Dataset Information

Genome-wide meta-analyses of plasma renin activity and concentration reveal association with the kininogen 1 and prekallikrein genes.

ABSTRACT: BACKGROUND:The renin-angiotensin-aldosterone system (RAAS) is critical for regulation of blood pressure and fluid balance and influences cardiovascular remodeling. Dysregulation of the RAAS contributes to cardiovascular and renal morbidity. The genetic architecture of circulating RAAS components is incompletely understood. METHODS AND RESULTS:We meta-analyzed genome-wide association data for plasma renin activity (n=5275), plasma renin concentrations (n=8014), and circulating aldosterone (n=13289) from ?4 population-based cohorts of European and European-American ancestry, and assessed replication of the top results in an independent sample (n=6487). Single-nucleotide polymorphisms (SNPs) in 2 independent loci displayed associations with plasma renin activity at genome-wide significance (P<5×10(-8)). A third locus was close to this threshold (rs4253311 in kallikrein B [KLKB1], P=5.5×10(-8)). Two of these loci replicated in an independent sample for both plasma renin and aldosterone concentrations (SNP rs5030062 in kininogen 1 [KNG1]: P=0.001 for plasma renin, P=0.024 for plasma aldosterone concentration; and rs4253311 with P<0.001 for both plasma renin and aldosterone concentration). SNPs in the NEBL gene reached genome-wide significance for plasma renin concentration in the discovery sample (top SNP rs3915911; P=8.81×10(-9)), but did not replicate (P=0.81). No locus reached genome-wide significance for aldosterone. SNPs rs5030062 and rs4253311 were not related to blood pressure or renal traits; in a companion study, variants in the kallikrein B locus were associated with B-type natriuretic peptide concentrations in blacks. CONCLUSIONS:We identified 2 genetic loci (kininogen 1 and kallikrein B) influencing key components of the RAAS, consistent with the close interrelation between the kallikrein-kinin system and the RAAS.

SUBMITTER: Lieb W

PROVIDER: S-EPMC4354880 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Genome-wide meta-analyses of plasma renin activity and concentration reveal association with the kininogen 1 and prekallikrein genes.

Lieb Wolfgang W Chen Ming-Huei MH Teumer Alexander A de Boer Rudolf A RA Lin Honghuang H Fox Ervin R ER Musani Solomon K SK Wilson James G JG Wang Thomas J TJ Völzke Henry H Petersen Ann-Kristin AK Meisinger Christine C Nauck Matthias M Schlesinger Sabrina S Li Yong Y Menard Jöel J Hercberg Serge S Wichmann H-Erich HE Völker Uwe U Rawal Rajesh R Bidlingmaier Martin M Hannemann Anke A Dörr Marcus M Rettig Rainer R van Gilst Wiek H WH van Veldhuisen Dirk J DJ Bakker Stephan J L SJ Navis Gerjan G Wallaschofski Henri H Meneton Pierre P van der Harst Pim P Reincke Martin M Vasan Ramachandran S RS

Circulation. Cardiovascular genetics 20141204 1

<h4>Background</h4>The renin-angiotensin-aldosterone system (RAAS) is critical for regulation of blood pressure and fluid balance and influences cardiovascular remodeling. Dysregulation of the RAAS contributes to cardiovascular and renal morbidity. The genetic architecture of circulating RAAS components is incompletely understood.<h4>Methods and results</h4>We meta-analyzed genome-wide association data for plasma renin activity (n=5275), plasma renin concentrations (n=8014), and circulating aldo ...[more]

PMID: 25477429

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Project description:BackgroundSince the diagnostic value of aldosterone to renin ratio (ARR) calculated by plasma renin concentration (PRC) or plasma renin activity (PRA) is still inconclusive, we conducted a meta-analysis by systematically reviewing relevant literature to explore the difference in the diagnostic efficacy of ARR calculated by PRC or PRA, so as to provide guidance for clinical diagnosis.MethodsWe searched PubMed, Embase, and Cochrane Library from the establishment of the database to March 2021. We included studies that report the true positive, false positive, true negative, and false negative values for the diagnosis of primary aldosteronism, and we excluded duplicate publications, research without full text, incomplete information, or inability to conduct data extraction, animal experiments, reviews, and systematic reviews. STATA 15.1 was used to analyze the data.ResultsThe pooled results showed that ARR (plasma aldosterone concentration [PAC]/PRC) had a sensitivity of 0.82 (95% confidence interval [CI]: 0.78-0.86), a specificity of 0.94 (95% CI: 0.92-0.95), a positive-likelihood ratio (LR) of 12.77 (95% CI: 7.04-23.73), a negative LR of 0.11 (95% CI: 0.07-0.17), and symmetric area under the curve (SAUC) of 0.982, respectively. Furthermore, the diagnostic odds ratio (DOR) of ARR (PAC/PRC) was 180.21. Additionally, the pooled results showed that ARR (PAC/PRA) had a sensitivity of 0.91 (95% CI: 0.86-0.95), a specificity of 0.91 (95% CI: 0.90-0.93), a positive LR of 7.30 (95% CI: 2.99-17.99), a negative LR of 0.10 (95% CI: 0.04-0.26), and SAUC of 0.976, respectively. The DOR of ARR (PAC/PRA) was 155.52. Additionally, we conducted a subgroup analysis for the different thresholds (<35 or ≥35) of PAC/PRC. The results showed that the DOR of the cut-off ≥35 groups was higher than the cut-off <35 groups (DOR = 340.15, 95% CI: 38.32-3019.66; DOR = 116.40, 95% CI = 23.28-581.92).ConclusionsThe research results suggest that the determination of ARR (PAC/PRC) and ARR (PAC/PRA) was all effective screening tools for PA. The diagnostic accuracy and diagnostic value of ARR (PAC/PRC) are higher than ARR (PAC/PRA). In addition, within a certain range, the higher the threshold, the better the diagnostic value.

Project description:Background:The renin-angiotensin-aldosterone system is closely associated with volume status and vascular tone in septic shock. The present study aimed to assess whether plasma renin activity (PRA) and plasma aldosterone concentration (PAC) measurements compared with conventional severity indicators are associated with mortality in patients with septic shock. Methods:We evaluated 105 patients who were admitted for septic shock. Plasma levels of the biomarkers PRA and PAC, the PAC/PRA ratio, C-reactive protein (CRP) level, and cortisol level on days 1, 3, and 7 were serially measured. During the intensive care unit stay, relevant clinical information and laboratory results were recorded. Results:Patients were divided into two groups according to 28-day mortality: survivors (n = 59) and non-survivors (n = 46). The survivor group showed lower PRA, PAC, Acute Physiologic and Chronic Health Evaluation (APACHE) II score, and Sequential Organ Failure Assessment (SOFA) score than did the non-survivor group (all P < 0.05). The SOFA score was positively correlated with PRA (r = 0.373, P < 0.001) and PAC (r = 0.316, P = 0.001). According to receiver operating characteristic analysis, the areas under the curve of PRA and PAC to predict 28-day mortality were 0.69 (95% confidence interval [CI], 0.58 to 0.79; P = 0.001) and 0.67 (95% CI, 0.56 to 0.77; P = 0.003), respectively, similar to the APACHE II scores and SOFA scores. In particular, the group with PRA value ?3.5 ng ml-1 h-1 on day 1 showed significantly greater mortality than did the group with PRA value <3.5 ng ml-1 h-1 (log-rank test, P < 0.001). According to multivariate analysis, SOFA score (hazard ratio, 1.11; 95% CI, 1.01 to 1.22), PRA value ?3.5 ng ml-1 h-1 (hazard ratio, 3.25; 95% CI, 1.60 to 6.60), previous history of cancer (hazard ratio, 3.44; 95% CI, 1.72 to 6.90), and coronary arterial occlusive disease (hazard ratio, 2.99; 95% CI, 1.26 to 7.08) were predictors of 28-day mortality. Conclusions:Elevated PRA is a useful biomarker to stratify the risk of critically ill patients with septic shock and is a prognostic predictor of 28-day mortality.

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Genome-wide meta-analyses of plasma renin activity and concentration reveal association with the kininogen 1 and prekallikrein genes.

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Genome-wide meta-analyses of plasma renin activity and concentration reveal association with the kininogen 1 and prekallikrein genes.

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