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      Genetic Variants in Renalase and Blood Pressure Responses to Dietary Salt and Potassium Interventions: A Family-Based Association Study


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          Background/Aims: Renalase (gene name RNLS), a recently discovered enzyme with monoamine oxidase activity, is implicated in the degradation of catecholamines. Recent studies indicate that common variations in the gene with RNLS are associated with hypertension. The aim of this study was to examine the association between genetic variants in RNLS and blood pressure (BP) responses to strict dietary interventions of salt and potassium intake. Methods: A total of 334 subjects from 124 families were selected and sequentially maintained on a low-salt diet for 7 days (3.0 g/day, NaCl), then a high-salt diet for 7 days (18.0 g/day, NaCl), high-salt diet with potassium supplementation for another 7 days (4.5 g/day, KCl). Results: SNPs rs919115 and rs792205 of the RNLS gene were significantly associated with diastolic BP (DBP) and mean arterial pressure (MAP) responses to high-salt intervention. In addition, rs12356177 was significantly associated with systolic BP (SBP) and DBP responses to low-salt diet, and SBP, DBP or MAP during the high-salt intervention. Unfortunately, no associations for the 7 RNLS SNPs with BP response to high-salt diet with potassium supplementation reached nominal statistical significance. Conclusions: This family-based study indicates that genetic variants in the RNLS gene are significantly associated with BP responses to dietary salt intake.

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          National, regional, and global trends in systolic blood pressure since 1980: systematic analysis of health examination surveys and epidemiological studies with 786 country-years and 5·4 million participants.

          Data for trends in blood pressure are needed to understand the effects of its dietary, lifestyle, and pharmacological determinants; set intervention priorities; and evaluate national programmes. However, few worldwide analyses of trends in blood pressure have been done. We estimated worldwide trends in population mean systolic blood pressure (SBP). We estimated trends and their uncertainties in mean SBP for adults 25 years and older in 199 countries and territories. We obtained data from published and unpublished health examination surveys and epidemiological studies (786 country-years and 5·4 million participants). For each sex, we used a Bayesian hierarchical model to estimate mean SBP by age, country, and year, accounting for whether a study was nationally representative. In 2008, age-standardised mean SBP worldwide was 128·1 mm Hg (95% uncertainty interval 126·7-129·4) in men and 124·4 mm Hg (123·0-125·9) in women. Globally, between 1980 and 2008, SBP decreased by 0·8 mm Hg per decade (-0·4 to 2·2, posterior probability of being a true decline=0·90) in men and 1·0 mm Hg per decade (-0·3 to 2·3, posterior probability=0·93) in women. Female SBP decreased by 3·5 mm Hg or more per decade in western Europe and Australasia (posterior probabilities ≥0·999). Male SBP fell most in high-income North America, by 2·8 mm Hg per decade (1·3-4·5, posterior probability >0·999), followed by Australasia and western Europe where it decreased by more than 2·0 mm Hg per decade (posterior probabilities >0·98). SBP rose in Oceania, east Africa, and south and southeast Asia for both sexes, and in west Africa for women, with the increases ranging 0·8-1·6 mm Hg per decade in men (posterior probabilities 0·72-0·91) and 1·0-2·7 mm Hg per decade for women (posterior probabilities 0·75-0·98). Female SBP was highest in some east and west African countries, with means of 135 mm Hg or greater. Male SBP was highest in Baltic and east and west African countries, where mean SBP reached 138 mm Hg or more. Men and women in western Europe had the highest SBP in high-income regions. On average, global population SBP decreased slightly since 1980, but trends varied significantly across regions and countries. SBP is currently highest in low-income and middle-income countries. Effective population-based and personal interventions should be targeted towards low-income and middle-income countries. Funding Bill & Melinda Gates Foundation and WHO. Copyright © 2011 Elsevier Ltd. All rights reserved.
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            An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis.

            Rheumatoid arthritis is a common inflammatory disease with complex genetic components. We investigated the genetic contribution of the cytokine gene cluster in chromosome 5q31 to susceptibility to rheumatoid arthritis in the Japanese population by case-control linkage disequilibrium (LD) mapping using single nucleotide polymorphisms (SNPs). Here we report that there is significant association between rheumatoid arthritis and the organic cation transporter gene SLC22A4 (P = 0.000034). We show that expression of SLC22A4 is specific to hematological and immunological tissues and that SLC22A4 is also highly expressed in the inflammatory joints of mice with collagen-induced arthritis. A SNP affects the transcriptional efficiency of SLC22A4 in vitro, owing to an allelic difference in affinity to Runt-related transcription factor 1 (RUNX1), a transcriptional regulator in the hematopoietic system. A SNP in RUNX1 is also strongly associated with rheumatoid arthritis (P = 0.00035). Our data indicate that the regulation of SLC22A4 expression by RUNX1 is associated with susceptibility to rheumatoid arthritis, which may represent an example of an epistatic effect of two genes on this disorder.
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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.

                Author and article information

                Kidney Blood Press Res
                Kidney and Blood Pressure Research
                S. Karger AG
                December 2014
                26 November 2014
                : 39
                : 5
                : 497-506
                Department of Cardiovascular Medicine, First Affiliated Hospital of Medical College, Xi'an Jiaotong University and Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, P. R. China
                Author notes
                *Jianjun Mu, PhD, Department of Cardiovascular Medicine, First Affiliated Hospital of Medical College,, Xi'an Jiaotong University, No. 277, Yanta West Road, Xi'an, 710061 (P. R. China), Tel. +86-29-85323804, E-Mail mujjun@163.com
                368460 Kidney Blood Press Res 2014;39:497-506
                © 2014 S. Karger AG, Basel

                Open Access License: This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) ( http://www.karger.com/OA-license), applicable to the online version of the article only. Distribution permitted for non-commercial purposes only. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                : 30 September 2014
                Page count
                Pages: 10
                Original Paper

                Cardiovascular Medicine,Nephrology
                Renalase,Salt,Potassium,Gene polymorphism,Blood pressure
                Cardiovascular Medicine, Nephrology
                Renalase, Salt, Potassium, Gene polymorphism, Blood pressure


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