Functional VEGF haplotypes affect the susceptibility to hypertension

Abstract

We examined whether vascular endothelial growth factor (VEGF) polymorphisms (C-2578A, G-1154A and G-634C) are associated with hypertension, response to antihypertensive therapy and nitric oxide (NO) formation. Substudy 1 compared the distribution of VEGF genotypes and haplotypes in 178 patients with arterial hypertension (100 whites and 78 blacks) and 186 healthy controls (115 whites and 71 blacks). Substudy 2 compared the distribution of VEGF markers in 82 patients with controlled hypertension, 89 patients with resistant hypertension and 101 normotensive (NT) patients. In substudy 3, plasma nitrite/nitrate (NOx) levels were determined (chemiluminescence assay) in 64 NT subjects and 48 hypertensive (HTN) subjects, and the distribution of VEGF markers was compared in subjects having low NOx with subjects having high NOx. Although the substudy 1 showed no differences in genotypes or allele distributions for the three VEGF polymorphisms between NT and HTN subjects, the 'C-A-G' haplotype was more common in white NT subjects than in the white HTN subjects, and the 'C-A-C' haplotype was more frequent in black and white HTN subjects than in black and white NT subjects. The substudy 2 showed similar results, with no differences between responsive and resistant HTN subjects. The substudy 3 showed that the 'C-A-G' haplotype, which had a protective effect against hypertension, was significantly more common in subjects with higher NOx concentrations than in subjects with lower NOx concentrations. VEGF haplotypes are associated with hypertension, and the haplotype associated with normotension was more common in subjects with increased NO formation, possibly offering a mechanistic clue for our findings.

Polymorphisms in VEGFA gene affect the antihypertensive responses to enalapril

“…Genotype/allele frequencies found in the present study are in agreement with previous studies in the Brazilian population [24-26, 28, 32, 39], including recent studies enrolling hypertensive patients [25,28]. No significant differences in genotype/ allele frequencies were found between the group of patients treated with enalapril 10 mg/day and the group of patients treated with enalapril 20 mg/day (Table S1; P>0.05).…”

“…Therefore, we analyzed VEGFA haplotypes, which may offer improved genetic information than the analysis of genetic markers individually [28]. Indeed, we consistently found that the AGG haplotype affects the antihypertensive responses to enalapril, resulting in more intense decrease in SBP, MBP, and DBP after treatment with enalapril 20 mg/day.…”

“…In fact, studies demonstrated that these SNPs affect VEGF expression [27,29]. Moreover, these three SNPs were associated with many pathological conditions, such as diabetic retinopathy [22], left ventricular hypertrophy [26], renal allograft rejection [29], and hypertensive disorders [28,31,32]. Taking all these findings into account, we hypothesized that genotypes or haplotypes of VEGFA polymorphisms modulate the antihypertensive response to the ACEi enalapril.…”

“…Among several polymorphisms in VEGFA gene, the singlenucleotide polymorphisms (SNPs) g.-2578C>A (rs699947), g.-1154G>A (rs1570360), and g.-634G>C (rs2010963) have been widely studied due to their functional implications and clinical relevance [22][23][24][25][26][27][28][29][30]. In fact, studies demonstrated that these SNPs affect VEGF expression [27,29].…”

Pharmacogenetic implications in the management of metabolic diseases in Brazilian populations

“…Moreover, the haplotype AGG (-2578C>A, c.-1154G>A and c.-634G>C polymorphisms) was associated with more intense decrease in BP, while the opposite was found to be associated with the CGG haplotype. Conversely, these VEGFA polymorphisms were not associated with resistance to antihypertensive treatment in another sample of the Brazilian population (Sandrim et al, 2013).…”