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      Association of Vascular Endothelial Growth Factor Gene Polymorphism with Myocardial Infarction in Patients with Type 2 Diabetes


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          Background: Many studies have reported increased serum levels of vascular endothelial growth factor (VEGF) in patients with acute coronary syndromes. We searched for the association between either the –634 C/G or the insertion/deletion (I/D) polymorphism of the VEGF gene and myocardial infarction (MI) in subjects with type 2 diabetes. Methods: 143 subjects with type 2 diabetes and MI were compared to 228 diabetic subjects without coronary artery disease (CAD). VEGF serum levels were analyzed in 94 subjects with type 2 diabetes without CAD. Results: A significantly higher frequency of the CC genotype of the –634 C/G VEGF polymorphism was found in the patients with MI compared to the patients without CAD (17.5 vs. 9.2%; p = 0.019), whereas the insertion/deletion VEGF polymorphism failed to yield an association with MI. Significantly higher VEGF serum levels were demonstrated in subjects with the CC genotype compared to those with the other (CG + GG) genotypes (60.4 ± 32.1 vs. 44.1 ± 23.5 ng/l; p < 0.01). Conclusions: The present study demonstrates that the CC genotype of the –634 C/G VEGF gene might be a risk factor for MI in Caucasians with type 2 diabetes of duration of more than 10 years.

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          Most cited references 15

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          Identification of polymorphisms within the vascular endothelial growth factor (VEGF) gene: correlation with variation in VEGF protein production.

          Dysregulated vascular endothelial growth factor (VEGF) expression has been implicated as a major contributor to the development of a number of common disease pathologies. The aim of this study was to establish the extent of genetic variability within the VEGF gene and to determine whether this genetic variation influenced levels of VEGF protein expression. The promoter region and exon 1 of the VEGF gene were screened for polymorphisms using single-stranded conformation (SSCP) polymorphism analysis and direct PCR-sequencing. We identified 15 novel sequence polymorphisms most of which were rare. Eleven of these polymorphisms were single base substitutions, three were single base insertions and one was a two base deletion. Thirteen of the polymorphisms were located within the promoter and two in the 5' untranslated region (5'UTR) of the gene. We established PCR-RFLP typing systems for ten of the polymorphisms. For the two common polymorphisms at -460 and +405, we developed a combined sequence specific priming (SSP) PCR typing system to determine the cis/trans orientation of each allele and hence, ascertain haplotypes. A significant correlation was observed between lipopolysaccharide (LPS) stimulated peripheral blood mononuclear cell (PBMC) VEGF protein production and genotype for the +405 polymorphism. Copyright 2000 Academic Press.
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            Early expression of angiogenesis factors in acute myocardial ischemia and infarction.

            When the myocardium is deprived of blood, a process of ischemia, infarction, and myocardial remodeling is initiated. Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator of vascular endothelial growth factor (VEGF) and is critical for initiating early cellular responses to hypoxia. We investigated the temporal and spatial patterns of expression of the alpha subunit of HIF-1 (HIF-1alpha) and VEGF in specimens of human heart tissue to elucidate the early molecular responses to myocardial hypoxia. Ventricular-biopsy specimens from 37 patients undergoing coronary bypass surgery were collected. The specimens were examined by microscopy for evidence of ischemia, evolving infarction, or a normal histologic appearance. The specimens were also analyzed with the reverse-transcriptase polymerase chain reaction for HIF-1alpha and VEGF messenger RNA (mRNA) expression and by immunohistochemical analysis for the location of the HIF-1alpha and VEGF proteins. HIF-1alpha mRNA was detected in myocardial specimens with pathological evidence of acute ischemia (onset, <48 hours before surgery) or early infarction (onset, <24 hours before surgery). In contrast, VEGF transcripts were seen in specimens with evidence of acute ischemia or evolving infarction (onset, 24 to 120 hours before surgery). Patients with normal ventricles or evidence of infarction in the distant past had no detectable levels of either VEGF mRNA or HIF-1alpha mRNA. HIF-1alpha immunoreactivity was detected in the nuclei of myocytes and endothelial cells, whereas VEGF immunoreactivity was found in the cytoplasm of endothelial cells lining capillaries and arterioles. An increase in the level of HIF-1alpha is an early response to myocardial ischemia or infarction. This response defines, at a molecular level, one of the first adaptations of human myocardium to a deprivation of blood. HIF-1alpha is a useful temporal marker of acutely jeopardized myocardium.
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              A common polymorphism in the 5'-untranslated region of the VEGF gene is associated with diabetic retinopathy in type 2 diabetes.

              Vascular endothelial growth factor (VEGF), a major mediator of vascular permeability and angiogenesis, may play a pivotal role in mediating the development and progression of diabetic retinopathy. In the present study, we examined the genetic variations of the VEGF gene to assess its possible relation to diabetic retinopathy in type 2 diabetic patients. Among seven common polymorphisms in the promoter region, 5'-untranslated region (UTR) and 3'UTR of the VEGF gene, genotype distribution of the C(-634)G polymorphism differed significantly (P = 0.011) between patients with (n = 150) and without (n = 118) retinopathy, and the C allele was significantly increased in patients with retinopathy compared with those without retinopathy (P = 0.0037). The odds ratio (OR) for the CC genotype of C(-634)G to the GG genotype was 3.20 (95% CI 1.45-7.05, P = 0.0046). The -634C allele was significantly increased in patients with nonproliferative diabetic retinopathy (non-PDR) (P = 0.0026) and was insignificantly increased in patients with proliferative diabetic retinopathy (PDR) (P = 0.081) compared with patients without retinopathy, although frequencies of the allele did not differ significantly between the non-PDR and PDR groups. Logistic regression analysis revealed that the C(-634)G polymorphism was strongly associated with an increased risk of retinopathy (P = 0.0018). Furthermore, VEGF serum levels were significantly higher in healthy subjects with the CC genotype of the C(-634)G polymorphism than in those with the other genotypes. These data suggest that the C(-634)G polymorphism in the 5'UTR of the VEGF gene is a novel genetic risk factor for diabetic retinopathy.

                Author and article information

                S. Karger AG
                May 2007
                29 January 2007
                : 107
                : 4
                : 291-295
                aInstitute of Histology and Embryology, Medical Faculty, University of Ljubljana, bEye Clinic, cUniversity Institute for Clinical Chemistry and Biochemistry, and dDivision of Medical Genetics, Department of Obstetrics and Gynecology, University Medical Centre Ljubljana, Ljubljana, Slovenia
                99064 Cardiology 2007;107:291–295
                © 2007 S. Karger AG, Basel

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                Page count
                Tables: 4, References: 19, Pages: 5
                Original Research


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