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      Association of Klotho gene polymorphism with hypertension and coronary artery disease in an Iranian population

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          Abstract

          Background

          Klotho, possibly an age-regulating protein, is considered an important factor contributing to the lifespan and pathophysiology of hypertension and coronary artery disease (CAD). The present study was carried out aiming to investigate the association of Klotho-rs564481 (C1818T) gene polymorphism with hypertension and CAD.

          Methods

          A total of 286 CAD-suspicious subjects were entered into this case-control study. The polymorphism was investigated in hypertensive patients with no CAD (H-Tens, n = 60); hypertensive patients with CAD (CAD + H-Tens, n = 95); CAD patients with no hypertension (CAD, n = 61); and non-hypertensive non-CAD subjects, which were regarded as the control group (Ctrl, n = 70). Genotype and allele frequencies were assessed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.

          Results

          A significant difference was found in allele frequency of Klotho C1818T among the four research groups ( P = 0.03). It was also found that wild-type homozygote subjects were negatively associated with hypertension as compared to heterozygote ones (OR = 0.07 [95% CI: 0.008–0.69] P = 0.02). Moreover, in the subgroups older than 57 years old, dominant genetic model demonstrated a negative association with CAD combined with hypertension (OR = 0.31 [95% CI: 0.10–0.95] P = 0.04).

          Conclusions

          In conclusion, Klotho C1818T variant may be associated with a decreased risk of hypertension. Moreover, aging enhanced positive effects of the Klotho polymorphism on CAD combined with hypertension, indicating the possibility that the KLOTHO gene might play a part in the age-related occurrence of CAD combined with hypertension.

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          Most cited references24

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          Balancing life-style and genomics research for disease prevention.

          W Willett (2002)
          Genetic and environmental factors, including diet and life-style, both contribute to cardiovascular disease, cancers, and other major causes of mortality, but various lines of evidence indicate that environmental factors are most important. Overly enthusiastic expectations regarding the benefits of genetic research for disease prevention have the potential to distort research priorities and spending for health. However, integration of new genetic information into epidemiologic studies can help clarify causal relations between both life-style and genetic factors and risks of disease. Thus, a balanced approach should provide the best data to make informed choices about the most effective means to prevent disease.
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            Association of human aging with a functional variant of klotho.

            Mice deficient in Klotho gene expression exhibit a syndrome resembling premature human aging. To determine whether variation in the human KLOTHO locus contributes to survival, we applied two newly characterized polymorphic microsatellite markers flanking the gene in a population-based association study. In a cohort chosen for its homogeneity, Bohemian Czechs, we demonstrated significant differences in selected marker allele frequencies between newborn and elderly individuals (P < 0.05). These results precipitated a search for functional variants of klotho. We identified an allele, termed KL-VS, containing six sequence variants in complete linkage disequilibrium, two of which result in amino acid substitutions F352V and C370S. Homozygous elderly individuals were underrepresented in three distinct populations: Bohemian Czechs, Baltimore Caucasians, and Baltimore African-Americans [combined odds ratio (OR) = 2.59, P < 0.0023]. In a transient transfection assay, secreted levels of klotho harboring V352 are reduced 6-fold, whereas extracellular levels of the S370 form are increased 2.9-fold. The V352/S370 double mutant exhibits an intermediate phenotype (1.6-fold increase), providing a rare example of intragenic complementation in cis by human single nucleotide polymorphisms. The remarkable conservation of F352 among homologous proteins suggests that it is functionally important. The corresponding substitution, F289V, in the closest human klotho paralog with a known substrate, cBGL1, completely eliminates its ability to cleave p-nitrophenyl-beta-D-glucoside. These results suggest that the KL-VS allele influences the trafficking and catalytic activity of klotho, and that variation in klotho function contributes to heterogeneity in the onset and severity of human age-related phenotypes.
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              Current understanding of klotho.

              Klotho is a new anti-aging gene. Genetic mutation of klotho causes multiple premature aging-like phenotypes and strikingly shortens lifespan. Overexpression of the klotho gene in mice suppresses aging and extends lifespan which may involve the mechanism of suppression of insulin signaling and oxidant stress. Klotho functions as a cofactor/coreceptor regulating fibroblast growth factor (FGF) 23 signaling. Klotho acts as a glucuronidase and activates ion channel TRPV5. Klotho protects against endothelial dysfunction and regulates the production of nitric oxide. Klotho also influences intracellular signaling pathways including p53/p21, cAMP, protein kinase C (PKC) and Wnt signaling pathways. The discovery of klotho has a great impact on aging research. The purpose of this review is to provide the recent progress and future directions of klotho research. Specifically, this review will cover: klotho and aging, structure and expression of the klotho gene, localization of klotho expression, source of circulating klotho, current understanding of klotho functions, and signaling pathways of klotho.
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                Author and article information

                Contributors
                hamedakbari6989@gmail.com
                +98 9131406916 , asadi_ka@yahoo.com , Gh_asadi@kmu.ac.ir
                haria256@yahoo.com
                sabafooladi@gmail.com
                sinavakili68@gmail.com
                masoomi@kmu.ac.ir , masoomidr@yahoo.com
                Journal
                BMC Cardiovasc Disord
                BMC Cardiovasc Disord
                BMC Cardiovascular Disorders
                BioMed Central (London )
                1471-2261
                14 December 2018
                14 December 2018
                2018
                : 18
                : 237
                Affiliations
                [1 ]ISNI 0000 0001 2092 9755, GRID grid.412105.3, Neuroscience Research Center, Institute of Neuropharmacology, , Kerman University of Medical Sciences, ; Kerman, Iran
                [2 ]ISNI 0000 0001 2092 9755, GRID grid.412105.3, Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, , Kerman University of Medical Sciences, ; Kerman, Iran
                [3 ]ISNI 0000 0001 2092 9755, GRID grid.412105.3, Department of Biochemistry, School of Medicine, , Kerman University of Medical Sciences, ; Kerman, Iran
                [4 ]ISNI 0000 0000 8819 4698, GRID grid.412571.4, Department of Immunology, School of Medicine, , Shiraz University of Medical Sciences, ; Shiraz, Iran
                [5 ]ISNI 0000 0000 8819 4698, GRID grid.412571.4, Bioinformatics and Computational Biology Research Center, , Shiraz University of Medical Sciences, ; Shiraz, Iran
                [6 ]ISNI 0000 0001 2092 9755, GRID grid.412105.3, Student Research Committee, School of Medicine, , Kerman University of Medical Sciences, ; Kerman, Iran
                [7 ]ISNI 0000 0000 8819 4698, GRID grid.412571.4, Biochemistry Department, School of Medicine, , Shiraz University of Medical Sciences, ; Shiraz, Iran
                [8 ]ISNI 0000 0001 2092 9755, GRID grid.412105.3, Cardiovascular Research Center, Institute of Basic and Clinical Physiology Sciences, , Kerman University of Medical Sciences, ; Kerman, Iran
                Author information
                http://orcid.org/0000-0002-9100-0756
                Article
                971
                10.1186/s12872-018-0971-5
                6295088
                30547758
                2dd83794-777e-4b0d-ae17-65ce5d2c4529
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 10 August 2018
                : 27 November 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100004621, Kerman University of Medical Sciences;
                Award ID: 292-93
                Award Recipient :
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2018

                Cardiovascular Medicine
                coronary artery disease,hypertension,klotho,polymorphism
                Cardiovascular Medicine
                coronary artery disease, hypertension, klotho, polymorphism

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