A Common 936 C/T Mutation in the Gene for Vascular Endothelial Growth Factor Is Associated with Vascular Endothelial Growth Factor Plasma Levels

Abstract

Background: Vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis. Strong interindividual variations of VEGF plasma levels have been reported previously. Aim of the present study was to search for mutations in the 3′ untranslated region (3′-UTR) of the VEGF gene and to analyze their relation to VEGF plasma levels. Methods: The complete 3′-UTR (nucleotide 700–2622) of the VEGF gene was screened for sequence variations by single-strand conformation polymorphism (SSCP) analysis. Frequencies of mutated alleles were determined in 119 healthy subjects; VEGF plasma levels were analyzed in a subgroup of 23 healthy men aged 18–36 years. Results: Three novel mutations (702 C/T, 936 C/T, 1612 G/A) were found, allele frequencies of 702T, 936T and 1612A were of 0.017, 0.160 and 0.471, respectively. VEGF plasma levels were significantly lower in carriers of the 936T allele (9.1 ± 2.7 pg/ml, mean ± SEM) than in noncarriers (28.0 ± 5.5 pg/ml, p = 0.033), whereas the 702 C/T and the 1612 G/A mutations showed no association with VEGF plasma levels. The 936 C/T exchange led to the loss of a potential binding site for transcription factor AP-4, although the functionality of this binding site remains unclear. Conclusion: We have found three common mutations in the VEGF gene; one of them, a 936 C/T exchange, may be an important determinant of VEGF plasma levels.

Role of genetic polymorphisms in tumour angiogenesis

“…The 936 T allele was associated with decreased (Renner et al, 2000). We have studied this polymorphism in breast cancer, but were unable to demonstrate any significant association (Balasubramanian et al, 2002).…”

Genetic alterations of IDH1 and Vegf in brain tumors

“…The presence of T allele has been related with the loss of a potential binding site for activator protein 4 (AP‐4). This may be the mechanism of variant allele for the inhibition of VEGF transcription, and explain the lower risk of T carriers in developing cancer (Renner et al., 2000). …”

“…This data is in agreement with those published by NCBI dbSNP database for European population (minor allele frequency, MAF, of 0.13) and comparable to previous results from Caucasian and European cohorts (frequency 0.13–0.16; Renner et al., 2000; Rinck‐Junior et al., 2015; Rodrigues et al., 2012; Vidaurreta et al., 2010), but quite different to Korean and Chinese cohorts (frequency 0.16–0.24; Jiang et al., 2013; Lee et al., 2005; Li et al., 2011) which present a MAF of 0.18 (NCBI dbSNP database; Li et al., 2011). In our study, T allele appears more frequently in pilocytic astrocytomas and oligodendroglial tumors, followed by meningiomas, ependymomas and anaplastic astrocytomas in frequency (Table 2).…”

“…The VEGF gene is located on chromosome 6p21.3 and more than 30 single‐nucleotide polymorphisms (SNPs) have been identified in this gene (Ku et al., 2005; Lin, Wu, Tsai, Chen, & Chen, 2003; Vincenti, Cassano, Rocchi, & Persico, 1996; Watson, Webb, Bottomley, & Brenchley, 2000). The VEGF +936 C/T polymorphism (rs3025039), is a common SNP located in the 3’ untranslated region, and C allele is associated with substantially increased serum VEGF levels when compared to the variant T allele (Krippl et al., 2003; Li et al., 2011; Renner, Kotschan, Hoffmann, Obermayer‐Pietsch, & Pilger, 2000; Watson et al., 2000). …”

The vascular endothelial growth factor (VEGF) +405 G/C polymorphism and its relationship with recurrent implantation failure in women in an IVF programme with ICSI

“…Several single nucleotide polymorphisms (SNPs) have been found in the VEGF gene. Some SNPs (such as VEGF −2578 A/C (in the promoter region), −1154 G/A (also in the promoter region), +405 G/C (in the 5′-untranslated region) and 936 C/T (in the 3′-untranslated region)) are associated with altered VEGF expression [4,22,33,42]. Dysregulation of VEGF expression is implicated in many disease situations in which angiogenesis may be critical, such as breast cancer progression [17], cardiovascular disease [34], essential hypertension [14] and psoriasis [44].…”