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Matrix Gla-protein is a vitamin K-dependent protein that strongly inhibits arterial calcification. Vitamin K deficiency leads to production of inactive nonphosphorylated and uncarboxylated matrix Gla protein (dp-ucMGP). The risk associated with dp-ucMGP in the population is unknown. In a Flemish population study, we measured circulating dp-ucMGP at baseline (1996-2011), genotyped MGP, recorded adverse health outcomes until December 31, 2012, and assessed the multivariable-adjusted associations of adverse health outcomes with dp-ucMGP. We applied a Mendelian randomization analysis using MGP genotypes as instrumental variables. Among 2318 participants, baseline dp-ucMGP averaged 3.61 μg/L. Over 14.1 years (median), 197 deaths occurred, 58 from cancer and 70 from cardiovascular disease; 85 participants experienced a coronary event. The risk of death and non-cancer mortality curvilinearly increased (P≤0.008) by 15.0% (95% confidence interval, 6.9-25.3) and by 21.5% (11.1-32.9) for a doubling of the nadir (1.43 and 0.97 μg/L, respectively). With higher dp-ucMGP, cardiovascular mortality log-linearly increased (hazard ratio for dp-ucMGP doubling, 1.14 [1.01-1.28]; P=0.027), but coronary events log-linearly decreased (0.93 [0.88-0.99]; P=0.021). dp-ucMGP levels were associated (P≤0.001) with MGP variants rs2098435, rs4236, and rs2430692. For non-cancer mortality and coronary events (P≤0.022), but not for total and cardiovascular mortality (P≥0.13), the Mendelian randomization analysis suggested causality. Higher dp-ucMGP predicts total, non-cancer and cardiovascular mortality, but lower coronary risk. For non-cancer mortality and coronary events, these associations are likely causal. [ABSTRACT FROM AUTHOR]

Objective: Platelet endothelial aggregation receptor 1 (PEAR1) is a membrane protein involved in platelet contact-induced activation and sustained platelet aggregation. Experimental studies identified PEAR1, as a candidate gene that may be linked to the blood-pressure driven kidney injury in salt-sensitive Dahl rats. Aim: In a family-based European population study (mean age 39.7 years; 52.2% women), we searched for association of changes in blood pressure or incidence of hypertension with genetic variation in PEAR1. Methods: Among 1973 randomly recruited people, genotyped for PEAR1, we measured blood pressure at baseline and follow-up. Results: Median follow-up was 10.0 years. While accounting for family clusters and blood pressure at baseline and with adjustments applied for sex, age, body mass index, smoking and drinking, total cholesterol, and antihypertensive drug treatment, all associations of systolic and diastolic blood pressure changes with nine single nucleotide polymorphisms (SNPs) in PEAR1 were all non-significant ( p ≥ 0.059). With similar adjustments, the incidence of hypertension (397 cases among 1532 participants were normotensive at baseline [25.9%]) was not related to the SNPs in PEAR1 (hazard ratios ≤ 1.09; p ≥ 0.09). Conclusion: Our study suggests that PEAR1 is not a hypertension susceptibility gene in humans. [ABSTRACT FROM AUTHOR]

The importance of excess salt intake in the pathogenesis of hypertension is widely recognized. Blood pressure is controlled primarily by salt and water balance because of the infinite gain property of the kidney to rapidly eliminate excess fluid and salt. Up to fifty percent of patients with essential hypertension are salt-sensitive, as manifested by a rise in blood pressure with salt loading. We conducted a two-stage genetic analysis in hypertensive patients very accurately phenotyped for their salt-sensitivity. All newly discovered never treated before, essential hypertensives underwent an acute salt load to monitor the simultaneous changes in blood pressure and renal sodium excretion. The first stage consisted in an association analysis of genotyping data derived from genome-wide array on 329 subjects. Principal Component Analysis demonstrated that this population was homogenous. Among the strongest results, we detected a cluster of SNPs located in the first introns of PRKG1 gene (rs7897633, p = 2.34E-05) associated with variation in diastolic blood pressure after acute salt load. We further focused on two genetic loci, SLC24A3 and SLC8A1 (plasma membrane sodium/calcium exchange proteins, NCKX3 and NCX1, respectively) with a functional relationship with the previous gene and associated to variations in systolic blood pressure (the imputed rs3790261, p = 4.55E-06; and rs434082, p = 4.7E-03). In stage 2, we characterized 159 more patients for the SNPs in PRKG1, SLC24A3 and SLC8A1. Combined analysis showed an epistatic interaction of SNPs in SLC24A3 and SLC8A1 on the pressure-natriuresis (p interaction = 1.55E-04, p model = 3.35E-05), supporting their pathophysiological link in cellular calcium homeostasis. In conclusions, these findings point to a clear association between body sodium-blood pressure relations and molecules modulating the contractile state of vascular cells through an increase in cytoplasmic calcium concentration. [ABSTRACT FROM AUTHOR]

This article discusses the relationship between the genetic regulation of renal sodium absorption and the prevention of hypertension. Patients with varying genetic polymorphisms are monitored for their ability to absorb sodium at the basal and luminal tubular cell membranes of nephron segments. The study focuses on the connection between a set of alleles that effect sodium transport and blood pressure, as they relate to patient responses to thiazide type drugs.

Background: We investigated the possible association between left ventricular diastolic function and the ADD1 Gly460Trp and ADD3 IVS11 +386A>G polymorphisms alone and in combination., Methods: In a family-based population study (473 subjects; 50.5% women; mean age 50.5 years), we measured early (Ea) and late (Aa) diastolic peak velocities of the mitral annulus by tissue Doppler imaging. In multivariate-adjusted analyses, we investigated phenotype-genotype associations, while accounting for confounders and family structure., Results: Lateral Ea/Aa ratio was higher in ADD1 Trp allele carriers than in GlyGly homozygotes (1.51 vs. 1.40; P = 0.005) and was lower in ADD3 A allele carriers than in GG homozygotes (1.42 vs. 1.55; P = 0.005). The effects of ADD1 on the lateral Ea and Ea/Aa weakened with older age (P < 0.05). The best fitting model for lateral Ea and Ea/Aa included ADD1, ADD3, and the three-way interaction term of both genes with age. Below the age of 50 years, the lateral Ea/Aa ratio was higher in ADD1 Trp allele carriers than in GlyGly homozygotes (1.91 vs. 1.73; P = 0.006), particularly in the presence of ADD3 GG homozygosity (2.46 vs. 1.80; P = 0.0008). In older subjects, these phenotype-genotype associations were not significant (P > 0.20). Transmission of the ADD1 Trp allele to offspring was associated with higher lateral Ea (+0.91; P = 0.026) and Ea/Aa ratio (+0.23; P = 0.0008)., Conclusion: Our population-based study demonstrated that left ventricular diastolic relaxation is modulated by genetic variation in ADD1 and ADD3. This association was more prominent in younger subjects in whom longstanding environmental factors and ageing are less likely to mask genetic effects.

In the recent years, several cytokines have been associated with Alzheimer's disease (AD) development and progression and many studies have correlated this risk with polymorphisms in the genes encoding these molecules. Also the type 1 cytokine interferon (IFN)-gamma belongs to a cytokine class that affects the immune function; in fact it plays a major role in defence against viruses and intracellular pathogens but also in the induction of the immune-mediated inflammatory response. The aim of this study was to evaluate the role of IFN-gamma in AD by studying the association of +874T-->A IFN-gamma gene polymorphism with AD. We included in this study 115 AD patients (70 women, 45 men, mean age 80) and 90 sex and age-matched healthy controls (HC, 51 women, 39 men, mean age 82) from northern Italy. Genomic DNA was extracted with the salting-out method from whole blood of all subjects; the genotyping at IFN-gamma loci was assessed with ARMS-PCR. The data obtained from the +874T-->A IFN-gamma gene polymorphism analysis of AD patients and HC lack of any statistically significant differences also when stratified according to gender. In conclusion these results confirm the previous shown lack of association between +874T-->A IFN-gamma gene polymorphism and the risk of AD. However, other polymorphisms have been demonstrated to influence IFN-gamma transcription and since natural killer cells of AD patients show higher production of the cytokine, further analysis will be necessary to clarify the role of this gene in the pathogenesis of the disease.