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Meniere's disease (MD) is an inner ear disorder, characterized by a burden of symptoms, probably arising from the interplay of genetic and environmental factors. In this brief review, we consider the role of ion channels and transporters in the pathophysiology of MD, focusing on genetic and biohumoral aspects. Pathophysiological mechanisms related to altered concentrations of ions in the endolymph include altered osmotic pressure leading to hydrops and/or immunomodulatory effects of K+ and Endogenous Ouabain (EO) concentrations in the inner ear. Aquaporins 1-5 (AQPs) have been found in the inner ear; AQP2 is the only isoform controlled by a hormone, namely, vasopressin (antidiuretic hormone, ADH). Genetic studies on AQPs have provided inconclusive results. Recently, two genetic polymorphisms have been associated with MD: rs3746951, a missense variant (Gly180Ser) in the Salt-Inducible Kinase-1 (SIK1) gene and rs487119, an intronic variant of gene SLC8A1 coding for a Na+,Ca++ exchanger (NCX-1). EO is a hormone released by the midbrain and adrenal glands. It controls the constitutive capacity of modulating Na+,K+-ATPase activity. Higher plasma levels of EO have been found in MD subjects compared to a control group.

Hypertension and obesity in the young population are major risk factors for renal and cardiovascular events, which could arise in adulthood. A candidate-gene approach was applied in a cohort observational study, in which we collected data from 2638 high school adolescent students. Participants underwent anthropometric and blood pressure (BP) measurements, as well as saliva and urine sample collection for genomic DNA extraction and renal function evaluation, respectively. We tested whether candidate genes previously implicated in salt-sensitive hypertension in adults impact BP also among adolescents. Since inflammatory mechanisms may be involved in pathophysiology of hypertension and in endothelial dysfunction and atherosclerosis through reactive oxygen species, the baseline urinary excretion of inflammatory and oxidative stress markers in a subgroup of adolescents stratified according to ADD1 (alpha adducin) rs4961 genotypes was assessed. Regression analysis of BP values with genetic polymorphisms, highlighted an association with a missense variant of LSS (lanosterol synthase, rs2254524), a gene coding for an enzyme involved in endogenous ouabain synthesis. Higher diastolic and systolic BP were associated with LSS A allele ( P =0.011 and P =0.023, respectively). BP resulted associated with 5 more SNPs. The KL (klotho) rs9536314 missense variant was associated with 24 hour urinary Na + excretion ( P =0.0083). Urinary protein tests showed a greater excretion of IL1β (interleukin 1β) and interleukin 10 ( P ADD1 rs4961 T allele. In conclusion, 3 missense gene variants already implicated in adult hypertension impact BP or Na + excretion among adolescents, and, together with activated pro-inflammatory pathways, might predispose to early cardiovascular damage.

Patients with systemic lupus erythematosus (SLE) carrying a TT genotype for the rs7925662 single nucleotide polymorphism (SNP) in the transient receptor potential canonical channel 6 (TRPC6) gene are more likely to develop neuropsychiatric manifestations (NPSLE). We functionally characterised the effects of TRPC6 on peripheral blood mononuclear cells from 18 patients with SLE and 8 healthy controls with a known genotype. TRPC6 influenced calcium currents, apoptosis rates and cytokine secretion in a disease- and genotype-dependent manner. Cells from TT patients with NPSLE were more dependent on TRPC6 for the generation of calcium currents.

BACKGROUND AND OBJECTIVES: Hypertension is a common aging-related disorder. Salt intake is one of the main environmental factors contributing to the development of hypertension. Transgenic mice with one-half Klotho deficiency displayed a spontaneous BP increase and salt-sensitive hypertension in response to high sodium intake. Usually circulating levels of α-Klotho decrease with age, and this reduction may be stronger in patients with several aging-related diseases. This study aimed at exploring the association of Klotho with salt sensitivity in humans. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The role of Klotho polymorphisms and α-Klotho serum levels was evaluated in patients with hypertension who were treatment naive and underwent an acute salt-sensitivity test (discovery n=673, intravenous 2 L of 0.9% saline in 2 hours). Salt sensitivity was defined as a mean BP increase of >4 mm Hg at the end of the infusion. A total of 32 single nucleotide polymorphisms in the Klotho gene (KL), previously identified with a genome-wide association study, were used in the genetic analysis and studied for a pressure-natriuresis relationship. RESULTS: Of the patients with hypertension, 35% were classified as salt sensitive. The most relevant polymorphism associated with pressure natriuresis was the common missense single nucleotide polymorphism rs9536314, and the GG and GT genotypes were more represented among patients who were salt sensitive (P=0.001). Those carrying the G allele showed a less steep pressure-natriuresis relationship, meaning that a significant increase in mean BP was needed to excrete the same quantity of salt compared with patients who were salt resistant. KL rs9536314 also replicated the pressure-natriuresis association in an independent replication cohort (n=193) and in the combined analysis (n=866). There was an inverse relationship between circulating Klotho and mean BP changes after the saline infusion (r=−0.14, P=0.03). Moreover, circulating α-Klotho was directly related to kidney function at baseline eGFR (r=0.22, P

Rationale & Objective: Studies of humans and animals have suggested that endogenous ouabain (EO) and related genes are mediators of acute (AKI) and chronic kidney injury. We sought to examine the relationship among EO levels, genetic variants in lanosterol synthase (LSS; an enzyme that catalyzes synthesis of cholesterol, a precursor of EO), and both AKI and chronic kidney injury. Study Design: 2 prospective observational cohort studies and a cross-sectional study of kidney tissue. Setting & Participants: (1) A prospective cohort study of patients undergoing cardiovascular surgery, (2) measurement of EO concentration in kidney tissue removed because of an adjacent tumor, and (3) a prospective cohort study of patients with newly diagnosed essential hypertension. Exposure: Missense variant in LSS (A instead of C allele at rs2254524), which leads to a valine to leucine substitution at amino acid 642. Outcomes: Development of postoperative AKI in the cardiovascular surgery cohort, EO concentration in kidney tissue, and estimated glomerular filtration rate (eGFR) reductions in the essential hypertension cohort. Analytical Approach: Logistic regression for analysis of postoperative AKI, analysis of variance for EO concentration in kidney tissue, and generalized linear models for changes in eGFR over time. Results: AKI incidence following cardiovascular surgery was greater among those with the LSS rs2254524 AA genotype (30.7%) than in those with the CC genotype (17.4%; P = 0.001). LSS rs2254524 AA kidneys had higher EO concentrations than CC kidneys (2.14 ± 0.29 vs 1.25 ± 0.08 ng/g; P < 0.001). In the longitudinal study of patients with essential hypertension (median follow-up, 4 years; range, 1-15 years), eGFR decline was greater among the LSS rs2254524 AA genotype group (−4.39 ± 1.18 mL/min/1.73 m2 per year) than in the AC or CC genotype groups (−1.07 ± 0.55 and −2.00 ± 0.45 mL/min/1.73 m2 per year respectively; P = 0.03). Limitations: These associations do not necessarily represent causal relationships; LSS rs2254524 variants may have effects on other steroid hormones. Conclusions: These findings support the potential value of LSS rs2254524 genotype–based risk stratification to identify patients at high risk for AKI before cardiovascular surgery, as well as predict accelerated eGFR in the setting of hypertension. These findings also suggest that LSS may in part drive EO-mediated kidney damage. EO may represent a new potential therapeutic target for the prevention of AKI and slowing of kidney damage in the setting of hypertension.

Aim of this work was to assess the role of polymorphisms belonging to genes involved in the regulation of ionic homeostasis in Caucasian patients with Ménière Disease (MD). We recruited 155 patients with definite Ménière Disease and 186 controls (Control Group 1) without a lifetime history of vertigo, overlapping with patients for age and rate of hypertension. We validated the positive results on 413 Caucasian subjects selected from a European general population (Control Group 2). The clinical history for migraine and hypertension was collected; genomic DNA was characterized for a panel of 33 SNPs encoding proteins involved in ionic transport. We found a higher rate of migraineurs in MD subjects compared to Group 1 (46.8 vs 15.5%, p = 0.00005). Four SNPs displayed differences in MD patients compared to Group 1 controls: rs3746951 and rs2838301 in SIK1 gene, rs434082 and rs487119 in SLC8A1; the p values of Chi-squared test for genotype frequencies are 0.009, 0.023, 0.009 and 0.048, respectively. SLC8A1 gene encodes for Na(+)-Ca(++) exchanger, while SIK1 gene encodes for Salt Inducible Kinase 1, an enzyme associated with Na(+)-K(+) ATPase function. The validation with Control Group 2 displayed that only rs3746951 and rs487119 are strongly associated to MD (p = 0.001 and p = 0.0004, respectively). These data support the hypothesis that a genetically induced dysfunction of ionic transport may act as a predisposing factors to develop MD. ispartof: European Archives of Oto-Rhino-Laryngology vol:274 issue:2 pages:757-763 ispartof: location:Germany status: published

Many single nucleotide polymorphisms (SNPs) have been associated with lung cancer but lack confirmation and functional characterization. We retested the association of 56 candidate SNPs with lung adenocarcinoma risk and overall survival in a cohort of 823 Italian patients and 779 healthy controls, and assessed their function as expression quantitative trait loci (eQTLs). In the replication study, eight SNPs (rs401681, rs3019885, rs732765, rs2568494, rs16969968, rs6495309, rs11634351, and rs4105144) associated with lung adenocarcinoma risk and three (rs9557635, rs4105144, and rs735482) associated with survival. Five of these SNPs acted as cis-eQTLs, being associated with the transcription of IREB2 (rs2568494, rs16969968, rs11634351, rs6495309), PSMA4 (rs6495309) and ERCC1 (rs735482), out of 10,821 genes analyzed in lung. For these three genes, we obtained experimental evidence of differential allelic expression in lung tissue, pointing to the existence of in-cis genomic variants that regulate their transcription. These results suggest that these SNPs exert their effects on cancer risk/outcome through the modulation of mRNA levels of their target genes.

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. peerreview_statement: The publishing and review policy for this title is described in its Aims & Scope. aims_and_scope_url: http://www.tandfonline.com/action/journalInformation?show=aimsScope&journalCode=iblo20 ispartof: Blood Pressure vol:24 issue:1 pages:61-4 ispartof: location:England status: published

cGMP-dependent protein kinase type I is a major mediator of cGMP signaling in the cardiovascular system. Recent studies on cardiac-specific PRKG1 knockout mice demonstrated that cGMP-dependent protein kinase type I mediates the negative inotropic effect of cGMP in the myocardium. We therefore investigated the association between left ventricular (LV) function and common polymorphisms in the PRKG1 gene in a general population. In 609 randomly selected participants (51.2% women; mean age, 48.8 years; 36.6% hypertensive) who were free from overt cardiac disease, we performed echocardiography and genotyped intronic tag single-nucleotide polymorphisms (SNPs) rs1904694, rs7897633, and rs7905063 in PRKG1. On the basis of color Doppler myocardial motion data, we calculated end-systolic longitudinal and radial deformation (strain) of the LV inferolateral wall. In multivariable-adjusted analyses accounting for confounders and relatedness, systolic radial strain was significantly ( P ≤0.005) higher in homozygotes for rs1904694 (GG), rs7897633 (AA), and rs7905063 (TT) compared with heterozygotes or noncarriers. Haplotype analysis confirmed that LV radial strain was significantly higher in GAT homozygotes than in noncarriers (62.3% versus 56.0%; P =0.0005). Transmission of the PRKG1 GAT haplotype to informative offspring was associated with higher LV radial strain (effect size, 6.11%; P =0.017). For other LV phenotypes, none of the phenotype–genotype associations reached statistical significance. In conclusion, LV systolic radial function was associated with common polymorphisms in PRKG1 . If experimental studies and longitudinal follow-up of LV function confirm the causality of this association, interference with cGMP-dependent protein kinase type I function might be a target for pharmacological intervention.

The Na+ pump and its Endogenous modulator Ouabain (EO) can be considered as an ancestral enzymatic system, conserved among species ranging from Drosophila to humans, related to Na handling. In this review, we examine how EO is linked with vascular function in hypertension and if it impacts the pathogenesis of heart and renal failure. Moreover, the molecular mechanism of endogenous ouabain-linked hypertension involves the sodium pump/sodium–calcium exchanger duet. Biosynthesis of EO occurs in adrenal glands and is under the control of angiotensin II, ACTH and epinephrine. Elevated concentrations of EO and in the sub-nanomolar concentration range were found to stimulate proliferation and differentiation of cardiac and smooth muscle cells. They may have a primary role in the development of cardiac dysfunction and failure. Experimental data suggest that the Na/K-ATPase α2-catalytic subunit causes EO-induced vasoconstriction. Finally, maneuvers that promote Na depletion, as diuretic therapy or reduced Na intake, raise the EO levels. Taken together, these findings suggest a key role for EO in body Na homeostasis.

Objective: Meniere's disease (MD) is an inner ear disorder characterized by recurrent episodic vertigo, hearing loss that is fluctuating in the first stages, aural fullness, and tinnitus. Raised endolymphatic pressure (hydrops) is commonly accepted as a causal condition. Approximately 90% of cases of MD are sporadic, whereas the remaining 10% of cases are linked to genetic factors. The ionic composition of endolymph may also depend on the activity of Na+, K+-ATPase. Adducin is a heterodimeric cytoskeleton protein consisting of 3 subunits (α, β, and γ) coded by 3 different genes (ADD1, ADD2, and ADD3). ADD1 Gly460Trp polymorphism is associated with salt-sensitive hypertension and increased Na+-K+ pump activity in transfected cells. This study aims to verify the role of adducin in the development of MD. Methods: We genotyped 28 patients affected by definite MD according to American Academy of Otolaryngology-Head and Neck Surgery Foundation criteria. Results were compared with those from 2 different control populations (normotensive control group from San Raffaele Hospital and general population group). Results: We have not found any significant difference in the distribution of ADD2 C1797T and ADD3 IVS11+386A/G polymorphism genotypes. On the other hand, the frequency of ADD1 Trp allele is significantly increased in patients with MD compared with controls. Conclusion: We present data supporting the possibility that increased Na+, K+-ATPase activity may be one of the pathologic mechanisms inducing hyperosmolarity in endolymph which, in turn, may lead to hydrops.

The kidney plays an important role in salt and blood pressure (BP) homeostasis. In previous studies, variants in the genes for α-adducin (ADD1), WNK1, and NEDD4L, which all regulate renal sodium absorption, have been associated with increased BP. However, findings have been inconsistent. We tested whether this is because of physiological interactions between the effects of variants in these genes. We assessed the single and combined effects of the ADD1 (Gly460Trp), WNK1 (rs880054 A/G), and NEDD4L (rs4149601 G/A) polymorphisms on renal and BP response to an acute Na load (n=344 subjects), BP decrease after 1 month of treatment with 12.5 mg of hydrochlorothiazide (n=193), and ambulatory 24-hour BP (n=690). Individually, the variants showed modest effects on some of the studied phenotypes. We found the ADD1 Trp allele to be permissive for the effects of variants of the other genes. In combination, the same variants (ADD1 Trp/WNK1 GG/Nedd4L GA+AA) showed a consistent effect on renal Na handling ( P =0.009) and acute BP response to a saline infusion ( P =0.021), BP lowering after thiazide treatment ( P =0.008), and nocturnal systolic BP ( P =0.044). Physiological interaction between the ADD1 and WNK1-NEDD4L pathways influences the effects of variants in these genes on sodium-related BP regulation. Relatively common alleles in the ADD1, WNK1, and NEDD4L genes when present in combination may have significant effects on renal sodium handling, BP, and antihypertensive response to thiazides.

Background In mice MEOX2/TCF15 heterodimers are highly expressed in heart endothelial cells and are involved in the transcriptional regulation of lipid transport. In a general population, we investigated whether genetic variation in these genes predicted coronary heart disease (CHD). Results In 2027 participants randomly recruited from a Flemish population (51.0 % women; mean age 43.6 years), we genotyped six SNPs in MEOX2 and four in TCF15. Over 15.2 years (median), CHD, myocardial infarction, coronary revascularisation and ischaemic cardiomyopathy occurred in 106, 53, 78 and 22 participants. For SNPs, we contrasted CHD risk in minor-allele heterozygotes and homozygotes (variant) vs. major-allele homozygotes (reference) and for haplotypes carriers (variant) vs. non-carriers. In multivariable-adjusted analyses with correction for multiple testing, CHD risk was associated with MEOX2 SNPs (P ≤ 0.049), but not with TCF15 SNPs (P ≥ 0.29). The MEOX2 GTCCGC haplotype (frequency 16.5 %) was associated with the sex- and age-standardised CHD incidence (5.26 vs. 3.03 events per 1000 person-years; P = 0.036); the multivariable-adjusted hazard ratio [HR] of CHD was 1.78 (95 % confidence interval, 1.25–2.56; P = 0.0054). For myocardial infarction, coronary revascularisation, and ischaemic cardiomyopathy, the corresponding HRs were 1.96 (1.16–3.31), 1.87 (1.20–2.91) and 3.16 (1.41–7.09), respectively. The MEOX2 GTCCGC haplotype significantly improved the prediction of CHD over and beyond traditional risk factors and was associated with similar population-attributable risk as smoking (18.7 % vs. 16.2 %). Conclusions Genetic variation in MEOX2, but not TCF15, is a strong predictor of CHD. Further experimental studies should elucidate the underlying molecular mechanisms. Electronic supplementary material The online version of this article (doi:10.1186/s12863-015-0272-2) contains supplementary material, which is available to authorized users.

Circulating levels of endogenous ouabain (EO), a vasopressor hormone of adrenocortical origin, are increased by sodium depletion. Furthermore, lanosterol synthase, an enzyme involved in cholesterol biosynthesis, has a missense polymorphism (rs2254524 V642L) that affects EO biosynthesis in adrenocortical cells. Here, we investigated the hypothesis that lanosterol synthase rs2254524 alleles in vivo impact the blood pressure (BP) and EO responses evoked by a low dietary Na intake (P =0.013) and diastolic BP (DBP: −5.1±0.98 versus −1.4±0.94 mm Hg; P P =0.028). In addition, BP rose in ≈25% of the patients in response to the low salt diet and this was associated with increased circulating EO. Lanosterol synthase gene polymorphisms influence both the salt sensitivity of BP and changes in circulating EO in response to a low salt diet. The response of BP and EO to the low salt diet is markedly heterogeneous. Approximately 25% of patients experienced adverse effects, that is, increased BP and EO when salt intake was reduced and may be at increased long-term risk. The augmented response of EO to the low salt diet further supports the view that adrenocortical function is abnormal in some essential hypertensives.

Thiazide diuretics have been recommended as a first-line antihypertensive treatment, although the choice of 'the right drug in the individual essential hypertensive patient' remains still empirical. Essential hypertension is a complex, polygenic disease derived from the interaction of patient's genetic background with the environment. Pharmacogenomics could be a useful tool to pinpoint gene variants involved in antihypertensive drug response, thus optimizing therapeutic advantages and minimizing side effects.We looked for variants associated with blood pressure response to hydrochlorothiazide over an 8-week follow-up by means of a genome-wide association analysis in two Italian cohorts of never-treated essential hypertensive patients: 343 samples from Sardinia and 142 from Milan. TET2 and CSMD1 as plausible candidate genes to affect SBP response to hydrochlorothiazide were identified. The specificity of our findings for hydrochlorothiazide was confirmed in an independent cohort of essential hypertensive patients treated with losartan. Our best findings were also tested for replication in four independent hypertensive samples of European Ancestry, such as GENetics of drug RESponsiveness in essential hypertension, Genetic Epidemiology of Responses to Antihypertensives, NORdic DILtiazem intervention, Pharmacogenomics Evaluation of Antihypertensive Responses, and Campania Salute Network-StayOnDiur. We validated a polymorphism in CSMD1 and UGGT2.This exploratory study reports two plausible loci associated with SBP response to hydrochlorothiazide: TET2, an aldosterone-responsive mediator of αENaC gene transcription; and CSMD1, previously described as associated with hypertension in a case-control study.

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.

Hypertension is a prevalent disorder in the world representing one of the major risk factors for heart attack and stroke. These risks are increased in salt sensitive individuals. Hypertension and salt sensitivity are complex phenotypes whose pathophysiology remains poorly understood and, remarkably, salt sensitivity is still laborious to diagnose. Here we present a urinary proteomic study specifically designed to identify urinary proteins relevant for the pathogenesis of hypertension and salt sensitivity. Despite previous studies that underlined the association of UMOD gene variants with hypertension, this work provides novel evidence showing different uromodulin protein level in the urine of hypertensive patients compared to healthy individuals. Notably, we also show that patients with higher level of uromodulin are homozygous for UMOD risk variant and display a decreased level of salt excretion, highlighting the essential role of UMOD in the regulation of salt reabsorption in hypertension. Additionally, we found that urinary nephrin 1, a marker of glomerular slit diaphragm, may predict a salt sensitive phenotype and positively correlate with increased albuminuria associated with this type of hypertension., Highlights • We identified urinary proteins differently excreted in hypertensive patients. • Nephrin 1 might predict salt sensitive phenotype and glomerular complications. • Uromodulin impacts salt homeostasis in hypertension. • We provide new insights into the pathogenesis of hypertension and salt sensitivity.

Twenty years of genetic studies have not contributed to improvement in the clinical management of primary arterial hypertension. Genetic heterogeneity, epistatic-environmental-biological interactions, and the pathophysiological complexity of hypertension have hampered the clinical application of genetic findings. In the companion article, we furnished data from rodents and human cells demonstrating two hypertension-triggering mechanisms-variants of adducin and elevated concentrations of endogenous ouabain (within a particular range)-and their selective inhibition by the drug rostafuroxin. Here, we have investigated the relationship between variants of genes encoding enzymes for ouabain synthesis [LSS (lanosterol synthase) and HSD3B1 (hydroxy-δ-5-steroid dehydrogenase, 3β- and steroid δ-isomerase 1)], ouabain transport {MDR1/ABCB1 [ATP-binding cassette, sub-family B (MDR/TAP), member 1]}, and adducin activity [ADD1 (adducin 1) and ADD3], and the responses to antihypertensive medications. We determined the presence of these variants in newly recruited, never-treated patients. The genetic profile defined by these variants predicted the antihypertensive effect of rostafuroxin (a mean placebo-corrected systolic blood pressure fall of 14 millimeters of mercury) but not that of losartan or hydrochlorothiazide. The magnitude of the rostafuroxin antihypertensive effect was twice that of antihypertensive drugs recently tested in phase 2 clinical trials. One-quarter of patients with primary hypertension display these variants of adducin or concentrations of endogenous ouabain and would be expected to respond to therapy with rostafuroxin. Because the mechanisms that are inhibited by rostafuroxin also underlie hypertension-related organ damage, this drug may also reduce the cardiovascular risk in these patients beyond that expected by the reduction in systolic blood pressure alone. ispartof: Science Translational Medicine vol:2 issue:59 ispartof: location:United States status: published

Objective: Endogenous Ouabain (EO) has been demonstrated to modulate the activity of Na+, K+-ATPase. Our purpose was to measure plasma levels of EO in Meniere's Disease (MD) subjects as a possible predisposing factor to developing and maintaining hydrops. Study Design: Case-control study. Settings: University hospital. Patients: Thirty-nine MD subjects and 29 controls with a lifetime negative history for vertigo and dizziness. Main Outcome Measures: Plasma levels of EO. Results: Plasma EO in MD subjects was in the range between 33 and 504 pmol/L (median, 135.5 pmol/L), whereas in the control group, plasma EO varied between 70 and 724 pmol/L (median, 205 pmol/L). The Mann-Whitney U test detected a statistically significant difference (p = 0.0001). Conclusion: Low plasma levels of EO have been proposed to augment Na-K pump activity, whereas high EO levels show an inhibitory effect on the pump activity. A proper pump activity may be necessary to keep the right ionic amount and osmolarity in endolymph. Although other possibilities may be considered, we suggest that altered control mechanisms of pump activity may be related to the pathogenesis and maintenance of MD.

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. ispartof: Journal of Hypertension vol:26 issue:6 pages:1229-1236 ispartof: location:Netherlands status: published

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.

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)-γ 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-γ in AD by studying the association of +874T→A IFN-γ 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-γ loci was assessed with ARMS-PCR. The data obtained from the +874T→A IFN-γ 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-γ gene polymorphism and the risk of AD. However, other polymorphisms have been demonstrated to influence IFN-γ 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.

Defective pressure-natriuresis related to abnormalities in the natriuretic response has been associated with hypertension development. A major signaling pathway mediating pressure natriuresis involves the cGMP-dependent protein kinase 1 (PRKG1) that, once activated by Src kinase, inhibits renal Na + reabsorption via a direct action on basolateral Na-K ATPase and luminal Na–H exchanger type 3, as shown in renal tubuli of animals. Because a clear implication of PRKG1 in humans is still lacking, here we addressed whether PRKG1 polymorphisms affect pressure-natriuresis in patients. Naive hypertensive patients (n=574), genotyped for PRKG1 rs1904694, rs7897633, and rs7905063 single nucleotide polymorphisms (SNPs), underwent an acute Na + loading, and the slope of the pressure–natriuresis relationship between blood pressure and Na + excretion was calculated. The underlying molecular mechanism was investigated by immunoblotting protein quantifications in human kidneys. The results demonstrate that the PRKG1 risk haplotype GAT (rs1904694, rs7897633, rs7905063, respectively) associates with a rightward shift of the pressure–natriuresis curve (0.017±0.004 μEq/mm Hg per minute) compared with the ACC (0.0013±0.003 μEq/mm Hg per minute; P =0.001). In human kidneys, a positive correlation of protein expression levels between PRKG1 and Src ( r =0.83; P r =0.557; P r =0.584; P r =0.691; P + reabsorption, suggestive of a blunt pressure–natriuresis response.