Genetics of primary hypertension: The clinical impact of adducin polymorphisms

AbstractThe usefulness of the results so far published on genetics of primary hypertension for establishing the clinical impact of candidate gene polymorphisms is weakened by the scanty information regarding: a) the functional effect of the gene variants of interest in humans; b) the regulatory genetic network (RGN) where the gene is operating with all the interacting environmental–biological factors and the respective hierarchical organization; c) the consistency between the natural history of the established pathophysiological mechanisms underlying hypertension and the new molecular mechanism detected with genetics; d) the limitations regarding the translation of animal data to human due to the differences among species of the genetic molecular mechanisms underlying similar organ function changes in the different species. Of course, not all these information are available for adducin polymorphisms. In this review, being aware of their importance, the evaluation of the clinical impact of adducin has been focused on data obtained together with the interacting genetic-environmental or biological factors. Adducin polymorphisms and endogenous ouabain (EO) were detected by a top-down approach in rodents after having demonstrated, at cellular and kidney level, that an increase in tubular Na reabsorption could underlies the transition from normotension to hypertension both in rodents and humans. Therefore, we hypothesized that adducin polymorphisms and EO may operate within the triggering RGN that initiates the increase in blood pressure in both species. The distinction between triggering RGN and the secondary RGN is important both to limit the level of genetic complexity arising from secondary changes, and to detect the molecular target to develop tailored therapeutic approach. The pharmacogenomic approach, both in rodents or humans, with newly discovered and never treated hypertension, may be useful to strengthen the “causation” of genetic mechanism. Mutant adducin increases tubular reabsorption: diuretics, because of their effect on overall tubular reabsorption, or rostafuroxin, because of its selective inhibition of the adducin and ouabain effects, may be used for this purpose. Indeed the pharmacogenomic approach with both drugs have provided data consistent with the role of adducin and EO. Taken together, all these findings indicate a clear impact of adducin polymorphism and EO in a subset of patients when the appropriate environmental, biological or genetic context is taken into account. The size of this impact is variable and affected by the context

Arterial Properties in Relation to Genetic Variations in the Adducin Subunits in a White Population

Background Adducin is a membrane skeleton protein, which consists of either α- and β- or α- and γ-subunits. We investigated whether arterial characteristics might be related to the genes encoding ADD1 (Gly460Trp-rs4961), ADD2 (C1797T-rs4984), and ADD3 (IVS11+386A>G-rs3731566). Methods We randomly recruited 1,126 Flemish subjects (mean age, 43.8 years; 50.3% women). Using a wall-tracking ultrasound system, we measured the properties of the carotid, femoral, and brachial arteries. We studied multivariate-adjusted phenotype-genotype associations, using a population- and family-based approach. Results In single-gene analyses, brachial diameter was 0.15 mm (P = 0.0022) larger, and brachial distensibility and cross-sectional compliance were 1.55 × 10-3/kPa (P = 0.013) and 0.017 mm2/kPa (P = 0.0029) lower in ADD3 AA than ADD3 GG homozygotes with an additive effect of the G allele. In multiple-gene analyses, the association of brachial diameter and distensibility with the ADD3 G allele occurred only in ADD1 GlyGly homozygotes. Otherwise, the associations between the arterial phenotypes in the three vascular beds and the ADD1 or ADD2 polymorphisms were not significant. In family-based analyses, the multivariate-adjusted heritability was 0.52, 0.38, and 0.30 for brachial diameter, distensibility, and cross-sectional compliance, respectively (P < 0.001). There was no evidence for population stratification (0.07 ≤ P ≤ 0.96). Transmission of the mutated ADD3 G allele was associated with smaller brachial diameter in 342 informative offspring (-0.12 ± 0.04 mm; P = 0.0085) and in 209 offspring, who were ADD1 GlyGly homozygotes (-0.14 ± 0.06 mm; P = 0.018). Conclusions In ADD1 GlyGly homozygotes, the properties of the brachial artery are related to the ADD3 (A386G) polymorphism, but the underlying mechanism needs further clarification. American Journal of Hypertension (2009). doi: 10.1038/ajh.2008.26

Lanosterol Synthase Genetic Variants, Endogenous Ouabain, and Both Acute and Chronic Kidney Injury

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±0.08ng/g; P 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

Main results of the Ouabain and Adducin for Specific Intervention on Sodium in Hypertension Trial (OASIS-HT): a randomized placebo-controlled phase-2 dose-finding study of rostafuroxin

Background. The Ouabain and Adducin for Specific Intervention on Sodium in Hypertension (OASIS-HT) Trial was a phase 2 dose-finding study of rostafuroxin, a digitoxygenin deivative, which selectively antagonizes the effects of endogenous ouabain (EO) on Na+,K+-ATPase and mutated adducin. Rostafuroxin lowered blood pressure (BP) in some animal models and in humans. Methods. OASIS-HT consisted of 5 concurrently running double-blind cross-over studies. After 4 weeks without treatment, 435 patients with uncomplicated systolic hypertension (140-169 mm Hg) were randomized to rostafuroxin (0.05, 0.15, 0.5, 1.5 or 5.0 mg/d) or matching placebo, each treatment period lasting 5 weeks. The primary endpoint was the reduction in systolic office BP. Among the secondary endpoints were diastolic office BP, 24 h ambulatory BP, plasma EO concentration and renin activity, 24-h urinary sodium and aldosterone excretion, and safety. ANOVA considered treatment sequence (fixed effect), subjects nested within sequence (random), period (fixed), and treatment (fixed). Results. Among 410 analyzable patients (40.5% women; mean age, 48.4 years), the differences in the primary endpoint (rostafuroxin minus placebo) ranged from -0.18 mm Hg (P=0.90) on 0.15 mg/d rostafuroxin to 2.72 mm Hg (P=0.04) on 0.05 mg/d. In the 5 dosage arms combined, the treatment effects averaged 1.30 mm Hg (P=0.03) for systolic office BP; 0.70 mm Hg (P=0.08) for diastolic office BP; 0.36 mm Hg (P=0.49) for 24-h systolic BP; and 0.05 mm Hg (P=0.88) for 24-h diastolic BP. In the 2 treatment groups combined, systolic (-1.36 mm Hg) and diastolic (-0.97 mm Hg) office BPs decreased from week 5 to 10 (P for period effect ≤=0.028), but carry-over effects were not significant (P≥=0.11). All other endpoints were not different on rostafuroxin and placebo. Minor side-effects occurred with similarly low frequency on rostafuroxin and placebo. Conclusions. In 5 concurrently running double-blind cross-over studies rostafuroxin did not reduce BP at any dose. Trial Registration: NCT00415038 http://www.clinicaltrials.gov)

MicroRNA 193b-3p as a predictive biomarker of chronic kidney disease in patients undergoing radical nephrectomy for renal cell carcinoma

Background: A significant proportion of patients undergoing radical nephrectomy (RN) for clear-cell renal cell carcinoma (RCC) develop chronic kidney disease (CKD) within a few years following surgery. Chronic kidney disease has important health, social and economic impact and no predictive biomarkers are currently available. MicroRNAs (miRs) are small non-coding RNAs implicated in several pathological processes. Methods: Primary objective of our study was to define miRs whose deregulation is predictive of CKD in patients treated with RN. Ribonucleic acid from formalin-fixed paraffin embedded renal parenchyma (cortex and medulla isolated separately) situated &gt;3 cm from the matching RCC was tested for miR expression using nCounter NanoString technology in 71 consecutive patients treated with RN for RCC. Validation was performed by RT–PCR and in situ hybridisation. End point was post-RN CKD measured 12 months post-operatively. Multivariable logistic regression and decision curve analysis were used to test the statistical and clinical impact of predictors of CKD. Results: The overexpression of miR-193b-3p was associated with high risk of developing CKD in patients undergoing RN for RCC and emerged as an independent predictor of CKD. The addition of miR-193b-3p to a predictive model based on clinical variables (including sex and estimated glomerular filtration rate) increased the sensitivity of the predictive model from 81 to 88%. In situ hybridisation showed that miR-193b-3p overexpression was associated with tubule-interstitial inflammation and fibrosis in patients with no clinical or biochemical evidence of pre-RN nephropathy. Conclusions: miR-193b-3p might represent a useful biomarker to tailor and implement surveillance strategies for patients at high risk of developing CKD following RN

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Endogenous Ouabain and Related Genes in the Translation from Hypertension to Renal Diseases

The endogenous ouabain (EO) is a steroid hormone secreted by the adrenal gland with cardio-tonic effects. In this article, we have reviewed and summarized the most recent reports about EO, particularly with regard to how it may interact with specific genetic backgrounds. We have focused our attention on the EO&rsquo;s potential pathogenic role in several diseases, including renal failure, essential hypertension and heart failure. Notably, these reports have demonstrated that EO acts as a pro-hypertrophic and growth-promoting hormone, which might lead to a cardiac remodeling affecting cardiovascular functions and structures. In addition, a possible role of EO in the development of acute kidney injury has been hypothesized. During the last decays, many important improvements permitted a deeper understanding of EO&rsquo;s metabolisms and functions, including the characteristics of its receptor and the effects of its activation. Such progresses indicated that EO has significant implications in the pathogenesis of many common diseases. The patho-physiological role of EO in the development of hypertension and other cardiac and renal complications have laid the basis for the development of a new selective compound that could selectively modulate the genetic and molecular mechanisms involved in EO&rsquo;s action. It is evident that the knowledge of EO has incredibly increased; however, many important areas remain to be further investigated

Left ventricular structure and function in relation to steroid biosynthesis genes in a white population

BackgroundBoth endogenous ouabain (EO) and aldosterone are steroid hormones which might play a role in the pathogenesis of left ventricular (LV) hypertrophy and cardiac remodeling. Cholesterol side-chain cleavage enzyme (CYP11A1) and 3β-hydroxysteroid dehydrogenase (HSD3B1) are two key enzymes in the pathway of steroid biosynthesis.MethodsWe investigated in 532 individuals (mean age, 50.3 years; 51.5% women) randomly recruited from a white European population whether LV structure and function were related to genetic variations in CYP11A1 and HSD3B1. We measured LV structure by conventional echocardiography and LV diastolic function by Doppler imaging of the transmitral blood flow and the mitral annular movement. We genotyped tag single nucleotide polymorphisms (SNPs) rs2279357, rs11638442 and rs2073475 in CYP11A1, and rs2236780, rs3765945, and rs6203 in HSD3B1.ResultsWhile adjusting for covariables and accounting for family clusters, LV mass index decreased (P ≤ 0.049) across the CYP11A1 genotypes in rs2279357 (CC vs. CT vs. TT), rs11638442 (GG vs. GC vs. CC), and rs2073475 (GG vs. GA+AA). Carriers of the CYP11A1 TCG haplotype had lower (P ≤ 0.017) LV mass and LV mass index than noncarriers. Carriers of HSD3B1 GCC haplotype had lower peak early (Ea; P = 0.004) and higher peak late (Aa; P = 0.066) diastolic mitral annular velocities and therefore a lower Ea/Aa ratio (P = 0.041) as compared with noncarriers. Neither plasma endogenous ouabain nor 24-h urinary aldosterone were related to any of the SNPs or haplotypes (P ≥ 0.07).ConclusionsPending confirmation in other studies, LV mass and LV diastolic function seem to be related to genetic variation in the steroid biosynthesis.American Journal of Hypertension 2012; doi:10.1038/ajh.2012.69.status: publishe