The Relationship Between Vascular Endothelial Growth Factor Cis- and Trans-Acting Genetic Variants and Metabolic Syndrome.

BACKGROUND: We have investigated the association between 4 cis- and trans-genetic variants (rs6921438, rs4416670, rs6993770 and rs10738760) of the vascular endothelial growth factor (VEGF) gene and metabolic syndrome (MetS) and its individual components in an Iranian population. MATERIAL & METHOD: Three hundred and thirty-six subjects were enrolled and MetS was defined according to the International-Diabetes-Federation (IDF) criteria. Genotyping was carried out in all the individuals for 4 VEGF genetic variants using an assay based on a combination of multiplex polymerase chain reaction and biochip array hybridization. RESULTS: As may be expected, patients with MetS had significantly higher levels of serum high-sensitivity C-reactive protein, waist circumference, hip circumference, body mass index, fat percentage, systolic blood pressure, diastolic blood pressure and triglyceride, whereas the high-density lipoprotein cholesterol levels were significantly lower, compared to the control group (P < 0.05). We also found that 1 of the VEGF- level associated genetic variants, rs6993770, was associated with the presence of MetS; the less common T allele at this locus was associated with an increased risk for MetS. This association remained significant after adjustment for confounding factors (P = 0.007). Individuals with MetS carrying the AT + TT genotypes had markedly higher levels of fasting blood glucose, triglyceride and systolic blood pressure (P < 0.05). CONCLUSIONS: We have found an association between the rs6993770 polymorphism and MetS. This gene variant was also associated with serum VEGF concentrations. There was also an association between this variant and the individual components of the MetS, including triglyceride, fasting blood glucose and systolic blood pressure.

Pro- and anti-angiogenic VEGF mRNAs in autoimmune thyroid diseases.

The aim of this study was to assess the relationships between five different splice isoforms of VEGF mRNA and its plasma levels in individuals treated for autoimmune thyroid diseases (AITD); mainly Graves' disease (GD) and Hashimoto's thyroiditis (HT). In a population from Tunisia, levels of thyroid hormones and antibodies were quantified simultaneously with plasma VEGF and VEGF mRNA isoforms after a period of 6 months of patients' treatment. Plasma VEGF was measured in 110 AITD patients (21 GD and 89 HT patients). VEGF isoforms (VEGF121, VEGF165, VEGF145 and VEGF189 pro-angiogenic isoforms and VEGF165b anti-angiogenic isoform) in peripheral blood mononuclear cells were quantified in 71 patients (20 GD and 51 HT patients) and 86 healthy controls. Decreased levels of VEGF189 mRNA were observed in AITD compared to controls. VEGF165 was increased in GD patients compared to controls and the VEGF165b was increased in HT patients compared to GD. We observed increased levels of VEGF165b in hypothyroid AITD patients after treatment. We have also shown that the VEGF145 isoform levels were determined by FT4 in all patients and by the thyroid status after 6 months of treatment only in HT patients. An association was observed for VEGF165 mRNA levels with anti-TPO antibodies in all patients. Finally, FT4 was associated with VEGF plasma levels but only in healthy controls. In conclusion, this descriptive study highlights the specificity of VEGF mRNA isoforms in AITD, a fact underlining the need for novel clinical trials and the development of personalised theranostic approaches.

Plasma VEGF-related polymorphisms are implied in autoimmune thyroid diseases.

Autoimmune thyroid diseases (AITD), including Graves' disease (GD) and Hashimoto thyroiditis (HT), are complex multifactorial diseases. Vascular endothelial growth factor (VEGF) is implicated in various inflammatory diseases, especially autoimmune diseases. Our aim was to elucidate the relationships between plasma VEGF levels and four genome-wide association study-identified single nucleotide polymorphisms (SNPs) related to VEGF with AITD in Tunisian patients. A total of 364 healthy controls and 389 patients with AITD were genotyped for the SNPs rs6921438, rs4416670, rs6993770 and rs10738760. Levels of thyroid hormones and antibodies were quantified simultaneously with plasma VEGF after a period of six months of treatment. We found that the minor alleles of rs10738760 and rs6921438 are associated with the presence of GD. A allele of rs10738760 polymorphism is associated with increased plasma levels of free tri-iodothyronin (FT3) while no relationship was found with circulating VEGF plasma levels after six months of treatment. We also showed that the T allele of rs4416670 polymorphism was associated with increased risk of hyperthyroidism in patients treated for six months, independently of their initial diagnosis. There was no significant association between the SNPs and the risk for HT compared with controls. This study shows that AITD are influenced by 3 SNPs linked to VEGF circulating levels. Whereas rs10738760 appeared specific to GD and FT3 production after six months of treatment, rs6921438 and rs4416670 were implicated in the risk for GD. This study opens new ways to test pharmacogenomics concepts in the future especially in GD in which recurrence prognosis is still challenging.

A common variant highly associated with plasma VEGFA levels also contributes to the variation of both LDL-C and HDL-C.

Vascular endothelial growth factor A (VEGFA) is among the most-significant stimulators of angiogenesis. Its effect on cardiovascular diseases and on the variation of related risk factors such as lipid parameters is considered important, although as yet unclear. Recently, we identified four common variants (rs6921438, rs4416670, rs6993770, and rs10738760) that explain up to 50% of the heritability of plasma VEGFA levels. In the present study, we aimed at assessing the contribution of these variants to the variation of blood lipid levels (including apoE, triglycerides, total cholesterol, low- and high-density lipoprotein cholesterol levels (LDL-C and HDL-C)] in healthy subjects. The effect of these single-nucleotide polymorphisms (SNPs) on lipid levels was assessed using linear regression in discovery and replication samples (n = 1,006 and n = 1,145; respectively), followed by a meta-analysis. Their gene×gene and gene×environment interactions were also assessed. SNP rs6921438 was associated with HDL-C (ß = -0.08 mmol/l, P(overall) = 1.2 × 10(-7)) and LDL-C (ß = 0.13 mmol/l, P(overall) = 1.5 × 10(-4)). We also identified a significant association between the interaction rs4416670×hypertension and apoE variation (P(overall) = 1.7 × 10(-5)). Therefore, our present study shows a common genetic regulation between VEGFA and cholesterol homeostasis molecules. The SNP rs6921438 is in linkage disequilibrium with variants located in an enhancer- and promoter-associated histone mark region and could have a regulatory effect in the expression of surrounding genes, including VEGFA.

Associations of vascular endothelial growth factor (VEGF) with adhesion and inflammation molecules in a healthy population.

Vascular endothelial growth factor (VEGF) is implicated in numerous pathologies through complex relationships with cellular adhesion molecules (CAMs) and inflammation markers. These have not been assessed in non-pathological conditions. Our aim was the evaluation of associations between VEGF and CAM/inflammation molecules in a healthy population, and of possible genomic interplays in order to better apprehend the underlying mechanisms leading to the pathology. We examined the associations between VEGF and ICAM-1, VCAM-1, E-, L-, P-selectins, TNF-α, CRP and IL-6 plasma levels in 403 healthy individuals. Gene expression of CAM/inflammation molecules and VEGF isoforms (121, 145, 165, and 189) were quantified in peripheral blood mononuclear cells (PBMCs). The effect of four genetic variants (explaining ≈ 50% of the heritability of circulating VEGF levels) and of their interactions on plasma and mRNA levels of CAM/inflammation molecules was examined. VEGF was associated with ICAM-1 and E-selectin in plasma. In PBMCs, VEGF(145) mRNA was associated with ICAM-1, L-selectin and TNF-α expression. Interactions of the genetic variants were shown to affect ICAM-1, E-selectin, IL-6 and TNF-α plasma levels, while rs4416670 was associated with L-selectin expression. These findings propose a biological connection between VEGF and CAM/inflammation markers. Common genetic and transcriptional mechanisms may link these molecules and control their effect in healthy conditions.

Serum aldosterone is correlated positively to parathyroid hormone (PTH) levels in patients with primary hyperparathyroidism.

BACKGROUND: Primary hyperparathyroidism is associated with an increased cardiovascular morbidity and mortality. However, mechanisms underlying this association are currently unclear. As there is clear evidence of the independent role of aldosterone on the cardiovascular system, the aim of this study was to evaluate aldosterone levels in patients with primary hyperparathyroidism. METHODS: A prospective study of 134 consecutive patients with primary hyperparathyroidism before and 3 months after parathyroidectomy. RESULTS: Pre-operative serum aldosterone and parathyroid hormone (PTH) levels were correlated positively in all patients (.238; P = .005). In the 62 patients (46%) that were not on antihypertensive medications, this correlation was stronger (.441; P = .0003). In the 72 patients (54%) treated with at least 1 antihypertensive medication, no correlation between preoperative aldosterone and PTH serum levels was observed. By multivariate analysis, pre-operative PTH level (.409; P = .005) was an independent predictor of aldosterone. Pre-operative PTH level >100 ng/L was an independent predictor of abnormally elevated plasma aldosterone level (odds ratio 3.5; P = .01). At 3 months after parathyroidectomy, no correlation was observed between postoperative PTH and aldosterone levels. CONCLUSION: Aldosterone is correlated positively to preoperative PTH levels in patients with primary hyperparathyroidism. Aldosterone might be a key mediator of cardiovascular symptoms in patients with primary hyperparathyroidism.