Identification of cis and trans acting genetic variants explaining up to half the variation in circulating VEGF levels

Vascular endothelial growth factor (VEGF, also referred to as VEGFA in contrast to other members of the VEGF family) is pivotal in many physiological and pathological processes.1 It is primarily known for its key role in the stimulation of angiogenesis, with a potent mitogenic effect on vascular endothelial cells from arteries, veins and lymphatics.2 VEGF also promotes vasodilatation by inducing the production of nitric oxide and prostacyclin by endothelial cells.3 In addition, VEGF is involved in hematopoietic development and chemotaxis of monocytes, regulation of osteoclast differentiation, stimulation of surfactant production,1 and has neurotrophic and neuroprotective effects on neuronal and glial cells.4 Elevated circulating VEGF levels have been observed in vascular disease (ischemic heart disease,5, 6 heart failure,7 stroke8), and in various other disorders, including diabetes,9 cognitive decline and dementia,10, 11 reproductive,12–14 immune-inflammatory disorders,15,16 and neoplastic diseases.17, 18 Administration of VEGF promotes angiogenesis in patients with critical leg ischemia, as well as in animal models of coronary and limb ischemia.19 VEGF inhibitors such as bevacizumab and sorafenib have been successfully used to inhibit angiogenesis in several tumors,20, 21 in macular degeneration22 and in rheumatoid arthritis.23 However, despite the considerable toxicity associated with VEGF inhibitor drugs,24 there have been no pharmacogenomic studies to identify potential subgroups of responders partly because the genetic determinants of VEGF concentrations remain poorly understood. Indeed, although the heritability of circulating VEGF levels is very high, ranging between 60 and 80%,25–27 few studies have assessed the relation between circulating VEGF levels and genetic variants, yielding inconsistent results. The aim of the present study was to identify genetic variants associated with circulating VEGF levels using an unbiased genome-wide approach in a large community-based sample.