[Show abstract][Hide abstract] ABSTRACT: Placental Growth Factor (PGF) is a key molecule in angiogenesis. Several studies have revealed an important role of PGF primarily in pathological conditions (e.g.: ischaemia, tumour formation, cardiovascular diseases and inflammatory processes) suggesting its use as a potential therapeutic agent. However, to date, no information is available regarding the genetics of PGF variability. Furthermore, even though the effect of environmental factors (e.g.: cigarette smoking) on angiogenesis has been explored, no data on the influence of these factors on PGF levels have been reported so far. Here we have first investigated PGF variability in two cohorts focusing on non-genetic risk factors: a study sample from two isolated villages in the Cilento region, South Italy (N=871) and a replication sample from the general Danish population (N=1,812). A significant difference in PGF mean levels was found between the two cohorts. However, in both samples, we observed a strong correlation of PGF levels with ageing and sex, men displaying PGF levels significantly higher than women. Interestingly, smoking was also found to influence the trait in the two populations, although differently. We have then focused on genetic risk factors. The association between five single nucleotide polymorphisms (SNPs) located in the PGF gene and the plasma levels of the protein was investigated. Two polymorphisms (rs11850328 and rs2268614) were associated with the PGF plasma levels in the Cilento sample and these associations were strongly replicated in the Danish sample. These results, for the first time, support the hypothesis of the presence of genetic and environmental factors influencing PGF plasma variability.
PLoS ONE 08/2012; 7(8):e42537. DOI:10.1371/journal.pone.0042537 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Childhood obesity is associated with an increased risk of atherosclerosis, which can be mediated by an increase in angiogenesis and inflammation. The objective was to investigate the association between body mass index (BMI) and circulating biomarkers of angiogenesis, inflammation, and cardiac dysfunction in children and adolescents.
The Genetic Park Study is a highly inclusive survey conducted in three isolated villages of southern Italy. One hundred fifty-one children and adolescents (age range 5-17 y, 45% male) were included and categorized as obese (BMI z-score ≥ 1.64, n = 38) or non-obese (n = 113). Metabolic and cardiovascular biomarkers included glucose, triacylglycerol, total cholesterol, high-density lipoprotein, vascular endothelial growth factor (VEGF), placental growth factor, soluble feline sarcoma virus (fms)-like tyrosine kinase-1, highly sensitive C reactive protein (hs-CRP), highly sensitive troponin T (hs-TnT), and N-terminal prohormone brain natriuretic peptide (NT-proBNP).
Obese subjects had higher levels of triacylglycerol (P = 0.03) and hs-CRP (P = 0.02) after adjustment for age and gender. Circulating levels of VEGF were directly associated with BMI z-score (r = 0.22, P = 0.007) and hs-CRP (r = 0.33, P < 0.001). BMI z-score was not associated with biomarkers of cardiac dysfunction (hs-TnT and NT-proBNP).
Increasing BMI was associated with plasma levels hs-CRP and VEGF, which are involved in the initiation and progression of atherosclerosis. The lack of association between BMI and markers of cardiac damage (hs-TnT) or ventricular volume overload (NT-proBNP) suggest that atherosclerotic risk may still at a preclinical stage in this population of obese but otherwise healthy young individuals. Collectively, this suite of biomarkers could provide mechanistic insights into the physiopathologic progression of cardiovascular risk associated with childhood obesity.
[Show abstract][Hide abstract] 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.
PLoS ONE 02/2011; 6(2):e16982. DOI:10.1371/journal.pone.0016982 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Metabolic syndrome (MetSyn) is associated with an increased risk of atherosclerosis and fatal cardiovascular events. Angiogenesis is thought to contribute to this risk as it might be involved in the progression of atherosclerotic plaques. We investigated the levels of circulating biomarkers of angiogenesis and cardiovascular risk in adults with MetSyn and assessed their association with established metabolic risk factors.
The Genetic Park project is a highly inclusive cross-sectional survey (about 80% of residents) conducted in three isolated populations in Southern Italy. A total of 1000 men and women (age range: 18-98 years) were included in the analysis. Anthropometric and blood pressure measurements were recorded. Metabolic and cardiovascular biomarkers included glucose, triglycerides, total cholesterol, HDL, vascular endothelial growth factor, placental growth factor (PlGF), soluble fms-like tyrosine kinase-1, high-sensitivity C-reactive protein, high-sensitivity troponin T (hs-TnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP).
Subjects with MetSyn had higher levels of PlGF and NT-proBNP after adjustment for age, smoking and body mass index. Circulating levels of PlGF, hs-TnT and NT-proBNP were directly related to the number of criteria of MetSyn, and this association interacted with gender. There was a strong correlation between ageing and cardiovascular risk.
The increase in circulating levels of biomarkers of angiogenesis and cardiac function in subjects with MetSyn mirrors the pathophysiological changes occurring in the cardiovascular system. Over time, these changes might accelerate the formation and progression of atherosclerotic plaques and contribute significantly to cardiovascular morbidity and mortality risk.
Journal of Internal Medicine 10/2010; 268(4):338-47. DOI:10.1111/j.1365-2796.2010.02255.x · 6.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Algorithms for inferring population structure from genetic data (ie, population assignment methods) have shown to effectively recognize genetic clusters in human populations. However, their performance in identifying groups of genealogically related individuals, especially in scanty-differentiated populations, has not been tested empirically thus far. For this study, we had access to both genealogical and genetic data from two closely related, isolated villages in southern Italy. We found that nearly all living individuals were included in a single pedigree, with multiple inbreeding loops. Despite F(st) between villages being a low 0.008, genetic clustering analysis identified two clusters roughly corresponding to the two villages. Average kinship between individuals (estimated from genealogies) increased at increasing values of group membership (estimated from the genetic data), showing that the observed genetic clusters represent individuals who are more closely related to each other than to random members of the population. Further, average kinship within clusters and F(st) between clusters increases with increasingly stringent membership threshold requirements. We conclude that a limited number of genetic markers is sufficient to detect structuring, and that the results of genetic analyses faithfully mirror the structuring inferred from detailed analyses of population genealogies, even when F(st) values are low, as in the case of the two villages. We then estimate the impact of observed levels of population structure on association studies using simulated data.
European journal of human genetics: EJHG 07/2009; 17(12):1635-41. DOI:10.1038/ejhg.2009.97 · 4.35 Impact Factor