Search

Endogenous ouabain (EO) is a steroid hormone secreted by the adrenal glands, usually associated with adverse cardiovascular effects. However, recent studies have highlighted its possible role in blood pressure control and in cardio-renal damage, and it seems to be involved in the adaptive response to hypoxia. The aim of this study is to detect the EO in human and animal models of hypoxia. We collected blood samples from seven competitive elite apnea divers, 11 noncompetitive elite apnea divers, and 26 healthy control subjects. Animal blood samples were collected from 16 common bottlenose dolphins (Tursiops truncatus), two phocids and two otariids kept under human care, and 11 wild loggerhead sea turtles (Caretta caretta) hosted in two rescue centers. We measured EO plasma concentrations with a Scintillation Proximity Assay. In elite apnea divers and healthy control subjects, EO plasma concentrations were positively correlated to weight (p < 0.05). Elite apnea divers showed statistically significant (p < 10-6) higher EO plasma concentrations compared to healthy subjects without any diving experience or experience in other sports activities involving breath-holding. In dolphins, EO plasma concentrations were positively correlated to age, total length, and weight (p < 0.05). In loggerhead sea turtles, EO plasma concentrations were negatively correlated to total length and weight (p < 0.05). In pinnipeds, correlation analysis was not performed due to the small number of animals. Herein, we demonstrate, for the first time, that different taxa, phylogenetically distant from each other and which perform apneas without reporting neurological damages, express EO. Our findings, although preliminary, are in line with the recently emerging hypothesis on a possible role of EO in the adaptive response to hypoxia and represent a helpful hint for future investigations aimed to identify novel molecules useful to treat very disabling pathological conditions such as idiopathic pulmonary arterial hypertension or obstructive sleep apnea.

Frailty is a major challenge facing the aging world. The phenotype of the frail subject is still far from being satisfactorily defined. We report data on mood, cognition, and quality of life (QoL) in relation to anamnestic factors, health, and socio-economic status in the FRASNET geriatric population (1204 subjects in stable health conditions), which is an observational cohort study that includes fairly balanced groups of Italian frail (421, 35%), pre-frail (449, 37.3%) and robust (334, 27.7%) subjects. A conditional inference tree analysis revealed a substantial influence of psychological variables on frailty. The physical indicator of QoL (Short Form Survey-36-Physical Component Summary, SF-36-PCS) was the predominant variable in the full model (threshold at 39.9, p < 0.001): higher frailty was found in subjects with a caregiver and lower SF-36-PCS. Frailty was also associated with the mental indicator of QoL (Short Form Survey-36-Mental Component Summary, SF-36-MCS), depression (Geriatric Depression Scale, GDS-15), leisure activities, and level of education. In support of the prominent role of inflammation in aging and mental illness, the SF-36-PCS score was correlated with the blood concentration of C-X-C motif chemokine ligand 10 (CXCL10) (r Pearson −0.355, p = 0.015), a critical signal in cell senescence and inflammaging, while the rs7567647 variant in FN1 gene encoding a glycoprotein in the extracellular matrix was significantly associated with frailty in a multivariable model (p = 0.0006). The perception of health-related QoL and subclinical depression contribute to frailty. Their assessment could improve the identification of older patients at increased risk of adverse outcomes.

Salt sensitivity is a powerful risk factor for cardiovascular (CV) disease and mortality in both normotensive and hypertensive patients. We investigated the predictive value of the salt sensitivity phenotype in the development of CV events and hypertensive target organ damage (TOD) among essential hypertensive patients.Eight hundred forty-four naive hypertensive patients were recruited and underwent an acute saline test during which blood pressure (BP) displayed either no substantial variation (salt-resistant, SR individuals), an increase (salt-sensitive, SS), or a paradoxical decrease (inverse salt-sensitive, ISS). Sixty-one patients with the longest monitored follow-up (median 16 years) for blood pressure and organ damage were selected for the present study. A clinical score for TOD development based on the severity and the age of onset was set up by considering hypertensive heart disease, cerebrovascular damage, microalbuminuria, and vascular events.CV events were significantly higher among SS and ISS than in SR patients. The relative risk of developing CV events was 12.67 times higher in SS than SR and 5.94 times higher in ISS than SR patients. The development of moderate to severe TOD was 10-fold higher in SS and over 15-fold higher in ISS than in SR patients. Among the three phenotypes, changes in plasma endogenous ouabain were linked with the blood pressure effects of saline.Salt sensitivity and inverse salt sensitivity appear to be equivalent risk factors for CV events. The response to an acute saline test is predictive of CV damage for newly identified ISS individuals.

Background: Hypertension is a complex disease and is the major cause of cardiovascular complications. In the vast majority of individuals, the aetiology of elevated blood pressure (BP) cannot be determined, thus impairing optimized therapies and prognosis for individual patients. A more precise understanding of the molecular pathogenesis of hypertension remains a pressing priority for both basic and translational research. Here we investigated the effect of salt on naive hypertensive patients in order to better understand the salt intake-blood pressure relationship. Methods: Patients underwent an acute saline infusion and were defined as salt-sensitive or salt-resistant according to mean blood pressure changes. Urinary proteome changes during the salt load test were analysed by a label-free quantitative proteomics approach. Results: Our data show that salt-sensitive patients display equal sodium reabsorption as salt-resistant patients, as major sodium transporters show the same behaviour during the salt load. However, salt-sensitive patients regulate the renin angiotensin system (RAS) differently from salt-resistant patients, and upregulate proteins, as epidermal growth factor (EGF) and plasminogen activator, urokinase (PLAU), involved in the regulation of epithelial sodium channel ENaC activity. Conclusions: Salt-sensitive and salt-resistant subjects have similar response to a saline/volume infusion as detected by urinary proteome. However, we identified glutamyl aminopeptidase (ENPEP), PLAU, EGF and Xaa-Pro aminopeptidase 2 precursor XPNPEP2 as key molecules of salt-sensitivity, through modulation of ENaC-dependent sodium reabsorption along the distal tubule. Graphic abstract: [Figure not available: see fulltext.].

A recent study called FRASNET enrolled on a voluntary basis a cohort on 1240 elderly people. They were either patients of the Nephrology and Dialysis unit at San Raffaele hospital in Milan, guests of care homes, or members of cultural, social and recreational centers for the elderly in the wider Milan area. Demographic, anthropometric and biochemical data were collected, together with information on comorbidities and pharmacological therapies, psychophysical test results and biological samples. After the first wave of the SARS-Cov-2 pandemic, we have interviewed the members of this same cohort to gather information on possible coronavirus infections and evaluate the impact of the pandemic on frail patients. It emerged that the prevalence of SARS-Cov-2 infections was 0.7% within this cohort. This encouraging result seems to confirm the effectiveness of the measures taken at the start of the pandemic, especially social distancing and personal protective equipment.

The recent COVID-19 pandemic has had a significant impact on the population worldwide. Patients with chronic kidney disease treated with kidney replacement therapy were no exception because they were considered highly vulnerable due to multiple comorbidities. The consequences of the physical, biological, and ecological system on the environment as a result of human activity represent a huge global health care danger. The purpose of this article is to identify strategies that improve environmental sustainability, improve prevention of COVID-19 infection in dialysis centers, and improve the environmental impact of hemodialysis centers.

Hemodialysis is the most common treatment in patients with end-stage chronic kidney disease and the wide accessibility of this therapy has prolonged the patients' lifespan. However, it involves alterations in their emotional sphere and, often, a reduction in therapeutic compliance as the chronicity of kidney disease requires lifestyle changes difficult to maintain in the long term. The management of a chronic medical condition is in fact a complex process that necessarily requires multidisciplinary action. The concepts of "Self-efficacy" and "Self-management" fall within the Self-Determination Theory and are relevant in this context because they refer to the beliefs that everyone has about their abilities to control behavior and determine the success in adhering to prescribed therapies. Furthermore, the promotion of self-efficacy and self-management through an educational approach that makes use of so-called "eHealth" tools can help develop greater self-awareness in dialysis patient, a better control over their care choices and an increased adherence to therapeutic-dietary indications. This article aims at highlighting the importance of implementing an approach based on eHealth in the management of hemodialysis patients. It also wants to raise awareness of the related multidisciplinary theories to be applied in this clinical context to promote greater therapeutic adherence, and therefore a better quality of life and care.

We compared a standard antihypertensive losartan treatment with a pharmacogenomics-guided rostafuroxin treatment in never-treated Caucasian and Chinese patients with primary hypertension. Rostafuroxin is a digitoxigenin derivative that selectively disrupts the binding to the cSrc-SH2 domain of mutant α-adducin and of the ouabain-activated Na-K pump at 10–11 M. Of 902 patients screened, 172 were enrolled in Italy and 107 in Taiwan. After stratification for country and genetic background, patients were randomized to rostafuroxin or losartan, being the difference in the fall in office systolic blood pressure (OSBP) after 2-month treatment the primary endpoint. Three pharmacogenomic profiles (P) were examined, considering: P1, adding to the gene variants included in the subsequent P2, the variants detected by post-hoc analysis of a previous trial; P2, variants of genes encoding enzymes for endogenous ouabain (EO) synthesis (LSS and HSD3B1), EO transport (MDR1/ABCB1), adducin (ADD1 and ADD3); P3, variants of the LSS gene only. In Caucasians, the group differences (rostafuroxin 50 μg minus losartan 50 mg in OSBP mmHg) were significant both in P2 adjusted for genetic heterogeneity (P2a) and P3 LSS rs2254524 AA [9.8 (0.6–19.0), P = 0.038 and 13.4 (25.4–2.5), P = 0.031, respectively]. In human H295R cells transfected with LSS A and LSS C variants, the EO production was greater in the former (P = 0.038); this difference was abolished by rostafuroxin at 10–11 M. Chinese patients had a similar drop in OSBP to Caucasians with losartan but no change in OSBP with rostafuroxin. These results show that genetics may guide drug treatment for primary hypertension in Caucasians.

Primary hypertension contributes to more than 50% of all the worldwide cardiovascular deaths. Current antihypertensive therapy is still targeting the physiological mechanisms regulating blood pressure, but not the “causal” ones. So far, genetic studies have been unable to prove gene causation in human primary hypertension. In this study we compared a standard antihypertensive losartan treatment with a pharmacogenomics-guided rostafuroxin treatment in never-treated Caucasian and Chinese patients with primary hypertension (PEARL-HT trial registration: EudraCT: 2010-022073-34, ClinicalTrials.gov: NCT01320397). Rostafuroxin is a digitoxigenin derivative that selectively disrupts the binding to the cSrc-SH2 domain of mutant α-adducin and of the ouabain-activated Na-K pump at 10 -11 M. Of 902 patients screened, 172 were enrolled in Italy and 107 in Taiwan. After stratification for country and genetic background, patients were randomized to rostafuroxin or losartan, being the difference in the fall in Office Systolic Blood Pressure (OSBP) after two-month treatment the primary endpoint. Three pharmacogenomic profiles (P) were examined, considering: P1, adding to the gene variants included in the subsequent P2, the variants detected by post-hoc analysis of a previous trial; P2, variants of genes encoding enzymes for endogenous ouabain (EO) synthesis ( LSS and HSD3B1 ), EO transport ( MDR1/ABCB1 ), adducin ( ADD1 and ADD3 ); P3, variants of the LSS gene only. In Caucasians, the group differences (rostafuroxin 50 μg minus losartan 50 mg in OSBP mmHg) were significant both in P2 adjusted for genetic heterogeneity (P2a) and P3 LSS rs2254524 AA [9.8 (0.6-19.0), P =0.038 and 13.4 (25.4-2.5), P =0.031, respectively]. In human H295R cells transfected with LSS A and LSS C variants, the EO production was greater in the former ( P =0.038); this difference was abolished by rostafuroxin at 10 -11 M. Chinese patients had a similar drop in OSBP to Caucasians with losartan but no change in OSBP with rostafuroxin. These results show that the selective blockade of mutant adducin and endogenous ouabain pressor mechanisms by rostafuroxin improves the therapy of primary hypertension in in Caucasians carriers of the related gene variants.

Among ~25% of patients with essential hypertension (EH), circulating endogenous ouabain (EO) and aldosterone (Aldo) are typically coelevated and their BP is especially salt-sensitive (SS). We probed for exaggerated natriuresis in a large cohort (712) of hypertensive patients that underwent an acute 2hr (T 120 ) load with saline (0.9%/2 L). Results: Using a quartiles analysis of sodium excretion, the 4th quartile subgroups showed higher SBP and DBP at T 120 , and at 2 hrs recovery (T 240 ). Fractional sodium excretion (FE Na) was significantly higher during loading and recovery in the 4 th quartile subgroup. Plasma Aldo was suppressed after saline in all subgroups as expected. SS patients showed an increased EO. In the 4 th quartiles EO was elevated at baseline and after saline (see figure), p Manova > 0.001 and the urinary Na/K ratio output was higher. Further, increases in plasma Na + were greater in the 4 th quartile group (1.91 ± 0.15 vs 0.83 ± 0.13 mM, p

Recently we have proposed LSS as genotype-based risk stratification to predict accelerated eGFR decay in a prospective cohort study of essential HYP patients. We extract clinical data of a general population from HYPERGENES consortium. We also collect genetic data for LSS polymorphism that was already demonstrated as involved in kidney damage. A cohort of 3137 patients were selected. At different age, as expected, HYP status have a deep impact on eGFR. Indeed in young (age < 50ys) eGFR is higher in HYP vs control (86.2 ± 19.3 vs 82.7 ± 16.3 ml/min; p=0.04); vice-versa in elder (age > 65ys) HYP have a reduction in eGFR (55.7 ± 12.9 vs 71.0 ± 12.9 ml/min; p Conclusion: Patients caring the risk allele of this specific LSS polymorphism seems to express hyper-filtration if compared to their counterparts.

Coronavirus disease 2019 (COVID-19) is a highly contagious viral disease causing a Severe Acute Respiratory distress syndrome. In 392 consecutive COVID-19 patients hospitalized in IRCCS San Raffaele in Milan (age 67 years range 28-94, Sex M, 74,7%) from march 2 until 25 April 2020, renal function was monitored. History of Hypertension (HYP) was the main comorbidity factors (58 %) under drug medications in 86.1% (ACEi/ARB 56,5). AKI (any stage) was detected in 6.2% of patients at emergency department (ED) admission. Baseline kidney function and HYP were the main determinants of ED-AKI (ED-AKI in HYP 89.5% vs 56.4 % in non-HYP; p=0.004) with an increased risk of 4.98 (95% CI 1.04-23.80; p=0.044) after adjustment by independent covariates, including age and respiratory distress.Moreover, MBP levels at presentation were inversely related with increased risk of ED-AKI. A stand-alone level of MBP < 86 mmHg (i.e.< 120/70 mmHg) or 65 yrs; 42.5% vs 24.3 %, X 2 16.62; p2 21.57; p

Background In February 2020 the corona virus disease 2019 (COVID-19) infection started spreading throughout Italy, hitting the Lombardy region very hard. Despite the high diffusion, only a subset of patients developed severe COVID-19: around 25% of them developed acute kidney injury (AKI) and one-third of them died. Elderly patients and patients with high comorbidities were identified as being at higher risk of severe COVID-19. Methods Our prospective observational cohort study includes 392 consecutive patients hospitalized for COVID-19 in Milan (median age 67 years, 75% male). We evaluated the relationship between blood pressure at presentation, presence of AKI at Emergency Department admission and during hospitalization, and total in-hospital mortality (24%). Results Although 58% of our study patients reported a history of hypertension (HYP) (86% on treatment), 30% presented with low blood pressure levels. Only 5.5% were diagnosed with AKI on admission; 75% of hypertensive patients discontinued therapy during hospitalization (only 20% were on treatment at discharge). Gender and hypertension were strongly associated with AKI at admission (odds ratio 11). Blood pressure was inversely correlated with increased risk of AKI upon admission, regardless of the severity of respiratory distress. Age over 65, history of hypertension, and severity of respiratory distress were the main predictors of AKI, which developed in 34.7% of cases during hospitalization. AKI was associated with increased in-hospital mortality. Hypertension and low blood pressure at presentation were the main predictors of in-hospital mortality, together with age over 65, baseline pulmonary involvement, and severity of illness. Conclusions In patients hospitalized for COVID-19, hypertension and low blood pressure at presentation are important risk factors for AKI and mortality. Early reduction of antihypertensive therapy may improve outcomes in patients with SARS-CoV-2 infection.

Aims: To evaluate whether angiotensin-converting enzyme (ACE) inhibitor and angiotensin II receptor blocker (ARB) combination therapy is more nephroprotective than ACE inhibitor or ARB monotherapy in people with type 2 diabetes and overt nephropathy. Materials and methods: In this prospective, randomized, open, blind-endpoint phase III trial sponsored by the Italian Drug Agency, 103 consenting patients with type 2 diabetes, aged >40 years, with serum creatinine levels 159 to 309 μmol/L, spot morning urinary albumin–creatinine ratio > 1000 mg/g (or > 500 mg/g in those on ACE inhibitor or ARB therapy at inclusion) were stratified by centre and randomized to 4.5-year treatment with valsartan 320 mg/d (n = 36), benazepril 20 mg/d (n = 34) or halved doses of both medications (n = 33). The primary endpoint was end-stage renal disease (ESRD). Modified intention-to-treat analyses were performed. Results: Recruitment took place between June 2007 and February 2013 at 10 centres in Italy and one in Slovenia. A total of 77 participants completed the study and 26 were prematurely withdrawn. During a median (interquartile range) of 41 (18–54) months, 12 participants on benazepril (35.3%) and nine on combination therapy (27.3%) progressed to ESRD, versus five on valsartan (13.9%). Differences between benazepril (hazard ratio [HR] 3.59, 95% confidence interval [CI] 1.25–10.30; P = 0.018) or combination therapy (HR 3.28, 95% CI 1.07–10.0; P = 0.038) and valsartan were significant, even after adjustment for age, gender and baseline serum creatinine, systolic blood pressure and 24-hour proteinuria (HR 5.16, 95% CI 1.50–17.75, P = 0.009 and HR 4.75, 95% CI 1.01–22.39, P = 0.049, respectively). Adverse events were distributed similarly among the groups. Conclusions: In people with type 2 diabetes with nephropathy, valsartan (320 mg/d) safely postponed ESRD more effectively than benazepril (20 mg/d) or than halved doses of both medications.

In late December 2019, some patients were hospitalized with an initial diagnosis of pneumonia of unknown etiology. These patients were epidemiologically linked to a wholesale market of seafood, wild animals and meat located in Wuhan, Hubei province, China. Acute respiratory disease caused by a new Coronavirus SARS-CoV-2, formerly known as 2019-nCoV, afterwards as Coronavirus disease 2019 (COVID-19), spread throughout China and received the attention of the entire world. Analysis of the genomic sequence of COVID-19 showed 88% of identity with two bat-derived severe acute respiratory syndrome-like Coronaviruses. Illegal and sustainable wildlife trade is the second largest direct threat to species after habitat destruction. Each year, hundreds of millions of plants and animals are captured or collected in the wild to be sold as food, pets, medicines, ornaments and for a variety of other reasons. Even the climate crisis could offer dangerous scenarios in addition to another fundamental chapter of the environmental pillar which is the one concerning air quality. There is a solid scientific literature which correlates the incidence of viral infection cases with concentrations of atmospheric particulate matter (e.g. PM10 and PM2.5). Despite the current regulations, which limit the levels of certain atmospheric pollutants, there are still numerous negative health effects deriving from exposure to these agents. However, it can be said that chronic air pollution, such as peaks of concentration of fine dust and other pollutants, acts as a pejorative factor in cases of epidemics. (GCND_planet)

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 Claudin-16 and -19 are proteins forming pores for the paracellular reabsorption of divalent cations in the ascending limb of Henle loop; conversely, claudin-14 decreases ion permeability of these pores. Single-nucleotide polymorphisms in gene coding for claudin-14 were associated with kidney stones and calcium excretion. This study aimed to explore the association of claudin-14, claudin-16, and claudin-19 single-nucleotide polymorphisms with calcium excretion. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We performed a retrospective observational study of 393 patients with hypertension who were naive to antihypertensive drugs, in whom we measured 24-hour urine calcium excretion; history of kidney stones was ascertained by interview; 370 of these patients underwent an intravenous 0.9% sodium chloride infusion (2 L in 2 hours) to evaluate the response of calcium excretion in three different 2-hour urine samples collected before, during, and after saline infusion. Genotypes of claudin-14, claudin-16, and claudin-19 were obtained from data of a previous genome-wide association study in the same patients. RESULTS Thirty-one single-nucleotide polymorphisms of the 3' region of the claudin-14 gene were significantly associated with 24-hour calcium excretion and calcium excretion after saline infusion. The most significant associated single-nucleotide polymorphism was rs219755 (24-hour calcium excretion in GG, 225±124 mg/24 hours; 24-hour calcium excretion in GA, 194±100 mg/24 hours; 24-hour calcium excretion in AA, 124±73 mg/24 hours; P

Na+ , K+ -ATPase (NKA) activity, which establishes the sodium and potassium gradient across the cell membrane and is instrumental in the propagation of the nerve impulses, is altered in a number of neurological and neuropsychiatric disorders, including autism spectrum disorders (ASD). In the present work, we examined a wide range of biochemical and cellular parameters in the attempt to understand the reason(s) for the severe decrease in NKA activity in erythrocytes of ASD children that we reported previously. NKA activity in leukocytes was found to be decreased independently from alteration in plasma membrane fluidity. The different subunits were evaluated for gene expression in leukocytes and for protein expression in erythrocytes: small differences in gene expression between ASD and typically developing children were not apparently paralleled by differences in protein expression. Moreover, no gross difference in erythrocyte plasma membrane oxidative modifications was detectable, although oxidative stress in blood samples from ASD children was confirmed by increased expression of NRF2 mRNA. Interestingly, gene expression of some NKA subunits correlated with clinical features. Excess inhibitory metals or ouabain-like activities, which might account for NKA activity decrease, were ruled out. Plasma membrane cholesterol, but not phosphatidylcholine and phosphatidlserine, was slighty decreased in erythrocytes from ASD children. Although no compelling results were obtained, our data suggest that alteration in the erytrocyte lipid moiety or subtle oxidative modifications in NKA structure are likely candidates for the observed decrease in NKA activity. These findings are discussed in the light of the relevance of NKA in ASD. Autism Res 2018, 11: 1388-1403. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The activity of the cell membrane enzyme NKA, which is instrumental in the propagation of the nerve impulses, is severely decreased in erythrocytes from ASD children and in other brain disorders, yet no explanation has been provided for this observation. We strived to find a biological/biochemical cause of such alteration, but most queries went unsolved because of the complexity of NKA regulation. As NKA activity is altered in many brain disorders, we stress the relevance of studies aimed at understanding its regulation in ASD.

BACKGROUND: Vitamin K (VK)-dependent γ-glutamate carboxylation and serine phosphorylation activate matrix Gla protein (MGP) to a potent locally acting inhibitor of calcification. Nephrolithiasis represents a process of unwanted calcification associated with substantial mortality and high recurrence rates. We hypothesized that the risk of nephrolithiasis increases with VK shortage, as exemplified by higher plasma levels of desphospho-uncarboxylated MGP (dp-ucMGP). METHODS: In 1748 randomly recruited Flemish individuals (51.1% women; mean age 46.8 years), we determined dp-ucMGP and the prevalence of nephrolithiasis at baseline (April 1996-February 2015) and its incidence during follow-up until March 2016. We estimated the multivariable-adjusted relative risk associated with the doubling of dp-ucMGP, using logistic or Cox regression. We did a Mendelian randomization analysis using four MGP genotypes as instrumental variables. RESULTS: With adjustments applied for sex, age and 24-h urinary volume and calcium excretion, the odds of having prevalent nephrolithiasis [n = 144 (8.2%)] associated with dp-ucMGP was 1.31 [95% confidence interval (CI) 1.04-1.64; P = 0.022]. dp-ucMGP levels were associated (P ≤ 0.001) with MGP variants rs2098435, rs4236 and rs2430692. In the Mendelian analysis, the causal odds ratio was 3.82 (95% CI 1.15-12.7; P = 0.029). The incidence of nephrolithiasis over 12.0 years (median) was 37 cases (0.2%). With similar adjustments as before, the hazard ratio in relation to dp-ucMGP was 2.48 (95% CI 1.71-3.61; P

International audience; Exfoliation syndrome (XFS) is the commonest known risk factor for secondary glaucoma and a significant cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A have been previously associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results between populations,and to identify new variants associated with XFS. We identified a rare, protective allele at LOXL1 (p.407Phe, OR= 25, P=2.9 x 10-14) through deep resequencing of XFS cases and controls from 9 countries. This variant results in increased cellular adhesion strength compared to the wild-type (p.407Tyr) allele. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 x 10-8). Index variants at the new loci map to chromosomes 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS, and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

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.