Abstract
Placental growth factor (PlGF) is a member of the vascular endothelial growth factor family and is involved in bone marrow-derived cell activation, endothelial stimulation and pathological angiogenesis. High levels of PlGF have been observed in several pathological conditions especially in cancer, cardiovascular, autoimmune and inflammatory diseases. Little is known about the genetics of circulating PlGF levels. Indeed, although the heritability of circulating PlGF levels is around 40%, no studies have assessed the relation between PlGF plasma levels and genetic variants at a genome-wide level. In the current study, PlGF plasma levels were measured in a population-based sample of 2085 adult individuals from three isolated populations of South Italy. A GWAS was performed in a discovery cohort (N = 1600), followed by a de novo replication (N = 468) from the same populations. The meta-analysis of the discovery and replication samples revealed one signal significantly associated with PlGF circulating levels. This signal was mapped to the PlGF co-receptor coding gene NRP1, indicating its important role in modulating the PlGF plasma levels. Two additional signals, at the PlGF receptor coding gene FLT1 and RAPGEF5 gene, were identified at a suggestive level. Pathway and TWAS analyses highlighted genes known to be involved in angiogenesis and immune response, supporting the link between these processes and PlGF regulation. Overall, these data improve our understanding of the genetic variation underlying circulating PlGF levels. This in turn could lead to new preventive and therapeutic strategies for a wide variety of PlGF-related pathologies.
Highlights
Placental growth factor (PlGF) is a member of the vascular endothelial growth factor family and is involved in bone marrow-derived cell activation, endothelial stimulation and pathological angiogenesis
These observations are in line with the results of the expression quantitative trait loci (eQTL) analysis, in which the T allele of the rs17296631 variant is associated with an increase of both PlGF levels and Neuropilin 1 (NRP1) gene expression
The PlGF binding to Flt-1 stimulates angiogenesis via both direct and indirect mechanisms: the activation of Flt-1 by PlGF results in phosphorylation of specific tyrosine residues in Flt-1 and downstream signaling different from those activated by VEGFA binding; it has been proposed, based on in vitro data and overexpression studies, that the binding of PlGF to Flt-1 induces pro-angiogenic effects as PlGF shifts VEGFA from Flt-1 to VEGFR2, enhancing the effects of VEGFA26
Summary
Placental growth factor (PlGF) is a member of the vascular endothelial growth factor family and is involved in bone marrow-derived cell activation, endothelial stimulation and pathological angiogenesis. Pathway and TWAS analyses highlighted genes known to be involved in angiogenesis and immune response, supporting the link between these processes and PlGF regulation Overall, these data improve our understanding of the genetic variation underlying circulating PlGF levels. Placental growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family It is a cytokine with a non essential role in healthy conditions, but with a specific involvement in several malignant, inflammatory and ischemic disorders[1,2,3]. A pregnancy-specific disorder characterized by the development of hypertension and proteinuria in the later stages of gestation[13], show lower PlGF circulating levels compared to healthy pregnant women[14,15,16] All these data show that the amount of PlGF has a relevant impact on the determination of pathological conditions. We have conducted the first genome-wide association study (GWAS) for PlGF in a general population sample with a deep genomic coverage based on imputation to the 1000 Genomes panel, to identify genetic variants that explain variation in circulating PlGF concentrations
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