Genetics of VEGF Serum Variation in Human Isolated Populations of Cilento: Importance of VEGF Polymorphisms

Abstract

Vascular Endothelial Growth Factor (VEGF) is the main player in angiogenesis. Because of its crucial role in this process, the study of the genetic factors controlling VEGF variability may be of particular interest for many angiogenesis-associated diseases. Although some polymorphisms in the VEGF gene have been associated with a susceptibility to several disorders, no genome-wide search on VEGF serum levels has been reported so far. We carried out a genome-wide linkage analysis in three isolated populations and we detected a strong linkage between VEGF serum levels and the 6p21.1 VEGF region in all samples. A new locus on chromosome 3p26.3 significantly linked to VEGF serum levels was also detected in a combined population sample. A sequencing of the gene followed by an association study identified three common single nucleotide polymorphisms (SNPs) influencing VEGF serum levels in one population (Campora), two already reported in the literature (rs3025039, rs25648) and one new signal (rs3025020). A fourth SNP (rs41282644) was found to affect VEGF serum levels in another population (Cardile). All the identified SNPs contribute to the related population linkages (35% of the linkage explained in Campora and 15% in Cardile). Interestingly, none of the SNPs influencing VEGF serum levels in one population was found to be associated in the two other populations. These results allow us to exclude the hypothesis that the common variants located in the exons, intron-exon junctions, promoter and regulative regions of the VEGF gene may have a causal effect on the VEGF variation. The data support the alternative hypothesis of a multiple rare variant model, possibly consisting in distinct variants in different populations, influencing VEGF serum levels.

Investigation of the role of VEGF gene polymorphisms in the risk of osteosarcoma

“…The VEGF gene is located on chromosome 6p21.3 and has a 14-kb coding region with 8 exons and 7 introns. There are over 30 variants in VEGF; three of the common polymorphisms in the VEGF gene can influence gene expression and alter the function of the protein, including -634G/C, +936C/T, and +1612G/A (Watson et al, 2000;Ruggiero et al, 2011). VEGF -634G/C, +936C/T, and +1612G/A are reported to have a role in VEGF protein synthesis and in the development of several kinds of cancers Dong-Ju et al, 2014;Lau et al, 2014;Rahoui et al, 2014;Yang et al, 2014b;Yu et al, 2014).…”

SNP-Based Linkage Analysis in Extended Pedigrees: Comparison between Two Alternative Approaches

“…Significance can be determined using permutation methods, as we did in this study, or with 36 more sophisticated methods, like for example the local false discovery rate [23] . MCMC methods extend the feasibility of linkage analysis with regard to the complexity of a pedigree that can be handled while leaving it intact and with regard to the number of loci that can be analyzed jointly.…”

Genetic variation in vascular endothelial growth factor gene and its association with recurrent spontaneous abortion

“…With regard to the population's genetic diversity, Ruggiero et al (20) carried out a genome-wide linkage analysis (77 SNPs including 64 SNPs and 13 Ins/Del) in three Italian isolated populations and detected linkage between VEGF serum levels and 6p21.1 VEGF region. Three common single nucleotide polymorphisms (SNPs) including rs3025039, rs25648, rs3025020 in one population and rs41282644 in another population were found to affect the VEGF serum levels.…”