Saleh Abdelsalam, Stathopoulou Maria G, Dadé Sébastien, Ndiaye Ndeye Coumba, Azimi-Nezhad Mohsen, Murray Helena, Masson Christine, Lamont John, Fitzgerald Peter, Visvikis-Siest Sophie
UMR INSERM U 1122, IGE-PCV "Interactions Gène-Environnement en Physiopathologie Cardio Vasculaire", Université de Lorraine, Nancy, F-54000, France.
Department of Medical Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
BMC Med Genet. 2015 Oct 5;16:90. doi: 10.1186/s12881-015-0234-6.
Vascular endothelial growth factor (VEGF) plays a key role in angiogenesis. The aim was to assess the genetic connections between the angiogenesis-related NOS3, CD14, MMP3, IL4R, IL4 genes and VEGF expression and plasma levels.
The associations between VEGF plasma levels with the polymorphisms of NOS3, CD14, MMP3, IL4R, and IL4 were assessed in 403 healthy unrelated adults. The epistatic and environmental interactions were explored, including four VEGF-related polymorphisms previously identified. The VEGF expression in peripheral blood mononuclear cells was quantified (n = 65) for the VEGF121, VEGF145, VEGF165, and VEGF189 isoforms.
The polymorphism rs1799983 of NOS3 was associated with the sum of all VEGF isoforms mRNA levels (P = 0.032) and VEGF145 (P = 0.033). Rs1800779 of NOS3 interacted with rs3918226 of the same gene and with the rs2569190 of CD14 (P = 0.022, P = 0.042, respectively) for VEGF plasma levels. Other epistatic interactions included the rs1801275 of IL4R with the rs6921438 (VEGF-related variant) and rs3025058 of MMP3 (P = 0.042, P = 0.010 respectively) and the rs2569190 of CD14 with the rs3025058 of MMP3 (P = 0.0119). We also identified an interaction of rs1800779 with obesity, high-density lipoprotein cholesterol and triglycerides (P = 0.018, P = 0.005, P = 0.043, respectively) as well as the interaction of rs6921438 with hypertension (P = 0.028).
Our findings indicated that genetic variants of NOS3, CD14, MMP3 and IL4R are implicated in the determination of VEGF expression and plasma levels. Thus, they support the hypothesis that in physiological conditions there are complex biological relationships between pathways (such as angiogenesis and inflammation), which are involved in the development of chronic diseases.
血管内皮生长因子（VEGF）在血管生成中起关键作用。目的是评估血管生成相关的NOS3、CD14、MMP3、IL4R、IL4基因与VEGF表达及血浆水平之间的遗传联系。
在403名健康无亲缘关系的成年人中评估VEGF血浆水平与NOS3、CD14、MMP3、IL4R和IL4多态性之间的关联。探索上位性和环境相互作用，包括先前鉴定的四种与VEGF相关的多态性。对VEGF121、VEGF145、VEGF165和VEGF189亚型在外周血单核细胞中的VEGF表达进行定量分析（n = 65）。
NOS3的多态性rs1799983与所有VEGF亚型mRNA水平总和（P = 0.032）及VEGF145（P = 0.033）相关。NOS3的rs1800779与同一基因的rs3918226以及CD14的rs2569190在VEGF血浆水平上存在相互作用（分别为P = 0.022，P = 0.042）。其他上位性相互作用包括IL4R的rs1801275与rs6921438（VEGF相关变体）和MMP3的rs3025058（分别为P = 0.042，P = 0.010）以及CD14的rs2569190与MMP3的rs3025058（P = 0.0119）。我们还发现rs1800779与肥胖、高密度脂蛋白胆固醇和甘油三酯存在相互作用（分别为P = 0.018，P = 0.005，P = 0.043）以及rs6921438与高血压存在相互作用（P = 0.028）。
我们的研究结果表明，NOS3、CD14、MMP3和IL4R的基因变异与VEGF表达及血浆水平的决定有关。因此，它们支持这样的假设，即在生理条件下，参与慢性病发展的途径（如血管生成和炎症）之间存在复杂的生物学关系。
