Rationale VEGF impacts angiogenesis, atherosclerosis and cancer. Although the heritability of circulating VEGF levels is high, little is known about its genetic underpinnings. Objective Our aim was to identify genetic variants associated with circulating VEGF levels using an unbiased genome-wide approach and explore their functional significance with gene expression and pathway analysis. Methods and results We undertook a genome-wide association study (GWAS) of serum VEGF levels in 3,527 participants of the Framingham Heart Study (FHS), with pre-planned replication in 1,727 participants from two independent samples, the STANISLAS Family Study (SFS) and the Prospective Investigation of the Vasculature in Uppsala Seniors study (PIVUS). One hundred and forty SNPs reached genome-wide significance (p<5×10−8). We found evidence of replication for the most significant associations in both replication datasets. In a conditional GWAS 4 SNPs mapping to 3 chromosomal regions were independently associated with circulating VEGF levels: rs6921438 and rs4416670 (6p21.1, p=6.11×10−506 and p=1.47×10−12), rs6993770 (8q23.1, p=2.50×10−16) and rs10738760 (9p24.2, p=1.96×10−34). A genetic score including these four SNPs explained 48% of the heritability of serum VEGF levels. Six of the SNPs that reached genome-wide significance in the GWAS were significantly associated with VEGF mRNA levels in PBMCs. Ingenuity pathway analyses showed found plausible biological links between VEGF and 2 novel genes in these loci (ZFPM2 and VLDLR). Conclusions Genetic variants explaining up to half the heritability of serum VEGF levels were identified. These new insights provide important clues to the pathways regulating circulating VEGF levels.

Hypertension is a multifactorial disorder that probably results from the inheritance of a number of susceptibility genes and involves multiple environmental determinants. Existing evidence suggests that the genetic contribution to blood pressure variation is about 30-50%. Although a number of candidate genes have been studied in different ethnic populations, results from genetic analysis are still inconsistent and specific causes of hypertension remain unclear. Furthermore, the abundance of data in the literature makes it difficult to piece together the puzzle of hypertension and to define candidate genes involved in the dynamic of blood pressure regulation. In this review, we attempt to highlight the genetic basis of hypertension pathogenesis, focusing on the most important existing genetic variations of candidate genes and their potential role in the development of this disease. Our objective is to review current knowledge and discuss limitations to clinical applications of genotypic information in the diagnosis, evaluation and treatment of hypertension. Finally, some principles of pharmacogenomics are presented here along with future perspectives of hypertension.

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ABSTRACT:We aimed to measure simultaneously the expression of drugmetabolizing enzymes (DME) and transcription factors (TF) with high importance in cardiovascular physiopathology in lymphocytes from healthy subjects. RNA was isolated from peripheral blood mononuclear cells (PBMC) of 20 subjects from the Stanislas Cohort. We used a microarray approach to measure 16 DME and 13 TF. Cytochromes P450 (P450s), including CYP2C19, CYP2C9, CYP2J2, CYP2D6, CYP1A1, CYP4F2, CYP4A11, CYP2E1, CYP11B2, CYP2C18, and CYP2A6, were expressed in all the subjects. CYP3A4 and CYP3A5 were not expressed. Glutathione S-transferases (GST) were expressed, but GSTM1 was seen only in some subjects. Pregnane X receptor (PXR), myocyte enhancer factor 2, vitamin D receptor, liver X receptor (LXR)-␣, aryl hydrocarbon receptor (AHR), T-cell factor 7, constitutive androstane receptor, and aryl hydrocarbon receptor nuclear translocator (ARNT) were expressed in the majority of the subjects. Glucocorticoid receptor, peroxisome proliferator-activated receptor (PPAR)-␥, and LXR␤ were expressed only in some individuals. PPAR␣ mRNA was found in one subject only, and farnesoid X-activated receptor was not expressed. In addition, we found significant correlations between the expression of AHR, ARNT, and CYP1A1 and between PXR and P450 involved in leukotriene metabolism (CYP2C, CYP4F2, CYP4A11, CYP2J2, and CYP11B2). We describe here for the first time the presence of the majority of TF and DME in PBMC of healthy subjects without previous induction. The expression of these genes in lymphocytes could be a useful tool for further studying the physiological and pathological variations of DME and TF related to environment, to drug intake, and to cardiovascular metabolic cycles.Drug-metabolizing enzymes (DME) and cytochromes P450 (P450s) in particular are central players in cardiovascular health and disease (Elbekai and El-Kadi, 2006). DME are important in the follow-up of cardiovascular drugs because many drugs are metabolized by them. These enzymes are also involved in the metabolism of natural substrates (such as leukotrienes, steroids, and bile acids) that are in turn implicated in several cardiovascular-related pathways, including inflammation, lipid metabolism, and blood pressure regulation. In addition, many environmental factors (tobacco, polycyclic hydrocarbons and dioxins, alcohol, and nutrients) modulate their patterns of expression, and expression of several of these genes is under control of transcription factors (TF), such as the pregnane X receptor (PXR), the constitutive androstane receptor (CAR), the glucocorticoid receptor (GR), or the aryl hydrocarbon receptor (AHR).Finally, some polymorphisms in genes coding for these DME are well known to influence the level of expression with clinical and pharmacological relevance.Some DME, including glutathione S-transferases (GST), N-acetyltransferases, and sulfotransferases (ST), are soluble enzymes measurable as phenotypes in the plasma. However, the majority is mainly localized in the endoplasmic retic...