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      Polymorphisms of vascular endothelial growth factor—2578C/A rs699947 are risk factors for diabetic retinopathy in type-2 diabetes mellitus patients in Bali, Indonesia

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          Abstract

          Background

          Diabetic retinopathy (DR) is one of the complications in diabetes mellitus (DM) which caused by microvascular-damage in the retina due to long termmetabolic changes in diabetes. To date, there has been much research targeted on the determinant of genetic identification in DR patients. In DR, Vascular Endothelial Growth Factor (VEGF) gene is accountable for breaking down the blood-retinal barrier and implicated in the role of neovascularization. It is thought that the polymorphism of VEGF -2578C/A (rs699947) contributed to the development of diabetic retinopathy in type 2 DM.

          Aim

          To determine whether the polymorphisms of VEGF-2578C/A are the risk factors for DR in type 2 DM patients in Bali, Indonesia.

          Methods

          This study is a case-control model comparing 33 cases DR patients in type-2 diabetes mellitus and 35 cases of non-DR as controls in Balinese ethnic. Polymorphisms of VEGF-2578C/A were examined by PCR analysis and DNA sequencing on rs699947 to identify any variation in A/C/T allele distribution. Chi-square test was used to analyze the data and determine the relation of polymorphism and DR.

          Results

          This research showed the genetic variation existence in VEGF-2578C/A polymorphism significantly (p = 0,000) with C allele was higher in the DR group, in contrast, A and T allele were greater in the non-DR group compared to DR group. The result showed that C allele in VEGF-2578 contributed as a risk factor (OR = 13.05; 95% CI = 2.69–63.18; p = 0.001) for DR in type-2 DM (T2DM) patients in Bali, Indonesia.

          Conclusion

          Polymorphism of VEGF-2578C/A (rs699947) allele distribution can be concluded as a risk factor of DR within T2DM patients in Bali, Indonesia. This study may also be used to expand the knowledge in managing DR patients at an earlier stage to avoid further complications.

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          Most cited references39

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          WITHDRAWN: Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9th edition

          To provide global estimates of diabetes prevalence for 2019 and projections for 2030 and 2045.
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            Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1.

            Expression of vascular endothelial growth factor (VEGF) is induced in cells exposed to hypoxia or ischemia. Neovascularization stimulated by VEGF occurs in several important clinical contexts, including myocardial ischemia, retinal disease, and tumor growth. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix protein that activates transcription of the human erythropoietin gene in hypoxic cells. Here we demonstrate the involvement of HIF-1 in the activation of VEGF transcription. VEGF 5'-flanking sequences mediated transcriptional activation of reporter gene expression in hypoxic Hep3B cells. A 47-bp sequence located 985 to 939 bp 5' to the VEGF transcription initiation site mediated hypoxia-inducible reporter gene expression directed by a simian virus 40 promoter element that was otherwise minimally responsive to hypoxia. When reporters containing VEGF sequences, in the context of the native VEGF or heterologous simian virus 40 promoter, were cotransfected with expression vectors encoding HIF-1alpha and HIF-1beta (ARNT [aryl hydrocarbon receptor nuclear translocator]), reporter gene transcription was much greater in both hypoxic and nonhypoxic cells than in cells transfected with the reporter alone. A HIF-1 binding site was demonstrated in the 47-bp hypoxia response element, and a 3-bp substitution eliminated the ability of the element to bind HIF-1 and to activate transcription in response to hypoxia and/or recombinant HIF-1. Cotransfection of cells with an expression vector encoding a dominant negative form of HIF-1alpha inhibited the activation of reporter transcription in hypoxic cells in a dose-dependent manner. VEGF mRNA was not induced by hypoxia in mutant cells that do not express the HIF-1beta (ARNT) subunit. These findings implicate HIF-1 in the activation of VEGF transcription in hypoxic cells.
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              Vascular endothelial growth factor in eye disease.

              Collectively, angiogenic ocular conditions represent the leading cause of irreversible vision loss in developed countries. In the US, for example, retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration are the principal causes of blindness in the infant, working age and elderly populations, respectively. Evidence suggests that vascular endothelial growth factor (VEGF), a 40kDa dimeric glycoprotein, promotes angiogenesis in each of these conditions, making it a highly significant therapeutic target. However, VEGF is pleiotropic, affecting a broad spectrum of endothelial, neuronal and glial behaviors, and confounding the validity of anti-VEGF strategies, particularly under chronic disease conditions. In fact, among other functions VEGF can influence cell proliferation, cell migration, proteolysis, cell survival and vessel permeability in a wide variety of biological contexts. This article will describe the roles played by VEGF in the pathogenesis of retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. The potential disadvantages of inhibiting VEGF will be discussed, as will the rationales for targeting other VEGF-related modulators of angiogenesis.
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                Author and article information

                Journal
                Biomedicine (Taipei)
                Biomedicine (Taipei)
                BioMedicine
                China Medical University
                2211-8020
                2211-8039
                2021
                01 June 2021
                : 11
                : 2
                : 11-17
                Affiliations
                [a ]Faculty of Medicine, Udayana University, Denpasar, Bali, Indonesia
                [b ]Department of Biochemistry, Faculty of Medicine, Udayana University, Denpasar, Bali, Indonesia
                Author notes
                [* ]Corresponding author at: Department of Biochemistry, Faculty of Medicine, Udayana University, Jl. PB Sudirman, Denpasar, 80232, Bali, Indonesia. Fax: +62361 222510. E-mail address: dmwihandani@ 123456unud.ac.id (D.M. Wihandani).
                Article
                bmed-11-02-011
                10.37796/2211-8039.1170
                8824245
                e31f0f7c-fb9f-4e2c-983f-3a0029e54a30
                © the Author(s)

                This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 11 November 2020
                : 29 January 2021
                Categories
                Original Article

                diabetes mellitus,diabetic retinopathy,snp rs699947,vegf polymorphism

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