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      Role of HIF1A, VEGFA and VEGFR2 SNPs in the Susceptibility and Progression of COPD in a Spanish Population

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          Abstract

          Hypoxia is involved in the development of chronic inflammatory processes. Under hypoxic conditions HIF1A, VEGF and VEGFR2 are expressed and mediate the course of the resultant disease. The aim of the present study was to define the associations between tSNPs in these genes and COPD susceptibility and progression in a Spanish cohort. The T alleles in rs3025020 and rs833070 SNPs ( VEGFA gene) were less frequent in the group of COPD cases and were associated with a lower risk of developing the disease (OR = 0.60; 95% CI = 0. 39–0.93; p = 0.023 and OR = 0.60; 95% CI = 0.38–0.96; p = 0.034, respectively) under a dominant model of inheritance. The haplotype in which both SNPs presented the T allele confirmed the association found (OR = 0.02; 95% CI = 0.00 to 0.66; p = 0.03). Moreover, patients with COPD carrying the T allele in homozygosis in rs3025020 SNP showed higher lung function values and this association remained constant during 3 years of follow-up. In conclusion, T allele in rs833070 and rs3025020 may confer a protective effect to COPD susceptibility in a Spanish population and the association of the SNP rs3025020 with lung function may be suggesting a role for VEGF in the progression of the disease.

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          Most cited references 16

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          Lung function testing: selection of reference values and interpretative strategies. American Thoracic Society.

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            Interleukin-1beta and tumor necrosis factor-alpha stimulate DNA binding of hypoxia-inducible factor-1.

            The rate of transcription of several genes encoding proteins involved in O(2) and energy homeostasis is controlled by hypoxia-inducible factor-1 (HIF-1), a heterodimeric DNA binding complex composed of alpha and beta subunits. HIF-1 is considered the primary trans-acting factor for the erythropoietin (EPO) and vascular endothelial growth factor (VEGF) genes. Since EPO gene expression is inhibited by the proinflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), while no such effect has been reported with respect to the VEGF gene, we investigated the effects of IL-1beta and TNF-alpha on the activation of the HIF-1 DNA-binding complex and the amount of HIF-1alpha protein in human hepatoma cells in culture. Under normoxic conditions, both cytokines caused a moderate activation of HIF-1 DNA binding. In hypoxia, cytokines strongly increased HIF-1 activity compared with the effect of hypoxia alone. Only IL-1beta increased HIF-1alpha protein levels. In transient transfection experiments, HIF-1-driven reporter gene expression was augmented by cytokines only under hypoxic conditions. In contrast to their effect on EPO synthesis, neither IL-1beta nor TNF-alpha decreased VEGF production. The mRNA levels of HIF-1alpha and VEGF were unaffected. Thus, cytokine-induced inhibition of EPO production is not mediated by impairment of HIF-1 function. We propose that HIF-1 may be involved in modulating gene expression during inflammation.
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              Clinical implications for Vascular Endothelial Growth Factor in the lung: friend or foe?

              Vascular endothelial growth factor (VEGF) is a potent mediator of angiogenesis which has multiple effects in lung development and physiology. VEGF is expressed in several parts of the lung and the pleura while it has been shown that changes in its expression play a significant role in the pathophysiology of some of the most common respiratory disorders, such as acute lung injury, asthma, chronic obstructive pulmonary disease, obstructive sleep apnea, idiopathic pulmonary fibrosis, pulmonary hypertension, pleural disease, and lung cancer. However, the exact role of VEGF in the lung is not clear yet, as there is contradictory evidence that suggests either a protective or a harmful role. VEGF seems to interfere in a different manner, depending on its amount, the location, and the underlying pathologic process in lung tissue. The lack of VEGF in some disease entities may provide implications for its substitution, whereas its overexpression in other lung disorders has led to interventions for the attenuation of its action. Many efforts have been made in order to regulate the expression of VEGF and anti-VEGF antibodies are already in use for the management of lung cancer. Further research is still needed for the complete understanding of the exact role of VEGF in health and disease, in order to take advantage of its benefits and avoid its adverse effects. The scope of the present review is to summarize from a clinical point of view the changes in VEGF expression in several disorders of the respiratory system and focus on its diagnostic and therapeutic implications.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                10 May 2016
                2016
                : 11
                : 5
                Affiliations
                [1 ]Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
                [2 ]Pulmonary Department, Clínica Universitaria de Navarra, Pamplona, Spain
                [3 ]Biochemical Analysis Department, Clínica Universitaria de Navarra, Pamplona, Spain
                [4 ]Pulmonary Department, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
                [5 ]Immunology Department, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
                University of Birmingham, UNITED KINGDOM
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: RBD ECL CC. Performed the experiments: RBD AEJ NV AM DAG. Analyzed the data: RBD ECL AAJ CC. Contributed reagents/materials/analysis tools: CC JZ MCRP. Wrote the paper: RBD ECL CC.

                ‡ ECL and CC share senior authorship on this work.

                Article
                PONE-D-15-56531
                10.1371/journal.pone.0154998
                4862690
                27163696
                © 2016 Baz-Dávila et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 1, Tables: 4, Pages: 11
                Product
                Funding
                Funded by: European Regional Development Funds (ERFD)
                Award Recipient :
                Funded by: Fondo de Investigación en Salud-Insituto Carlos III
                Award ID: 09/00977
                Award Recipient :
                This work was supported by Fondo de Investigación en Salud-Instituto Carlos III 09/00977, http://www.isciii.es/ISCIII/es/contenidos/fd-el-instituto/quienes-somos.shtml, author who received the funding: CC. Project was co-financed by the European Regional Development Funds. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Pulmonology
                Chronic Obstructive Pulmonary Disease
                Biology and Life Sciences
                Evolutionary Biology
                Population Genetics
                Haplotypes
                Biology and Life Sciences
                Genetics
                Population Genetics
                Haplotypes
                Biology and Life Sciences
                Population Biology
                Population Genetics
                Haplotypes
                Research and Analysis Methods
                Mathematical and Statistical Techniques
                Statistical Methods
                Regression Analysis
                Physical Sciences
                Mathematics
                Statistics (Mathematics)
                Statistical Methods
                Regression Analysis
                Biology and Life Sciences
                Genetics
                Genetic Loci
                Alleles
                Biology and Life Sciences
                Behavior
                Habits
                Smoking Habits
                Medicine and Health Sciences
                Pulmonology
                Medical Hypoxia
                Physical Sciences
                Chemistry
                Chemical Elements
                Oxygen
                Biology and Life Sciences
                Immunology
                Immune Response
                Inflammation
                Medicine and Health Sciences
                Immunology
                Immune Response
                Inflammation
                Medicine and Health Sciences
                Diagnostic Medicine
                Signs and Symptoms
                Inflammation
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Signs and Symptoms
                Inflammation
                Custom metadata
                Based on signed consent forms of study participants, data are available on request. Requests should be addressed to Dra. Elizabeth Córdoba or Dr. Ciro Casanova, who will respond as appropriate.

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