effects of the chemotherapeutic drug 5-fluorouracil, as shown by increased apoptosis (p<0.05). These effects were mediated via upregulation of the proapoptotic mediators caspase-3, cleaved PARP and Bax and downregulation of the pro-survival mediator survivin. Our findings suggest a novel and distinct function of VEGF in mediating autocrine/intracrine CRC cell survival.