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.     

VEGF基因多态性与子宫内膜异位症发病风险的相关性研究

目的探讨血管内皮生长因子（vascular endothelial growth factor,VEGF）-460C/T、-1154G/A、-2578C/A和＋936C/T单核苷酸多态性与子宫内膜异位症的关系。方法采用PCR-RFLP方法检测344例子宫内膜异位症患者（病例组）和360名对照妇女（对照组）的VEGF基因多态性位点的基因型频率分布情况。结果VEGF-460C/T和＋936C/T多态的基因型和等位基因频率分布在病例组与对照组间差异均无统计学意义（P〉0.05）。在病例组和对照组中,VEGF-1154G/A和VEGF-2578C/A多态的基因型及等位基因频率分布差异均有统计学意义（P〈0.05）;与GA＋AA/AA＋CA基因型相比,携带GG/CC基因型明显增加内异症的发病风险（OR=1.43,95%CI：1.05～1.96）/（OR=1.47,95%CI：1.09～2.00）。VEGF-460C/T、-1154G/A、-2578C/A多态的单倍型频率在病例组和对照组间差异有统计学意义（P=0.000）。结论1.携带VEGF-1154GG和-2578CC基因型显著增加子宫内膜异位症的发病风险;2.单倍型VEGF-460/-1154/-2578TGC,CAA,TAA和TAC与子宫内膜异位症的发病明显相关。     

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.     

The tumor necrosis factor-alpha promoter -1031C polymorphism is associated with decreased risk of endometriosis in a Japanese population

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is a multifunctional proinflammatory cytokine, associated with various inflammatory and autoimmune diseases. Elevated TNF-alpha levels in peritoneal fluid have been reported in women with endometriosis, suggesting that TNF-alpha may be involved in the development of endometriosis. In this study, we investigated the possible association between endometriosis and the TNF-alpha gene promoter polymorphisms -238G/A, -308G/A, -857C/T, -863C/A and -1031T/C in a Japanese population. METHODS: We compared the distribution of the -238G/A, -308G/A, -857C/T, -863C/A and -1031T/C polymorphisms in the promoter region of TNF-alpha in 130 endometriosis cases and 185 controls using PCR-RFLP analysis. RESULTS: The allele frequencies of -238A, -308A, -857T, -863A and -1031C in controls were 2.0%, 1.3%, 19.4%, 17.0% and 18.6%, and in the cases 1.1%, 0.3%, 19.6%, 18.6% and 13.6%, respectively. No significant differences in frequencies were found between the crude endometriosis cases and controls. However, when the endometriosis group was divided into a subgroup of women with stage IV disease only, the frequency of the -1031C allele was significantly lower in this subgroup than controls. CONCLUSIONS: The variability of the -1031T/C polymorphism of the TNF-alpha gene may be associated with susceptibility to (AUTHOR: as meant?) endometriosis.     

Tumour necrosis factor-alpha gene haplotype is associated with pre-eclampsia

We determined whether polymorphisms in the promoter region of the tumour necrosis factor alpha (TNF-alpha) gene contributes to differences in susceptibility to develop pre-eclampsia. The study involved 133 pre-eclamptic and 115 healthy pregnant women who were genotyped for the G-308A polymorphism of the TNF-alpha gene. The frequency of the G-308A allele was more common in the pre-eclampsia group than among the controls (P=0.046), giving an odds ratio of 0.57 (95% CI: 0.32-0.99), but there were no differences in the genotype distribution. The data from the G-308A polymorphism was combined with the previously published genotype and allele data from the C-850T polymorphism of the TNF-alpha gene, and used to assess a haplotype estimation analysis. Estimated overall pair of loci haplotype frequencies differed significantly between the groups (P=0.023+/-0.004). In the single haplotype association analysis, the haplotype C-A versus others was over-represented in the pre-eclampsia group (P=0.041+/-0.003), whereas the haplotype T-G versus others was less common in the pre-eclampsia group (P=0.035+/-0.003), compared with the controls. In conclusion, the polymorphisms of the TNF-alpha gene showed a significant haplotype association with susceptibility to pre-eclampsia in the Finnish population.     

Analysis of vascular endothelial growth factor gene 936 C/T polymorphism in patients with familial Mediterranean fever

Vascular endothelial growth factor (VEGF) is a cytokine that promotes endothelial cell proliferation, leucocyte chemotaxis and expression of adhesion molecules and is a major mediator of vascular permeability. It has been demonstrated that VEGF directly activates neutrophils and it could promote acute recruitment of leucocytes. It is known that neutrophils are the major cell population involved in acute inflammation in familial Mediterranean fever (FMF) and the role of VEGF in these cells may be crucial. The aim of this study was to investigate whether the 936 C/T functional polymorphism of the VEGF gene is associated with susceptibility to FMF and its relationship with the main clinical features of the disease. Polymerase chain reaction-restriction fragment length polymorphism technique was used to determine 936 C/T polymorphism within the VEGF gene in 75 patients with FMF and 122 non-related healthy controls. Genotype and allele frequencies of the VEGF 936 C/T polymorphism between patients with FMF and healthy control groups were not significantly different (OR = 0.74, 95% CI = 0.40-1.37, P = 0.335 for CT genotype; OR = 1.11, 95% CI = 0.67-1.83, P = 0.700, for T allele). Although VEGF 936 TT genotype was found to be more frequent in patients with FMF than in healthy controls (6.7% vs. 1.6%, respectively), the difference was not significant (OR = 4.28, 95% CI = 0.81-22.67, P = 0.108). No associations were found between the studied polymorphism and either the clinical features such as arthritis, abdominal pain, pleuritis, myalgia, arthralgia and erysipelas-like erythema of the disease or the four common studied exon 10 mutations (M694V, M680I, V726A, M694I) of the Mediterranean fever gene. Present results suggest that VEGF gene 936 C/T polymorphism does not seem to be associated with susceptibility to FMF and its clinical manifestations.     

ORIGINAL ARTICLE: Association Study of Vascular Endothelial Growth Factor and Polymorphisms of its Gene with Ectopic Pregnancy

Citation Elito J Jr, Daher S, Fernandes da Silva MO, Marconi NMH, Pendeloski KPT, Moron AF, Camano L. Association study of vascular endothelial growth factor and polymorphisms of its gene with ectopic pregnancy. Am J Reprod Immunol 2010; 63: 120–125 Problem In ectopic pregnancy, increased levels of vascular endothelial growth factor are present. The aims of this study were to determine the association between ?634C/G, ?460T/C, and +936C/T vascular endothelial growth factor (VEGF) polymorphisms and ectopic pregnancy, and to determine whether serum levels of VEGF were affected by genetic factors. Method of study This is a case–control study wherein 74 women with a history of ectopic pregnancy in a tertiary care center were compared to 134 post‐menopausal controls with two pregnancies and no ectopic pregnancy for the genotyping of VEGF polymorphisms. For 35 patients with the diagnosis of ectopic pregnancy, serum concentrations of VEGF were obtained before the treatment. Genotyping of VEGF (?634C/G, ?460T/C, and +936C/T) polymorphisms was performed by PCR, followed by endonuclease digestion. ELISA was performed to evaluate the VEGF serum levels. Results The ?634C/G, ?460T/C, and +936C/T VEGF polymorphisms were not associated with ectopic pregnancy (P = 0.170, P = 0.285, and P = 0.700, respectively). The serum levels of VEGF were not associated with the genotype of ?634C/G, ?460T/C, and +936C/T VEGF polymorphisms (P = 0.702; P = 0.347, and P = 0.256, respectively). Conclusion There was no association between ectopic pregnancy and ?634C/G, ?460T/C, and +936C/T VEGF polymorphisms. There was no correlation between VEGF genotype and the expression of VEGF in blood samples.     

海南汉族人群中α和β纤维蛋白原基因核苷酸多态性及其单倍型与缺血性脑卒中的关联分析

目的研究α纤维蛋白原基因的Taq Ⅰ多态性和β纤维蛋白原基因-455G／A、-249C／T、-148 C／T、＋1689T／G、βBsmA ⅠG／C、448G／A、Be／ⅠG／A、Hinf Ⅰ A／C单核苷酸多态性及其单倍型与缺血性脑卒中的关系。方法用比浊法测定160例海南籍缺血性脑卒中和130名海南籍对照个体的血浆纤维蛋白原浓度，用PCR-限制性片段长度多态法确定基因型。用EH＋程序分析核苷酸多态性的连锁不平衡关系及单倍型，用卡方检验分析病例组和对照组的等位基因频率、基因型频率及单倍型频率的差异。结果-455G／A、-148C／T、448G／A多态性的基因型频率、等位基因频率在病例组和对照组之间的差异有统计学意义（P〈0．01），其余6个核苷酸多态性的基因型频率、等位基因频率在病例和对照组间的差异无统计学意义（P〉0．05），A^-455、T^-148、A^448携带者患缺血性脑卒中的相对危险度比非携带者分别大2．46倍、2．30倍和2．08倍。连锁不平衡分析未发现所分析的区域内存在单倍型板块。9个位点构建的单倍型在病例组和对照组之间的差异无统计学意义，以4个位点构建的单倍型中，某些单倍型在病例组和对照组之间的差异有统计学意义，对照组中某些携带G^-455、C^148、G^448位点的单倍型的频率高于病例组，而病例组中某些携带A^-455、T^-148、A^448位点的单倍型的频率高于对照组。结论多个位点和单倍型分析的结果提示8纤维白原455G／A、-148C／T、448G／A可能是海南汉族人群中与缺血性脑卒中关联的危险因素。     

VEGF polymorphisms and serum VEGF levels in Parkinson's disease

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

Haplotypic association of DDAH1 with susceptibility to pre-eclampsia

Association between pre-eclampsia (PEE1) and the dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2 genes, which play a role in the regulation of nitric oxide synthesis and release, was studied. In a case-control study design single nucleotide polymorphisms (SNPs) were determined at eight sites in the DDAH1 gene and at one site (Pro231Pro) in the DDAH2 gene from 132 women with pre-eclampsia and 112 healthy controls. Three SNPs in the DDAH1 gene were associated with pre-eclampsia, showing complete linkage disequilibrium with each other, but none of the associations in the allele or genotype data reached statistical significance in either of the genes after the correction for multiple testing. Haplotype frequencies were estimated using a population based on a maximum likelihood method (EM algorithm). Four common DDAH1 haplotypes were present and a significant association of haplotypes H2 and H3 with pre-eclampsia (P=0.03) was found. The risk of pre-eclampsia was greatest in individuals (odds ratio: 3.93; 95% confidence interval: 1.54-9.99) who had two copies of the high-risk haplotypes (H2 or H3). The observed haplotypic association provides the first evidence of the importance of DDAH1 polymorphisms in pre-eclampsia susceptibility.     

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

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

Gender-specific association between polymorphism of vascular endothelial growth factor (VEGF 936C>T) gene and patients with stomach cancer

Purpose

Angiogenesis plays an important role in the growth, progression, and metastasis of tumors. Vascular endothelial growth factor (VEGF) overexpression has been associated with advanced stage and poor survival in several cancers. We investigated the present case-control study to determine whether there is an association between the VEGF 936C > T polymorphism and stomach cancer.

Patients and Methods

The association of functional single nucleotide polymorphisms (SNPs) of the VEGF gene with stomach cancer development was evaluated in a case-control study of 154 Korean stomach cancer patients. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis.

Results

Our results revealed significant association of T allele-bearing genotypes with increased risk for stomach cancer development. Genotype frequencies of the VEGF 936C > T polymorphisms were significantly different between patient and control groups (CT, AOR: 2.007, 95% CI: 1.277 - 3.156, TT, AOR: 4.790, 95% CI: 1.174 - 19.539, CT + TT, AOR: 2.147, 95% CI: 1.382 - 3.337). When stratified by gender and age, genotype frequencies were significantly different for stomach cancer in women and in patients younger than 55 years (in women, CT, OR: 3.049, 95% CI: 1.568 - 5.930, CT+TT, OR: 3.132, 95% CI: 1.638 - 5.990; in < 55 years, CT, OR: 3.306, 95% CI: 1.413 - 7.732, CT + TT, OR: 3.967, 95% CI: 1.729 - 9.104). In addition, this association partially remained in cases with intestinal and diffuse-type stomach cancer.

Conclusion

Our present study suggests that the VEGF 936C > T polymorphism is a susceptibility factor for stomach cancer, at least in Korean.     

Interleukin 8 and Susceptibility to Coronary Artery Disease: a Population Genetics Perspective.

INTRODUCTION: Interleukin 8 is a strong chemoattractant factor for neutrophils and T lymphocytes. We investigated the potential influence of two common polymorphisms of the interleukin-8 gene, -251A/T, and 781C/T on susceptibility to coronary artery disease. MATERIALS AND METHODS: The hypothesis was tested by screening for the prevalence of the above polymorphisms in 241 angiographically diagnosed coronary artery disease patients compared to 157 selected controls with negative coronary angiography. RESULTS AND DISCUSSION: We found no significant differences between cases and controls concerning the allelic and genotypic frequencies of both the studied polymorphisms. Nevertheless, a statistically significant lower frequency of the AA containing genotypes was observed in cases presenting with acute coronary syndromes compared to asymptomatic subjects or patients with stable coronary artery disease (OR = 0.44, 95%CI: 0.2-0.98, p = 0.04). The strongest statistical significance was observed in the AA(251)TT(781) combined genotype (OR = 0.34, 95%CI: 0.14-0.85, p = 0.02). CONCLUSION: Our results suggest that the genetic diversity of the interleukin-8 gene influences the clinical manifestation of CAD.     

Interleukin-1 gene complex in schizophrenia: an association study.

The aim of this study is to investigate the association between three polymorphisms of the interleukin-1 (IL-1) gene complex and schizophrenia. We genotyped 228 outpatients with schizophrenia (DSM-IV criteria) and 419 unrelated healthy controls. The following polymorphisms were analyzed: IL-1alpha -889 C/T, IL-1beta +3953 C/T, and IL-1RA (86 bp)n. No significant differences in genotype or in allelic distribution of the Il-1alpha, IL-1beta, and IL-1RA polymorphisms were found. Estimated haplotype frequencies were similar in both groups. Our data do not suggest that genetically determined changes in the IL-1 gene complex confer increased susceptibility for schizophrenia.     

Polymorphisms in the tumor necrosis factor-alpha gene in Turkish women with pre-eclampsia and eclampsia

The genetic background predisposing pregnant women to pre-eclampsia/eclampsia (PE/E) is still unknown. The aim of the current study was to investigate whether there is an association between the TNF-alpha-308 and 850 polymorphisms and PE or eclampsia. In this study, 40 cases of eclampsia, 113 cases of PE and 80 normotensive control cases were genotyped for the TNF-alpha-G-308A and C-850 polymorphisms. At position 308, the replacement of Guanine with Adenosine was denoted as TNF2. We found a significant difference between the TNF2 allele frequencies of the eclamptic, pre-eclamptic and normotensive controls. TNF2 (AA) polymorphism frequency was significantly higher among the eclamptics and pre-eclamptics (control : 5%, PE : 13.3%, E : 12.9%). A significantly different genotype distribution of C-850T polymorphism was observed between the PE/E and control groups, with the frequency of the variant TT genotype being significantly reduced in the preeclamptics (PE : 17% ; E : 17.5%) when compared with the control group (24.3%). We have demonstrated an association between TNF-alpha polymorphisms and pre-eclampsia susceptibility. However, it is not known whether C-850T polymorphism has a functional effect on the TNF-alpha gene. In addition, it was not possible to determine whether this polymorphism promotes the progression from PE to eclampsia because of no statistically significant difference between eclampsia and the controls.     

Analysis of TAP1 and TAP2 polymorphism of mother-infant in Chinese patients with pre-eclampsia

To analyze the polymorphism of TAP gene and the shared rates of alleles between mothers and their infants inChinese patients with pre-eclampsia,TAP1 and TAP2 genotyping was performed by the amplification refractorymutation system-polymerase chain reaction(ARMS-PCR)in 42 patients,106 normal pregnant women,and theirneonates.The allelic frequency of TAP and the alleles shared in maternal-fetus were compared and analyzed in thetwo groups.Our results showed that,with totally eight alleles of TAP1 and TAP2 examined in the samples,nosignificant difference was found in allelic frequencies between pre-eclampsia group and control group,as well asbetween mothers and their neonates.Similar finding was obtained in the comparison with shared alleles.Inconclusion,our results do not support a role for the polymorphisms of TAP in the etiology of pre-eclampsia.Cellular & Molecular Immunology.2005;2(2):141-144.     

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.     

Steroid-sensitive nephrotic syndrome and vascular endothelial growth factor gene polymorphisms.

Genetic polymorphisms have been recognized as important determinants of gene expression. Three common single nucleotide polymorphisms have been identified in the promoter and 5' untranslated region of the vascular endothelial growth factor (VEGF) gene: -460 C --> T, -141 A --> C and +405 G --> C. As VEGF has been postulated to play a role in the pathogenesis of childhood steroid-sensitive nephrotic syndrome (SSNS), this study tested the hypothesis that VEGF genotype may be associated with susceptibility to SSNS. We examined the genotype frequencies of these polymorphisms in a total of 116 children with SSNS and 150 control subjects, using polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP). There were no statistically significant differences in any of the genotype frequencies between SSNS patients and controls. We conclude that VEGF -460, -141 and +405 genotypes are not associated with susceptibility to childhood SSNS.     

KIR2DL4 expression rather than its single nucleotide polymorphisms correlates with pre-eclampsia

Objective: To evaluate the single nucleotide polymorphisms and expression of KIR2DL4 (killer cell immunoglobulin-like receptors) gene in pre-eclampsia patients. Methods: KIR2DL4 gene polymorphisms were detected in 100 patients with pre-eclampsia and 100 healthy pregnant women, respectively, by using PCR-SS. Then, the expression of KIR2DL4 was measured in 5 cases of placentas tissues with pre-eclampsia and normal pregnancies by using qRT-PCR. Results: Compared with healthy controls, 16 loci of single nucleotide polymorphisms (SNP) were identified in pre-eclampsia patients, including 7 new polymorphisms loci. But, no significant difference was found in genotype distributions and allele frequencies in pre-eclampsia and controls (P>0.05). However, qRT-PCR results showed that KIR2DL4 mRNA in placenta tissues with pre-eclampsia was significantly lower than those with normal pregnancy, and the difference was statistically significant. Conclusion: Decreased level of KIR2DL4 rather than its SNP is correlated with the susceptibility of pre-eclampsia.