Role of VEGF Polymorphisms in the Susceptibility and Severity of Interstitial Lung Disease (original) (raw)
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Scientific reports, 2014
The etiology and pathogenesis of idiopathic interstitial lung disease (ILD) remain incompletely understood. Genetic susceptibility to ILD has been demonstrated in previous studies. It is well known that EGFR inhibitors can induce ILD in human lung cancer patient with ethnic differences, which prompted us to hypothesize that genetic variation in EGFR pathway genes confer susceptibility to ILD. We aimed in this study to investigate whether functional polymorphisms of EGFR and its ligands genes (EGF and TGFA) were associated with ILD. Three EGFR [-216G/T (rs712830), -191A/C (rs712829), 497R > K(A/G) (rs2227983)], one EGF [61A/G, (rs4444903)] and one TGFA (rs3821262C/T) polymorphisms previously demonstrated to alter gene functions were genotyped in 229 sporadic idiopathic ILD patients and 693 normal healthy individuals. Allelic and genotypic association tests between these polymorphisms and ILD were performed. The EGF 61A/G polymorphism was significantly associated with elevated risk...
Association of VEGF polymorphisms with childhood asthma, lung function and airway responsiveness
European Respiratory Journal, 2009
Vascular endothelial growth factor (VEGF) is an angiogenic factor implicated in asthma severity. The objective of this study was to determine whether VEGF single nucleotide polymorphisms (SNPs) are associated with asthma, lung function, and airways responsiveness. We analyzed 10 SNPs in 458 white families in the Childhood Asthma Management Program (CAMP). Tests of association with asthma, lung function, and airways responsiveness were performed using PBAT. Family and population-based repeated measures analysis of airflow obstruction were conducted. Replication studies were performed in 412 asthmatic children and their parents from Costa Rica. Associations with asthma, lung function, and airways responsiveness were observed in both cohorts. SNP rs833058 was associated with asthma in both cohorts (CAMP p=0.004, Costa Rica p=0.01). This SNP was also associated with increased airways responsiveness in both populations (CAMP p=0.01, Costa Rica p=0.03). An association of rs4711750 and its haplotype with FEV¬11/FVC ratio in both cohorts (CAMP p=0.01, Costa Rica p=0.01) was observed. Longitudinal analysis in CAMP confirmed an association of rs4711750 with FEV1/FVC decline over approximately 4.5 years of observation (p=0.03). VEGF polymorphisms are associated with childhood asthma, lung function, and airways responsiveness in two populations, suggesting that VEGF polymorphisms influences asthma susceptibility, airflow obstruction, and airways responsiveness.
Cytokine gene polymorphisms and serum cytokine levels in patients with idiopathic pulmonary fibrosis
BMC Medical Genetics, 2013
Background: Studies have demonstrated associations between cytokine gene polymorphisms and the risk of idiopathic pulmonary fibrosis (IPF). We therefore examined polymorphisms in the genes encoding interleukin (IL)-6, IL-10, interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and transforming growth factor-beta 1 (TGF-β 1 ), and compared the serum levels of these cytokines in IPF patients and healthy controls. Furthermore, we examined the association of the studied genotypes and serum cytokine levels with physiological parameters and the extent of parenchymal involvement determined by high-resolution computed tomography (HRCT).
Genetic Variation in Vascular Endothelial Growth Factor-A and Lung Function
American Journal of Respiratory and Critical Care Medicine, 2012
Rationale: Given the role of vascular endothelial growth factor (VEGF) in lung development, we hypothesized that polymorphisms in VEGF-A may be associated with lung function. Objectives: The current study was designed to assess the role of genetic variants in VEGF-A as determinants of airway function from infancy through early adulthood. Methods: Association between five single-nucleotide polymorphisms (SNPs) in VEGF-A and lung function were assessed longitudinally in two unselected birth cohorts and cross-sectionally among infants. Replication with two SNPs was conducted in adults and children with asthma. We investigated the functionality of the SNP most consistently associated with lung function (rs3025028) using Western blotting to measure the ratio of plasma VEGF-A 165b /panVEGF-A 165 among homozygotes. Measurements and Main Results: In two populations in infancy, C-allele homozygotes of rs3025028 had significantly higher VmaxFRC, forced expiratory flow 50 , and forced expiratory flow 25-75 compared with other genotype groups. Among preschool children (age 3 yr), C allele of rs3025028 was associated with significantly higher specific airway conductance, with similar findings observed for lung function in school-age children. For FEV 1 /FVC ratio similar findings were observed among adolescents and young adults (birth cohort), and then replicated in adults and schoolchildren with asthma (cross-sectional studies). For rs3025038, plasma VEGF-A 165b /panVEGF-A 165 was significantly higher among CC versus GG homozygotes (P < 0.02) at birth, in school-age children, and in adults. Conclusions: We report significant associations between VEGF-A SNP rs3025028 and parameters of airway function measured throughout childhood, with the effect persisting into adulthood. We propose that the mechanism may be mediated through the ratios of active and inhibitory isoforms of VEGF-A 165 , which may be determined by alternative splicing.
VEGF (Vascular Endothelial Growth Factor) and Fibrotic Lung Disease
International Journal of Molecular Sciences
Interstitial lung disease (ILD) encompasses a group of heterogeneous diseases characterised by varying degrees of aberrant inflammation and fibrosis of the lung parenchyma. This may occur in isolation, such as in idiopathic pulmonary fibrosis (IPF) or as part of a wider disease process affecting multiple organs, such as in systemic sclerosis. Anti-Vascular Endothelial Growth Factor (anti-VEGF) therapy is one component of an existing broad-spectrum therapeutic option in IPF (nintedanib) and may become part of the emerging therapeutic strategy for other ILDs in the future. This article describes our current understanding of VEGF biology in normal lung homeostasis and how changes in its bioavailability may contribute the pathogenesis of ILD. The complexity of VEGF biology is particularly highlighted with an emphasis on the potential non-vascular, non-angiogenic roles for VEGF in the lung, in both health and disease.
Variations in the Vascular Endothelial Growth Factor Pathway Predict Pulmonary Complications
The Annals of Thoracic Surgery, 2012
Background-Clinical factors predicting pulmonary complications after lung resection have been well described, whereas the role of genetics is unknown. The vascular endothelial growth factor (VEGF) signaling pathway has been linked to acute lung injury. We hypothesized that genetic variations in this pathway may be associated with postoperative pulmonary complications after lung resection. Methods-One hundred ninety-six single nucleotide polymorphisms (SNPs) in 17 genes in the VEGF pathway were genotyped in a discovery set of 264 patients and a replication set of 264 patients who underwent lobectomy for lung cancer. Multivariable analysis adjusting for baseline clinical factors was used to identify SNPs associated with pulmonary complications. Cumulative and classification and regression tree (CART) analyses were used to further stratify risk groups. Results-The overall number of pulmonary complications was 164/528 (31%). The effects of 6 SNPs were consistent in the discovery and replication sets (pooled p value < 0.05). The rs9319425 SNP in the VEGF receptor gene FLT1 resulted in a 1.50-fold increased risk (1.15-1.96; p = 0.003). A cumulative effect for the number of risk genotypes and complications was also evident (p < 0.01). Patients carrying 5 risk genotypes had a 5.76-fold increase in risk (2.73-12.16; p = 4.44 × 10 −6). Regression tree analysis identified potential gene-gene interactions between FLT1:rs9319425 and RAF1:rs713178. The addition of the 6 SNPs to the clinical model increased the area under the receiver operating characteristic curve by 6.8%. Conclusions-Genetic variations in the VEGF pathway are associated with risk of pulmonary complications after lobectomy. This may offer insight into the underlying biological mechanisms of pulmonary complications. Since Graham's [1] report of the first successful pneumonectomy in 1933, thoracic surgeons have attempted to identify patients at higher risk for complications after lung resection. A variety of clinical models have been created to help predict postoperative complications and aid in patient selection [2-5]. These models have included factors such as patient smoking history, spirometry, diffusion capacity, and exercise testing. These clinical models, however, often fail to identify patients who have postoperative complications. Modern series still report morbidity rates of 15% to 50% and mortality rates of 3% to 6% [5, 6]. Many patients
Journal of Korean medical science, 2016
Vascular endothelial growth factor (VEGF) contributes to tumor angiogenesis. The role of VEGF single nucleotide polymorphisms (SNPs) in lung cancer susceptibility and its prognosis remains inconclusive and controversial. This study was performed to investigate whether VEGF polymorphisms affect survival outcomes of patients with early stage non-small cell lung cancer (NSCLC) after surgery. Three potentially functional VEGF SNPs (rs833061T>C, rs2010963G>C, and rs3025039C>T) were genotyped. A total of 782 NSCLC patients who were treated with surgical resection were enrolled. The association of the SNPs with overall survival (OS) and disease free survival (DFS) was analyzed. In overall population, none of the three polymorphisms were significantly associated with OS or DFS. However, when the patients were stratified by tumor histology, squamous cell carcinoma (SCC) and adenocarcinoma (AC) had significantly different OS (Adjusted hazard ratio [aHR] = 0.76, 95% CI = 0.56-1.03 in ...