Genetics of PlGF plasma levels highlights a role of its receptors and supports the link between angiogenesis and immunity

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.

Figure 1

Manhattan plot of genome-wide association results in discovery analysis. Manhattan Plot showing − log10(p-values) for all SNPs of the PlGF discovery GWAS ordered by their chromosomal position. The blue dashed line indicates the suggestive association threshold (p-value < 1 × 10^–6), while the red dashed line indicates the genome-wide significant threshold (p-value < 5 × 10^–8). Blue dots are the SNPs associated at the suggestive significance level (p-value < 1 × 10^–6). For each locus, the nearest gene is reported.