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      Association of Renalase SNPs rs2296545 and rs2576178 with the Risk of Hypertension: A Meta-Analysis

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          Abstract

          Background/Aims

          Two renalase single nucleotide polymorphisms (SNPs) rs2296545 and rs2576178 have been reported to be associated with the susceptibility to hypertension (HT). Given the inconsistent results, we conducted a meta-analysis to assess the association between these two SNPs and the risk of HT.

          Methods

          Electronic databases were systematically searched to find relevant studies. Subgroup analysis was conducted according to the different concomitant diseases and ethnicities in the study population. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated using fixed-effect or random-effect models.

          Results

          A total of six case–control studies on rs2296545 and six studies on rs2576178 were included. In the combined analysis, results showed a significant association between SNP rs2296545 and risk of HT in all genetic models (dominant model CG+CC/GG: OR = 1.43, 95% CI = 1.24–1.65; recessive model CC/CG+GG: OR = 1.36, 95% CI = 1.09–1.69; codominant model CC/GG: OR = 1.63, 95% CI = 1.20–2.20, CG/GG: OR = 1.30, 95% CI = 1.12–1.52; allelic model C/G: OR = 1.29, 95% CI = 1.10–1.51). In subgroup analysis, we observed a significant association between rs2296545 and risk of essential HT. Although we did not observe an association between rs2576178 polymorphism and HT in the combined analysis, an increased risk was observed in the essential HT patients versus healthy controls (subgroup 1) analysis under the dominant, recessive, and codominant genetic models.

          Conclusions

          Renalase gene rs2296545 polymorphism is significantly associated with increased risk of HT, whereas rs2576178 polymorphism may not be associated with the susceptibility to HT.

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          Most cited references25

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          Renalase is a novel, soluble monoamine oxidase that regulates cardiac function and blood pressure.

          The kidney not only regulates fluid and electrolyte balance but also functions as an endocrine organ. For instance, it is the major source of circulating erythropoietin and renin. Despite currently available therapies, there is a marked increase in cardiovascular morbidity and mortality among patients suffering from end-stage renal disease. We hypothesized that the current understanding of the endocrine function of the kidney was incomplete and that the organ might secrete additional proteins with important biological roles. Here we report the identification of a novel flavin adenine dinucleotide-dependent amine oxidase (renalase) that is secreted into the blood by the kidney and metabolizes catecholamines in vitro (renalase metabolizes dopamine most efficiently, followed by epinephrine, and then norepinephrine). In humans, renalase gene expression is highest in the kidney but is also detectable in the heart, skeletal muscle, and the small intestine. The plasma concentration of renalase is markedly reduced in patients with end-stage renal disease, as compared with healthy subjects. Renalase infusion in rats caused a decrease in cardiac contractility, heart rate, and blood pressure and prevented a compensatory increase in peripheral vascular tone. These results identify renalase as what we believe to be a novel amine oxidase that is secreted by the kidney, circulates in blood, and modulates cardiac function and systemic blood pressure.
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            Essential hypertension.

            Hypertension is a frequent, chronic, age-related disorder, which often entails debilitating cardiovascular and renal complications. Blood pressure is usually noted in combination with other cardiovascular risk factors. Diagnosis of hypertension increasingly relies on automated techniques of blood pressure measurement. The pathophysiology of essential hypertension depends on the primary or secondary inability of the kidney to excrete sodium at a normal blood pressure. The central nervous system, endocrine factors, the large arteries, and the microcirculation also have roles in the disorder. Although monogenic forms of blood pressure dysregulation exist, hypertension mostly arises as a complex quantitative trait that is affected by varying combinations of genetic and environmental factors. Non-pharmacological strategies can reduce blood pressure. Antihypertensive drug treatment diminishes the complications of hypertension. The concept that a few major genes will provide the final clue to the pathogenesis of essential hypertension is an oversimplification that contradicts the heterogeneous nature of this disorder. Further integration of genetic, molecular, clinical, and epidemiological research could disclose subsets of patients in whom specific combinations of genetic and environmental factors raise blood pressure, and might lead to more individualised treatment.
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              Renalase deficiency aggravates ischemic myocardial damage.

              Chronic kidney disease (CKD) leads to an 18-fold increase in cardiovascular complications not fully explained by traditional risk factors. Levels of renalase, a recently discovered oxidase that metabolizes catecholamines, are decreased in CKD. Here we show that renalase deficiency in a mouse knockout model causes increased plasma catecholamine levels and hypertension. Plasma blood urea nitrogen, creatinine, and aldosterone were unaffected. However, knockout mice had normal systolic function and mild ventricular hypertrophy but tolerated cardiac ischemia poorly and developed myocardial necrosis threefold more severe than that found in wild-type mice. Treatment with recombinant renalase completely rescued the cardiac phenotype. To gain insight into the mechanisms mediating this cardioprotective effect, we tested if gene deletion affected nitrate and glutathione metabolism, but found no differences between hearts of knockout and wild-type mice. The ratio of oxidized (NAD) to reduced (NADH) nicotinamide adenine dinucleotide in cardiac tissue, however, was significantly decreased in the hearts of renalase knockout mice, as was plasma NADH oxidase activity. In vitro studies confirmed that renalase metabolizes NADH and catecholamines. Thus, renalase plays an important role in cardiovascular pathology and its replacement may reduce cardiac complications in renalase-deficient states such as CKD. © 2011 International Society of Nephrology
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                19 July 2016
                2016
                : 11
                : 7
                : e0158880
                Affiliations
                [1 ]Department of Cardiology, First Affiliated Hospital of Medical School, Xi’an Jiaotong University, Xi’an, China
                [2 ]Key Laboratory of Molecular Cardiology of Shaanxi Province, Xi’an, China
                Yale School of Public Health, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: JJM YBL YW. Performed the experiments: YBL WGM DYY. Analyzed the data: YBL WLZ CC TSG ZYY. Wrote the paper: YBL YW.

                Author information
                http://orcid.org/0000-0002-1759-8673
                Article
                PONE-D-16-02184
                10.1371/journal.pone.0158880
                4951046
                27434211
                1f96cc58-3678-42da-a622-2a30afcb40d9
                © 2016 Lv et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 24 January 2016
                : 23 June 2016
                Page count
                Figures: 5, Tables: 3, Pages: 14
                Funding
                Y.W. is grateful to the China Scholarship Council (No. 201506280092) for a PhD fellowship. This work was supported by the grants: the National Basic Research Program (also called 973 Program) of China (No. 2012CB517804), the National Natural Science Foundation of China (No. 81370357 and No. 81570381), the Clinical Research Award of the First Affiliated Hospital of Xi’an Jiangtong University of China (No. XJTU1AF-CRF-2015-006). The sponsor or funding organization had no role in the design or conduct of this research.
                Categories
                Research Article
                Research and Analysis Methods
                Mathematical and Statistical Techniques
                Statistical Methods
                Meta-Analysis
                Physical Sciences
                Mathematics
                Statistics (Mathematics)
                Statistical Methods
                Meta-Analysis
                Research and Analysis Methods
                Database and Informatics Methods
                Database Searching
                Medicine and Health Sciences
                Vascular Medicine
                Blood Pressure
                Hypertension
                People and Places
                Population Groupings
                Ethnicities
                Chinese People
                Medicine and Health Sciences
                Nephrology
                Chronic Kidney Disease
                Medicine and Health Sciences
                Epidemiology
                Ethnic Epidemiology
                Biology and Life Sciences
                Genetics
                Genetic Dominance
                Biology and Life Sciences
                Genetics
                Human Genetics
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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