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Song J, Li H, Fang X. The inflection point: α-Klotho levels and the risk of all-cause mortality. Front Endocrinol (Lausanne) 2025; 16:1405003. [PMID: 40134808 PMCID: PMC11932894 DOI: 10.3389/fendo.2025.1405003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 02/21/2025] [Indexed: 03/27/2025] Open
Abstract
Purpose The controversial nature of the association between α-Klotho and mortality risk in the general population warrants further investigation. This study aims to examine the correlation between circulating α-Klotho levels and the risk of all-cause mortality. Methods A sample size of 13,748 individuals from the NAHNES 2005-2016 cycles was included in this study. The effect of different α-Klotho levels (divided into quartiles) on survival was assessed using Kaplan-Meier (KM) curves. Cox proportional hazards models were used to analyze the linear relationship between log α-Klotho and the risk of all-cause mortality. Restricted cubic spline Cox proportional hazards regression model was used to analyze the non-linear relationship between log α-Klotho and risk of all-cause mortality. Threshold effect analysis was performed to determine the most favorable inflection point for log α-Klotho. Stratification and sensitivity analyses were performed to assess the robustness of the results. Results A total of 1,569 deaths were reported during the median follow-up period of 5.33 years (2.83-7.83 years). Among the log α-Klotho quartile groups, quartile 1 had the highest mortality rate compared to quartiles 2, 3, and 4. Multifactorial Cox regression analysis revealed a weak association between log α-Klotho and a 44% reduction in the risk of all-cause mortality (p=0.0473). We also found a U-shaped non-linear association between log α-Klotho and risk of all-cause mortality, with an optimal inflection point identified at 2.89 pg/mL. The stability of the U-shaped association between log α-Klotho and mortality risk was observed in various stratification and sensitivity analyses. Conclusion This study identified a U-shaped association between circulating α-Klotho levels and risk of all-cause mortality, with a notable inflection point at 2.89 pg/mL. Further investigation is warranted to fully elucidate the potential mechanisms underlying the association between α-Klotho and risk of all-cause mortality in the broader population.
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Affiliation(s)
- Jianling Song
- Department of Nephrology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Hong Li
- Department of Medical Records, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Xiangdong Fang
- Department of Nephrology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
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Li Y, Zhang Q, Bao H, Nie C. Association of Klotho Gene Polymorphism with Cerebral Infarction. J Med Biochem 2021; 41:204-210. [PMID: 35510207 PMCID: PMC9010054 DOI: 10.5937/jomb0-34196] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 11/01/2021] [Indexed: 11/02/2022] Open
Abstract
Background: We aimed to investigate the expression of Klotho gene in peripheral blood of patients with cerebral infarction (CI) and the association of its polymorphisms with the occurrence of CI.
Methods: A total of 60 CI patients (CI group) and 20 healthy people receiving physical examination (control group) were enrolled as the research subjects. The expression of Klotho gene in CI group and control group was determined using enzyme-linked immunosorbent assay kit. Single nucleotide polymorphisms (rs192031, rs200131 and rs102312) in the promoter region of the Klotho gene were typed via conformational difference gel electrophoresis. Besides, whether the distribution frequencies of Klotho genotypes conformed to Hardy-Weinberg equilibrium was evaluated by chi-square test. Meanwhile, the associations of Klotho alleles and gene polymorphisms with CI occurrence were analyzed.
Results: The protein expression level of Klotho in the peripheral blood was remarkably lower in patients in CI group than that in control group (P<0.05). Hardy-Weinberg equilibrium analysis revealed that Klotho gene polymorphisms (rs192031, rs200131 and rs102312) conformed to the genetic equilibrium distribution (P>0.05). Gene-based association analysis manifested that only rs192031 polymorphism and alleles were correlated with CI occurrence (P<0.05). Systolic blood pressure and high-density lipoprotein cholesterol were notably higher in CI patients with TT genotype of Klotho gene polymorphism rs192031 than those in control group (P<0.05). Furthermore, there were no associations of rs200131 and rs102312 polymorphisms and alleles with the occurrence of CI (P>0.05).
Conclusions: The expression level of Klotho is evidently reduced in the peripheral blood of CI patients. Rs192031 in the promoter region of the Klotho gene is associated with the occurrence of CI, while rs200131 and rs102312 have no relations with CI.
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Affiliation(s)
- Yu Li
- The Second Affiliated Hospital of Dalian Medical University, Department of Neurology, Dalian, China
| | - Qiang Zhang
- Dalian Shipyard Rehabilitation Hospital, Department of Rehabilitation Medicine, Dalian, China
| | - Haiping Bao
- The Second Affiliated Hospital of Dalian Medical University, Department of Neurology, Dalian, China
| | - Chen Nie
- The Second Affiliated Hospital of Dalian Medical University, Department of Neurology, Dalian, China
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Hutchings G, Kruszyna Ł, Nawrocki MJ, Strauss E, Bryl R, Spaczyńska J, Perek B, Jemielity M, Mozdziak P, Kempisty B, Nowicki M, Krasiński Z. Molecular Mechanisms Associated with ROS-Dependent Angiogenesis in Lower Extremity Artery Disease. Antioxidants (Basel) 2021; 10:735. [PMID: 34066926 PMCID: PMC8148529 DOI: 10.3390/antiox10050735] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/01/2021] [Accepted: 05/04/2021] [Indexed: 02/06/2023] Open
Abstract
Currently, atherosclerosis, which affects the vascular bed of all vital organs and tissues, is considered as a leading cause of death. Most commonly, atherosclerosis involves coronary and peripheral arteries, which results in acute (e.g., myocardial infarction, lower extremities ischemia) or chronic (persistent ischemia leading to severe heart failure) consequences. All of them have a marked unfavorable impact on the quality of life and are associated with increased mortality and morbidity in human populations. Lower extremity artery disease (LEAD, also defined as peripheral artery disease, PAD) refers to atherosclerotic occlusive disease of the lower extremities, where partial or complete obstruction of peripheral arteries is observed. Decreased perfusion can result in ischemic pain, non-healing wounds, and ischemic ulcers, and significantly reduce the quality of life. However, the progressive atherosclerotic changes cause stimulation of tissue response processes, like vessel wall remodeling and neovascularization. These mechanisms of adapting the vascular network to pathological conditions seem to play a key role in reducing the impact of the changes limiting the flow of blood. Neovascularization as a response to ischemia induces sprouting and expansion of the endothelium to repair and grow the vessels of the circulatory system. Neovascularization consists of three different biological processes: vasculogenesis, angiogenesis, and arteriogenesis. Both molecular and environmental factors that may affect the process of development and growth of blood vessels were analyzed. Particular attention was paid to the changes taking place during LEAD. It is important to consider the molecular mechanisms underpinning vessel growth. These mechanisms will also be examined in the context of diseases commonly affecting blood vessel function, or those treatable in part by manipulation of angiogenesis. Furthermore, it may be possible to induce the process of blood vessel development and growth to treat peripheral vascular disease and wound healing. Reactive oxygen species (ROS) play an important role in regulation of essential cellular signaling pathways such as cell differentiation, proliferation, migration and apoptosis. With regard to the repair processes taking place during diseases such as LEAD, prospective therapeutic methods have been described that could significantly improve the treatment of vessel diseases in the future. Summarizing, regenerative medicine holds the potential to transform the therapeutic methods in heart and vessel diseases treatment.
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Affiliation(s)
- Greg Hutchings
- The School of Medicine, Medical Sciences and Nutrition, Aberdeen University, Aberdeen AB25 2ZD, UK;
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.J.N.); (R.B.); (J.S.)
| | - Łukasz Kruszyna
- Department of Vascular and Endovascular Surgery, Angiology and Phlebology, Poznan University of Medical Sciences, 60-848 Poznan, Poland; (Ł.K.); (E.S.); (Z.K.)
| | - Mariusz J. Nawrocki
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.J.N.); (R.B.); (J.S.)
| | - Ewa Strauss
- Department of Vascular and Endovascular Surgery, Angiology and Phlebology, Poznan University of Medical Sciences, 60-848 Poznan, Poland; (Ł.K.); (E.S.); (Z.K.)
- Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland
| | - Rut Bryl
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.J.N.); (R.B.); (J.S.)
| | - Julia Spaczyńska
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.J.N.); (R.B.); (J.S.)
| | - Bartłomiej Perek
- Department of Cardiac Surgery and Transplantology, Poznan University of Medical Sciences, 61-848 Poznan, Poland; (B.P.); (M.J.)
| | - Marek Jemielity
- Department of Cardiac Surgery and Transplantology, Poznan University of Medical Sciences, 61-848 Poznan, Poland; (B.P.); (M.J.)
| | - Paul Mozdziak
- Physiology Graduate Program, North Carolina State University, Raleigh, NC 27695, USA;
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA;
| | - Bartosz Kempisty
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.J.N.); (R.B.); (J.S.)
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA;
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Toruń, 87-100 Toruń, Poland
| | - Michał Nowicki
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA;
| | - Zbigniew Krasiński
- Department of Vascular and Endovascular Surgery, Angiology and Phlebology, Poznan University of Medical Sciences, 60-848 Poznan, Poland; (Ł.K.); (E.S.); (Z.K.)
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Cambray S, Bermudez-Lopez M, Bozic M, Valdivielso JM. Association of a single nucleotide polymorphism combination pattern of the Klotho gene with non-cardiovascular death in patients with chronic kidney disease. Clin Kidney J 2021; 13:1017-1024. [PMID: 33391745 PMCID: PMC7769551 DOI: 10.1093/ckj/sfaa014] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 01/13/2020] [Indexed: 12/20/2022] Open
Abstract
Background Chronic kidney disease (CKD) is associated with an elevated risk of all-cause mortality, with cardiovascular death being extensively investigated. However, non-cardiovascular mortality represents the biggest percentage, showing an evident increase in recent years. Klotho is a gene highly expressed in the kidney, with a clear influence on lifespan. Low levels of Klotho have been linked to CKD progression and adverse outcomes. Single nucleotide polymorphisms (SNPs) of the Klotho gene have been associated with several diseases, but studies investigating the association of Klotho SNPs with non-cardiovascular death in CKD populations are lacking. Methods The main aim of this study was to assess whether 11 Klotho SNPs were associated with non-cardiovascular death in a subpopulation of the National Observatory of Atherosclerosis in Nephrology (NEFRONA) study (n = 2185 CKD patients). Results After 48 months of follow-up, 62 cardiovascular deaths and 108 non-cardiovascular deaths were recorded. We identified a high non-cardiovascular death risk combination of SNPs corresponding to individuals carrying the most frequent allele (G) at rs562020, the rare allele (C) at rs2283368 and homozygotes for the rare allele (G) at rs2320762 (rs562020 GG/AG + rs2283368 CC/CT + rs2320762 GG). Among the patients with the three SNPs genotyped (n = 1016), 75 (7.4%) showed this combination. Furthermore, 95 (9.3%) patients showed a low-risk combination carrying all the opposite genotypes (rs562020 AA + rs2283368 TT + rs2320762 GT/TT). All the other combinations [n = 846 (83.3%)] were considered as normal risk. Using competing risk regression analysis, we confirmed that the proposed combinations are independently associated with a higher {hazard ratio [HR] 3.28 [confidence interval (CI) 1.51–7.12]} and lower [HR 6 × 10−6 (95% CI 3.3 × 10−7–1.1 × 10−5)] risk of suffering a non-cardiovascular death in the CKD population of the NEFRONA cohort compared with patients with the normal-risk combination. Conclusions Determination of three SNPs of the Klotho gene could help in the prediction of non-cardiovascular death in CKD.
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Affiliation(s)
- Serafi Cambray
- Vascular and Renal Translational Research Group, Institute for Biomedical Research Dr. Pifarré Foundation, IRBLleida and RedinRen RETIC, ISCIII, Lleida, Spain
| | - Marcelino Bermudez-Lopez
- Vascular and Renal Translational Research Group, Institute for Biomedical Research Dr. Pifarré Foundation, IRBLleida and RedinRen RETIC, ISCIII, Lleida, Spain
| | - Milica Bozic
- Vascular and Renal Translational Research Group, Institute for Biomedical Research Dr. Pifarré Foundation, IRBLleida and RedinRen RETIC, ISCIII, Lleida, Spain
| | - Jose M Valdivielso
- Vascular and Renal Translational Research Group, Institute for Biomedical Research Dr. Pifarré Foundation, IRBLleida and RedinRen RETIC, ISCIII, Lleida, Spain
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Solache-Berrocal G, Rolle-Sóñora V, Martín-Fernández N, Cambray S, Valdivielso JM, Rodríguez I. CYP24A1 and KL polymorphisms are associated with the extent of vascular calcification but do not improve prediction of cardiovascular events. Nephrol Dial Transplant 2020; 36:2076-2083. [PMID: 33219692 PMCID: PMC8577629 DOI: 10.1093/ndt/gfaa240] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Indexed: 11/25/2022] Open
Abstract
Background Novel ways of determining cardiovascular risk are needed as a consequence of population ageing and the increased prevalence of chronic kidney disease (CKD), both of which favour vascular calcification. Since the formation of arterial calcium deposits has a genetic component, single nucleotide polymorphisms (SNPs) could predict cardiovascular events. Methods A selection of 1927 CKD patients and controls recruited by the NEFRONA study were genotyped for 60 SNPs from 22 candidate genes. A calcium score was calculated from the echogenicity of arterial atherosclerotic plaques and the presence of cardiovascular events during a 4-year period was recorded. Association of SNPs with the calcium score was identified by multiple linear regression models and their capacity to predict events was assessed by means of Cox proportional hazards regression and receiver operating characteristics curves. Results Two variants, rs2296241 of CYP24A1 and rs495392 of KL, were associated with the calcium score. Despite this, only heterozygotes for rs495392 had a lower risk of suffering an event compared with homozygotes for the major allele {hazard ratio (HR) 0.67 [95% confidence interval (CI) 0.48−0.93]}. Of note, the calcium score was associated with an increased risk of cardiovascular events [HR 1.71 (95% CI 1.35−2.17)]. The addition of the rs495392 genotype to classical cardiovascular risk factors did not increase the predictive power [area under the curve (AUC) 71.3 (95% CI 61.1−85.5) versus 71.4 (61.5−81.4)]. Conclusions Polymorphisms of CYP24A1 and KL are associated with the extent of calcification but do not predict cardiovascular events. However, the echogenic determination of the extent of calcium deposits seems a promising non-irradiating method for the scoring of calcification in high-risk populations.
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Affiliation(s)
- Guillermo Solache-Berrocal
- Cardiac Pathology Research Group, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain.,Renal Research Network (REDinREN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Valeria Rolle-Sóñora
- Biostatistics and Epidemiology Platform, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
| | | | - Serafí Cambray
- Vascular and Renal Translational Research Group, Biomedical Research Institute IRBLleida, Lleida, Spain
| | - José Manuel Valdivielso
- Renal Research Network (REDinREN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.,Vascular and Renal Translational Research Group, Biomedical Research Institute IRBLleida, Lleida, Spain
| | - Isabel Rodríguez
- Cardiac Pathology Research Group, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain.,Renal Research Network (REDinREN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
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Sachdeva A, Gouge J, Kontovounisios C, Nikolaou S, Ashworth A, Lim K, Chong I. Klotho and the Treatment of Human Malignancies. Cancers (Basel) 2020; 12:cancers12061665. [PMID: 32585905 PMCID: PMC7352559 DOI: 10.3390/cancers12061665] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 06/16/2020] [Indexed: 12/24/2022] Open
Abstract
Klotho was first discovered as an anti-ageing protein linked to a number of age-related disease processes, including cardiovascular, renal, musculoskeletal, and neurodegenerative conditions. Emerging research has also demonstrated a potential therapeutic role for Klotho in cancer biology, which is perhaps unsurprising given that cancer and ageing share similar molecular hallmarks. In addition to functioning as a tumour suppressor in numerous solid tumours and haematological malignancies, Klotho represents a candidate therapeutic target for patients with these diseases, the majority of whom have limited treatment options. Here, we examine contemporary evidence evaluating the anti-neoplastic effects of Klotho and describe the modulation of downstream oncogenic signalling pathways, including Wnt/β-catenin, FGF, IGF1, PIK3K/AKT, TGFβ, and the Unfolded Protein Response. We also discuss possible approaches to developing therapeutic Klotho and consider technological advances that may facilitate the delivery of Klotho through gene therapy.
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Affiliation(s)
- Aishani Sachdeva
- The Royal Marsden NHS Foundation Trust, London SW6 6JJ, UK; (A.S.); (C.K.)
- Department of Surgery and Cancer, Chelsea and Westminster Hospital, London SW10 9NH, UK;
| | - Jerome Gouge
- Institute of Structural and Molecular Biology, Birkbeck College, London WC1E 7HX, UK;
| | - Christos Kontovounisios
- The Royal Marsden NHS Foundation Trust, London SW6 6JJ, UK; (A.S.); (C.K.)
- Department of Surgery and Cancer, Chelsea and Westminster Hospital, London SW10 9NH, UK;
| | - Stella Nikolaou
- Department of Surgery and Cancer, Chelsea and Westminster Hospital, London SW10 9NH, UK;
| | - Alan Ashworth
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA;
| | - Kenneth Lim
- Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202-5181, USA;
| | - Irene Chong
- The Royal Marsden NHS Foundation Trust, London SW6 6JJ, UK; (A.S.); (C.K.)
- The Institute of Cancer Research, London SW3 6JB, UK
- Correspondence:
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KLOTHO polymorphisms and age-related outcomes in community-dwelling older subjects: The São Paulo Ageing & Health (SPAH) Study. Sci Rep 2020; 10:8574. [PMID: 32444684 PMCID: PMC7244540 DOI: 10.1038/s41598-020-65441-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 05/05/2020] [Indexed: 02/06/2023] Open
Abstract
Defective KLOTHO gene expression in mice led to a syndrome resembling human ageing. This study evaluated three KLOTHO polymorphisms, namely G395A, C1818T, and C370S, in an elderly population (mean age of 73 years) and their associations with ageing-related outcomes (cardiovascular events, kidney function, osteoporosis, sarcopenia) and mortality. Estimated glomerular filtration rates (eGFR) was lower in subjects with 1818TT (P = 0.047) and 370SS (P = 0.046) genotypes. The 1818TT genotype (P = 0.006) and 1818T allele were associated with higher frequency of myocardial infarction (MI) (CC:1.7% vs. CT + TT:7.0%; P = 0.002). The 370SS genotype was associated with lower stroke frequency (P = 0.001). MI (OR 3.35 [95% CI: 1.29–8.74]) and stroke (OR 3.64 [95% CI: 1.48–8.97]) were associated with mortality. Regarding MI, logistic regression showed 1818T allele was a risk factor for death-related MI (OR 4.29 [95% CI: 1.60–11.52]; P = 0.003), while 370C was protective (OR 0.03 [95% CI: 0.01–0.08]; P < 0.001). Regarding stroke, the 395A and 370C alleles were protective factors (respectively: OR 0.28 [95% CI: 0.20–0.80]; P = 0.018; OR 0.10 [95% CI: 0.05–0.18]; P < 0.001). This is the first study to determine potential associations between common ageing-related outcomes/mortality and KLOTHO polymorphisms. The 1818T allele was a risk factor for MI-related death. The 395A and 370C alleles were protective factors for stroke-related death in elderly from community.
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Zhu Z, Xia W, Cui Y, Zeng F, Li Y, Yang Z, Hequn C. Klotho gene polymorphisms are associated with healthy aging and longevity: Evidence from a meta-analysis. Mech Ageing Dev 2019; 178:33-40. [PMID: 30633899 DOI: 10.1016/j.mad.2018.12.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 12/10/2018] [Accepted: 12/30/2018] [Indexed: 01/11/2023]
Abstract
Klotho gene polymorphisms have been implicated in healthy aging, but inconsistences in findings from previous case-control studies have raised concerns regarding the associations between KLOTHO gene polymorphisms and susceptibility to aging-related diseases and longevity. Hence, this meta-analysis was performed. We assessed the associations between two polymorphisms (G-395 A/rs1207568 and F352 V/rs9536314) and five parameters (urolithiasis, cognitive impairment, cardiovascular disease, cancer, and longevity) by calculating pooled odds ratios with 95% confidence intervals. According to the pooled results, the G allele of the G-395 A polymorphism conferred a significantly higher risk of urolithiasis; G-395 A was related to the susceptibility to cardiovascular disease under allele, dominant, and recessive models. There was no significant association between the G-395 A polymorphism and cognitive impairment among the elderly. The F allele of the F352 V polymorphism protected against breast and ovarian cancer susceptibility. Interestingly, based on the results of the subgroup analysis, the F352 V polymorphism was associated with the overall risk of neoplasms in BRCA1 mutation carriers but not in BRCA2 mutation carriers. Moreover, the F allele played a protective role in determining human longevity. In conclusion, Klotho G-395 A polymorphisms were associated with urolithiasis and cardiovascular disease but not with cognitive impairment. Additionally, Klotho F352 V polymorphisms were associated with cancers and longevity.
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Affiliation(s)
- Zewu Zhu
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Weiping Xia
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yu Cui
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Feng Zeng
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yang Li
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Zhongqing Yang
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Chen Hequn
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
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Association of Klotho gene polymorphism with hypertension and coronary artery disease in an Iranian population. BMC Cardiovasc Disord 2018; 18:237. [PMID: 30547758 PMCID: PMC6295088 DOI: 10.1186/s12872-018-0971-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Accepted: 11/27/2018] [Indexed: 01/18/2023] Open
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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Effects of Klotho polymorphisms on Preeclampsia risk in a case-control study. Pregnancy Hypertens 2018; 13:95-99. [DOI: 10.1016/j.preghy.2018.04.016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Revised: 04/17/2018] [Accepted: 04/22/2018] [Indexed: 12/15/2022]
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Santos I, Arango M, Pérez A. Utilidad del factor de crecimiento fibroblástico 23 en la prevención de enfermedades cardiovasculares en pacientes con enfermedad renal crónica. REVISTA COLOMBIANA DE CARDIOLOGÍA 2016. [DOI: 10.1016/j.rccar.2015.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
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Donate-Correa J, Martín-Núñez E, Martínez-Sanz R, Muros-de-Fuentes M, Mora-Fernández C, Pérez-Delgado N, Navarro-González JF. Influence of Klotho gene polymorphisms on vascular gene expression and its relationship to cardiovascular disease. J Cell Mol Med 2016; 20:128-133. [PMID: 26538295 PMCID: PMC4717853 DOI: 10.1111/jcmm.12710] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Accepted: 09/01/2015] [Indexed: 12/13/2022] Open
Abstract
Klotho protein has been associated with beneficial effects that contribute to the maintenance of cardiovascular health. Diverse studies suggest that alterations in the levels of this molecule may be associated with pathophysiological abnormalities that result in increased cardiovascular risk. The primary aim of this proof-of-concept study was to analyse the existence of a potential link between Klotho gene polymorphisms and the expression level of this gene in the vascular wall, and additionally with the incidence of cardiovascular disease and cardiovascular risk factors. Our results indicate that the variant G-395A, located in the promoter region, influences Klotho gene vascular expression and is associated with the incidence of diabetes. Similarly, the exonic variant KL-VS was associated with the incidence of atherosclerotic vascular disease and coronary artery disease. Moreover, vascular expression levels of Klotho were related with the incidence of diabetes mellitus and coronary artery disease. These findings, which need to be confirmed in larger studies, suggest a potential role of Klotho in the pathogenesis of vascular damage.
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Affiliation(s)
- Javier Donate-Correa
- Research Unit, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | - Ernesto Martín-Núñez
- Research Unit, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | - Rafael Martínez-Sanz
- Cardiovascular Surgery Service, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
| | - Mercedes Muros-de-Fuentes
- Clinical Biochemistry Service, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | - Carmen Mora-Fernández
- Research Unit, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | - Nayra Pérez-Delgado
- Clinical Biochemistry Service, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | - Juan F Navarro-González
- Research Unit, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
- Nephrology Service, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
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Mengel-From J, Soerensen M, Nygaard M, McGue M, Christensen K, Christiansen L. Genetic Variants in KLOTHO Associate With Cognitive Function in the Oldest Old Group. J Gerontol A Biol Sci Med Sci 2015; 71:1151-9. [PMID: 26405063 DOI: 10.1093/gerona/glv163] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Accepted: 08/28/2015] [Indexed: 12/19/2022] Open
Abstract
Decline in cognitive abilities is a major concern in aging individuals. A potential important factor for functioning of the central nervous system in late-life stages is the KLOTHO (KL) gene. KL is expressed in various organs including the brain and is involved in multiple biological processes, for example, growth factor signaling. In the present study, 19 tagging gene variants in KL were studied in relation to 2 measures of cognitive function, a 5-item cognitive composite score and the Mini Mental State Examination, in 1,480 Danes 92-100 years of age. We found that heterozygotes for the previously reported KL-VS had poorer cognitive function than noncarriers. Two other variants positioned in the 5' end of the gene, rs398655 and rs562020, were associated with better cognitive function independently of KL-VS, and the common haplotype AG was associated with poorer cognition, consistently across two cognitive measures in two cohort strata. The haplotype effect was stronger than that of KL-VS. Two variants, rs2283368 and rs9526984, were the only variants significantly associated with cognitive decline over 7 years. We discuss an age-dependent effect of KL and the possibility that multiple gene variants in KL are important for cognitive function among the oldest old participants.
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Affiliation(s)
- Jonas Mengel-From
- The Danish Aging Research Center and The Danish Twin Registry, Epidemiology, Biostatistics and Biodemography Unit, Department of Public Health, University of Southern Denmark, Odense, Denmark. Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
| | - Mette Soerensen
- The Danish Aging Research Center and The Danish Twin Registry, Epidemiology, Biostatistics and Biodemography Unit, Department of Public Health, University of Southern Denmark, Odense, Denmark. Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
| | - Marianne Nygaard
- The Danish Aging Research Center and The Danish Twin Registry, Epidemiology, Biostatistics and Biodemography Unit, Department of Public Health, University of Southern Denmark, Odense, Denmark. Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
| | - Matt McGue
- The Danish Aging Research Center and The Danish Twin Registry, Epidemiology, Biostatistics and Biodemography Unit, Department of Public Health, University of Southern Denmark, Odense, Denmark. Department of Psychology, University of Minnesota, Minneapolis
| | - Kaare Christensen
- The Danish Aging Research Center and The Danish Twin Registry, Epidemiology, Biostatistics and Biodemography Unit, Department of Public Health, University of Southern Denmark, Odense, Denmark. Department of Clinical Genetics, Odense University Hospital, Odense, Denmark. Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark
| | - Lene Christiansen
- The Danish Aging Research Center and The Danish Twin Registry, Epidemiology, Biostatistics and Biodemography Unit, Department of Public Health, University of Southern Denmark, Odense, Denmark
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Ding HY, Ma HX. Significant roles of anti-aging protein klotho and fibroblast growth factor23 in cardiovascular disease. J Geriatr Cardiol 2015; 12:439-47. [PMID: 26347327 PMCID: PMC4554784 DOI: 10.11909/j.issn.1671-5411.2015.04.017] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2014] [Revised: 11/06/2014] [Accepted: 02/26/2015] [Indexed: 02/07/2023] Open
Abstract
The klotho gene has been identified as an aging suppressor that encodes a protein involved in cardiovascular disease (CVD). The inactivation of the klotho gene causes serious systemic disorders resembling human aging, such as atherosclerosis, diffuse vascular calcification and shortened life span. Klotho has been demonstrated to ameliorate vascular endothelial dysfunction and delay vascular calcification. Furthermore, klotho gene polymorphisms in the human are associated with various cardiovascular events. Recent experiments show that klotho may reduce transient receptor potential canonical6 (TRPC6) channels, resulting in protecting the heart from hypertrophy and systolic dysfunction. Fibroblast growth factor23 (FGF23) is a bone-derived hormone that plays an important role in the regulation of phosphate and vitamin D metabolism. FGF23 accelerates urinary phosphate excretion and suppresses 1,25-dihydroxy vitaminD3 (1,25(OH)2D3) synthesis in the presence of FGF receptor1 (FGFR1) and its co-receptor klotho, principally in the kidney. The hormonal affects of circulating klotho protein and FGF23 on vascular and heart have contributed to an understanding of their roles in the pathophysiology of arterial stiffness and left ventricular hypertrophy. Klotho and FGF23 appear to play a critical role in the pathogenesis of vascular disease, and may represent a novel potential therapeutic strategy for clinical intervention.
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Affiliation(s)
- Hong-Ying Ding
- Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hou-Xun Ma
- Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Martín-Núñez E, Donate-Correa J, Muros-de-Fuentes M, Mora-Fernández C, Navarro-González JF. Implications of Klotho in vascular health and disease. World J Cardiol 2014; 6:1262-1269. [PMID: 25548616 PMCID: PMC4278161 DOI: 10.4330/wjc.v6.i12.1262] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Revised: 09/13/2014] [Accepted: 10/10/2014] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular disease (CVD) is a prevalent condition in general population and the first cause of death overall. Klotho, a pleiotropic protein related to longevity that acts as a co-receptor of the fibroblast growth factor 23, has been proposed as a key regulator of the development of CVD. In the few clinical studies made, it has been observed a relationship between low levels of soluble Klotho and the occurrence and severity of CVD, as well as a reduction of cardiovascular risk when they are high. Also, different polymorphisms of human Klotho gene have been related to the incidence of cardiovascular events. Moreover, several experimental studies indicate that this protein acts in the maintenance of vascular homeostasis. Klotho improves endothelial dysfunction through promotion of NO production and mediates anti-inflammatory and anti-aging effects such as suppression of adhesion molecules expression, attenuation of nuclear factor-kappa B or inhibition of Wnt signaling. Furthermore, this protein is related to the attenuation of vascular calcification as well as prevention of cardiac hypertrophy. The expression of this protein in the vascular wall implies a new scenario for the treatment of vascular disorders. The purpose of this review is to provide an overview of the relationship between the Klotho protein and CVD, in addition to its role in the maintenance of functional vascular integrity.
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Fortier C, Mac-Way F, De Serres SA, Marquis K, Douville P, Desmeules S, Larivière R, Agharazii M. Active vitamin D and accelerated progression of aortic stiffness in hemodialysis patients: a longitudinal observational study. Am J Hypertens 2014; 27:1346-54. [PMID: 24695980 DOI: 10.1093/ajh/hpu057] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND We hypothesized that high-dose active vitamin D therapy in the form of alphacalcidol (α-calcidol), used to treat secondary hyperparathyroidism in chronic kidney disease, could lead to vascular calcification and accelerated progression of aortic stiffness. METHODS We conducted an observational study in 85 patients on chronic hemodialysis, among which 70 were taking a weekly dose of α-calcidol of <2 µg and 15 were taking a weekly dose of ≥2 µg (pharmacological dose). Parathyroid hormone, 25-hydroxyvitamin D, fibroblast growth factor 23, and α-klotho were determined. Aortic stiffness was assessed by determination of carotid-femoral pulse wave velocity (cf-PWV) at baseline and after a mean follow-up of 1.2 years. A multivariable regression model was used to evaluate the impact of pharmacological dose of α-calcidol on the progression of aortic stiffness. RESULTS At baseline, clinical, biological, and hemodynamic parameters were similar. At follow-up, cf-PWV increased more in patients with pharmacological dose of α-calcidol (0.583±2.291 m/s vs. 1.948±1.475 m/s; P = 0.04). After adjustment for changes in mean blood pressure and duration of follow-up, pharmacological dose of α-calcidol was associated with a higher rate of progression of cf-PWV (0.969 m/s; 95% confidence interval = 0.111-1.827; P = 0.03), and this association persisted after further adjustments for parameters of mineral metabolism. CONCLUSIONS In this study, pharmacological dose of α-calcidol was associated with accelerated progression of aortic stiffness. This study suggest that the vascular safety of active vitamin D posology may need to be specifically addressed in the treatment of chronic kidney disease-related bone mineral disorder.
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Affiliation(s)
- Catherine Fortier
- CHU de Québec Research Center, L'Hôtel-Dieu de Québec Hospital, Québec, QC, Canada; Division of Nephrology, Faculty of Medicine, Université Laval, Québec, QC, Canada
| | - Fabrice Mac-Way
- CHU de Québec Research Center, L'Hôtel-Dieu de Québec Hospital, Québec, QC, Canada; Division of Nephrology, Faculty of Medicine, Université Laval, Québec, QC, Canada
| | - Sacha A De Serres
- CHU de Québec Research Center, L'Hôtel-Dieu de Québec Hospital, Québec, QC, Canada; Division of Nephrology, Faculty of Medicine, Université Laval, Québec, QC, Canada
| | - Karine Marquis
- CHU de Québec Research Center, L'Hôtel-Dieu de Québec Hospital, Québec, QC, Canada
| | - Pierre Douville
- Département de biologie moléculaire, de biochimie médicale et de pathologie, Faculty of Medicine, Université Laval, Québec, QC, Canada; Département de biologie médicale, CHU de Québec- L'Hôtel-Dieu de Québec Hospital, Québec, QC, Canada
| | - Simon Desmeules
- CHU de Québec Research Center, L'Hôtel-Dieu de Québec Hospital, Québec, QC, Canada; Division of Nephrology, Faculty of Medicine, Université Laval, Québec, QC, Canada
| | - Richard Larivière
- CHU de Québec Research Center, L'Hôtel-Dieu de Québec Hospital, Québec, QC, Canada; Division of Nephrology, Faculty of Medicine, Université Laval, Québec, QC, Canada
| | - Mohsen Agharazii
- CHU de Québec Research Center, L'Hôtel-Dieu de Québec Hospital, Québec, QC, Canada; Division of Nephrology, Faculty of Medicine, Université Laval, Québec, QC, Canada;
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Kestenbaum B, Sachs MC, Hoofnagle AN, Siscovick DS, Ix JH, Robinson-Cohen C, Lima JAC, Polak JF, Blondon M, Ruzinski J, Rock D, de Boer IH. Fibroblast growth factor-23 and cardiovascular disease in the general population: the Multi-Ethnic Study of Atherosclerosis. Circ Heart Fail 2014; 7:409-17. [PMID: 24668259 DOI: 10.1161/circheartfailure.113.000952] [Citation(s) in RCA: 120] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Fibroblast growth factor-23 (FGF-23) is a phosphate regulatory hormone that directly stimulates left ventricular hypertrophy in experimental models. The role of FGF-23 in cardiovascular disease development in the general population is unclear. We tested associations of FGF-23 with major subclinical and clinical cardiovascular disease outcomes in a large prospective cohort. METHODS AND RESULTS We evaluated 6547 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) who were initially free of cardiovascular disease. We measured serum FGF-23 using the Kainos immunoassay. The MESA measured left ventricular mass by MRI, coronary calcium by computed tomography, and carotid intima-media thickness by ultrasound. The MESA adjudicated incident heart failure, coronary heart disease, and stroke by medical record review. After adjustment, the highest FGF-23 quartile was associated with an estimated 2.4-g greater left ventricular mass (95% confidence interval, 0.4-4.5 greater) and a 26% greater odds of higher coronary calcium scores (95% confidence interval, 9%-46% greater) compared with the lowest quartile. During 7.5-year follow-up, each 20-pg/mL higher FGF-23 concentration was associated with a 19% greater risk of heart failure (95% confidence interval, 3%-37% greater) and a 14% greater risk of coronary heart disease (95% confidence interval, 1%-28% greater). FGF-23 was not associated with carotid intima-media thickness or stroke. CONCLUSIONS Higher serum FGF-23 concentrations are associated with subclinical cardiac disease and with new heart failure and coronary disease events, but not with carotid intima-media thickness or stroke. FGF-23 may be a novel cardiovascular risk factor in the general population.
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Affiliation(s)
- Bryan Kestenbaum
- From the Kidney Research Institute, Department of Medicine, Division of Nephrology (B.K., M.C.S., C.R.-C., J.R., D.R., I.H.d.B.), Department of Laboratory Medicine (A.N.H.), Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology (D.S.S.), and Department of Epidemiology (M.B.), University of Washington, Seattle; Division of Nephrology, Department of Medicine, University of California at San Diego (J.H.I.); Nephrology Section, Veterans Affairs San Diego Healthcare System, CA (J.H.I.); and Division of Preventive Medicine, Department of Family and Preventive Medicine, University of California at San Diego (J.H.I.); Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (J.A.C.L.); and Department of Radiology, Tufts-New England Medical Center, Boston, MA (J.F.P.).
| | - Michael C Sachs
- From the Kidney Research Institute, Department of Medicine, Division of Nephrology (B.K., M.C.S., C.R.-C., J.R., D.R., I.H.d.B.), Department of Laboratory Medicine (A.N.H.), Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology (D.S.S.), and Department of Epidemiology (M.B.), University of Washington, Seattle; Division of Nephrology, Department of Medicine, University of California at San Diego (J.H.I.); Nephrology Section, Veterans Affairs San Diego Healthcare System, CA (J.H.I.); and Division of Preventive Medicine, Department of Family and Preventive Medicine, University of California at San Diego (J.H.I.); Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (J.A.C.L.); and Department of Radiology, Tufts-New England Medical Center, Boston, MA (J.F.P.)
| | - Andy N Hoofnagle
- From the Kidney Research Institute, Department of Medicine, Division of Nephrology (B.K., M.C.S., C.R.-C., J.R., D.R., I.H.d.B.), Department of Laboratory Medicine (A.N.H.), Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology (D.S.S.), and Department of Epidemiology (M.B.), University of Washington, Seattle; Division of Nephrology, Department of Medicine, University of California at San Diego (J.H.I.); Nephrology Section, Veterans Affairs San Diego Healthcare System, CA (J.H.I.); and Division of Preventive Medicine, Department of Family and Preventive Medicine, University of California at San Diego (J.H.I.); Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (J.A.C.L.); and Department of Radiology, Tufts-New England Medical Center, Boston, MA (J.F.P.)
| | - David S Siscovick
- From the Kidney Research Institute, Department of Medicine, Division of Nephrology (B.K., M.C.S., C.R.-C., J.R., D.R., I.H.d.B.), Department of Laboratory Medicine (A.N.H.), Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology (D.S.S.), and Department of Epidemiology (M.B.), University of Washington, Seattle; Division of Nephrology, Department of Medicine, University of California at San Diego (J.H.I.); Nephrology Section, Veterans Affairs San Diego Healthcare System, CA (J.H.I.); and Division of Preventive Medicine, Department of Family and Preventive Medicine, University of California at San Diego (J.H.I.); Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (J.A.C.L.); and Department of Radiology, Tufts-New England Medical Center, Boston, MA (J.F.P.)
| | - Joachim H Ix
- From the Kidney Research Institute, Department of Medicine, Division of Nephrology (B.K., M.C.S., C.R.-C., J.R., D.R., I.H.d.B.), Department of Laboratory Medicine (A.N.H.), Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology (D.S.S.), and Department of Epidemiology (M.B.), University of Washington, Seattle; Division of Nephrology, Department of Medicine, University of California at San Diego (J.H.I.); Nephrology Section, Veterans Affairs San Diego Healthcare System, CA (J.H.I.); and Division of Preventive Medicine, Department of Family and Preventive Medicine, University of California at San Diego (J.H.I.); Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (J.A.C.L.); and Department of Radiology, Tufts-New England Medical Center, Boston, MA (J.F.P.)
| | - Cassianne Robinson-Cohen
- From the Kidney Research Institute, Department of Medicine, Division of Nephrology (B.K., M.C.S., C.R.-C., J.R., D.R., I.H.d.B.), Department of Laboratory Medicine (A.N.H.), Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology (D.S.S.), and Department of Epidemiology (M.B.), University of Washington, Seattle; Division of Nephrology, Department of Medicine, University of California at San Diego (J.H.I.); Nephrology Section, Veterans Affairs San Diego Healthcare System, CA (J.H.I.); and Division of Preventive Medicine, Department of Family and Preventive Medicine, University of California at San Diego (J.H.I.); Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (J.A.C.L.); and Department of Radiology, Tufts-New England Medical Center, Boston, MA (J.F.P.)
| | - Joao A C Lima
- From the Kidney Research Institute, Department of Medicine, Division of Nephrology (B.K., M.C.S., C.R.-C., J.R., D.R., I.H.d.B.), Department of Laboratory Medicine (A.N.H.), Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology (D.S.S.), and Department of Epidemiology (M.B.), University of Washington, Seattle; Division of Nephrology, Department of Medicine, University of California at San Diego (J.H.I.); Nephrology Section, Veterans Affairs San Diego Healthcare System, CA (J.H.I.); and Division of Preventive Medicine, Department of Family and Preventive Medicine, University of California at San Diego (J.H.I.); Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (J.A.C.L.); and Department of Radiology, Tufts-New England Medical Center, Boston, MA (J.F.P.)
| | - Joseph F Polak
- From the Kidney Research Institute, Department of Medicine, Division of Nephrology (B.K., M.C.S., C.R.-C., J.R., D.R., I.H.d.B.), Department of Laboratory Medicine (A.N.H.), Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology (D.S.S.), and Department of Epidemiology (M.B.), University of Washington, Seattle; Division of Nephrology, Department of Medicine, University of California at San Diego (J.H.I.); Nephrology Section, Veterans Affairs San Diego Healthcare System, CA (J.H.I.); and Division of Preventive Medicine, Department of Family and Preventive Medicine, University of California at San Diego (J.H.I.); Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (J.A.C.L.); and Department of Radiology, Tufts-New England Medical Center, Boston, MA (J.F.P.)
| | - Marc Blondon
- From the Kidney Research Institute, Department of Medicine, Division of Nephrology (B.K., M.C.S., C.R.-C., J.R., D.R., I.H.d.B.), Department of Laboratory Medicine (A.N.H.), Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology (D.S.S.), and Department of Epidemiology (M.B.), University of Washington, Seattle; Division of Nephrology, Department of Medicine, University of California at San Diego (J.H.I.); Nephrology Section, Veterans Affairs San Diego Healthcare System, CA (J.H.I.); and Division of Preventive Medicine, Department of Family and Preventive Medicine, University of California at San Diego (J.H.I.); Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (J.A.C.L.); and Department of Radiology, Tufts-New England Medical Center, Boston, MA (J.F.P.)
| | - John Ruzinski
- From the Kidney Research Institute, Department of Medicine, Division of Nephrology (B.K., M.C.S., C.R.-C., J.R., D.R., I.H.d.B.), Department of Laboratory Medicine (A.N.H.), Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology (D.S.S.), and Department of Epidemiology (M.B.), University of Washington, Seattle; Division of Nephrology, Department of Medicine, University of California at San Diego (J.H.I.); Nephrology Section, Veterans Affairs San Diego Healthcare System, CA (J.H.I.); and Division of Preventive Medicine, Department of Family and Preventive Medicine, University of California at San Diego (J.H.I.); Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (J.A.C.L.); and Department of Radiology, Tufts-New England Medical Center, Boston, MA (J.F.P.)
| | - Denise Rock
- From the Kidney Research Institute, Department of Medicine, Division of Nephrology (B.K., M.C.S., C.R.-C., J.R., D.R., I.H.d.B.), Department of Laboratory Medicine (A.N.H.), Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology (D.S.S.), and Department of Epidemiology (M.B.), University of Washington, Seattle; Division of Nephrology, Department of Medicine, University of California at San Diego (J.H.I.); Nephrology Section, Veterans Affairs San Diego Healthcare System, CA (J.H.I.); and Division of Preventive Medicine, Department of Family and Preventive Medicine, University of California at San Diego (J.H.I.); Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (J.A.C.L.); and Department of Radiology, Tufts-New England Medical Center, Boston, MA (J.F.P.)
| | - Ian H de Boer
- From the Kidney Research Institute, Department of Medicine, Division of Nephrology (B.K., M.C.S., C.R.-C., J.R., D.R., I.H.d.B.), Department of Laboratory Medicine (A.N.H.), Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology (D.S.S.), and Department of Epidemiology (M.B.), University of Washington, Seattle; Division of Nephrology, Department of Medicine, University of California at San Diego (J.H.I.); Nephrology Section, Veterans Affairs San Diego Healthcare System, CA (J.H.I.); and Division of Preventive Medicine, Department of Family and Preventive Medicine, University of California at San Diego (J.H.I.); Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (J.A.C.L.); and Department of Radiology, Tufts-New England Medical Center, Boston, MA (J.F.P.)
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Navarro-González JF, Donate-Correa J, Muros de Fuentes M, Pérez-Hernández H, Martínez-Sanz R, Mora-Fernández C. Reduced Klotho is associated with the presence and severity of coronary artery disease. Heart 2014; 100:34-40. [PMID: 24165855 DOI: 10.1136/heartjnl-2013-304746] [Citation(s) in RCA: 114] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
OBJECTIVE Klotho is involved in vascular health. We aimed to analyse in a cross-sectional study the relationship between Klotho and human coronary artery disease (CAD). METHODS The study included 371 subjects who underwent coronary angiography and 70 patients who underwent elective cardiac surgery recruited between May 2008 and June 2009. The presence and severity (stenosis index) of CAD, cardiovascular risk factors, Klotho gene expression in the thoracic aorta, and serum soluble Klotho concentrations were evaluated. RESULTS The soluble Klotho concentration was lower (p<0.001) in patients with significant CAD (n=233). The maximal stenosis observed in every epicardial artery and the stenosis severity index was significantly lower in patients within the higher soluble Klotho concentrations (p<0.0001). Multiple regression analysis showed that serum Klotho concentrations were inverse and significantly associated with CAD (adjusted R(2)=0.67, p<0.001). Multivariate logistic regression analysis showed that risk factors for significant CAD included age, diabetes, smoking and inflammation, whereas high serum Klotho values were associated with a lower risk for CAD. Lower mRNA expression level of Klotho was observed in 46 patients with significant CAD, as compared with subjects without CAD (p=0.01). Logistic regression analysis showed that high Klotho gene expression was independently associated with lower risk for CAD. CONCLUSIONS Patients with significant CAD present lower soluble concentrations of Klotho, as well as reduced levels of Klotho gene expression in the vascular wall. Reduced serum Klotho concentrations and decreased vascular Klotho gene expression were associated with the presence and severity of CAD independently of established cardiovascular risk factors.
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Affiliation(s)
- Juan F Navarro-González
- Research Division, Hospital Universitario Nuestra Señora de Candelaria, , Santa Cruz de Tenerife, Spain
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Donate-Correa J, Muros-de-Fuentes M, Mora-Fernández C, Navarro-González JF. [Fibroblast growth factor 23/Klotho system in the context of cardiovascular damage]. Med Clin (Barc) 2013; 140:420-423. [PMID: 23337450 DOI: 10.1016/j.medcli.2012.11.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2012] [Accepted: 11/08/2012] [Indexed: 11/16/2022]
Affiliation(s)
- Javier Donate-Correa
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Tenerife, España
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Donate-Correa J, Mora-Fernández C, Martínez-Sanz R, Muros-de-Fuentes M, Pérez H, Meneses-Pérez B, Cazaña-Pérez V, Navarro-González JF. Expression of FGF23/KLOTHO system in human vascular tissue. Int J Cardiol 2013; 165:179-183. [PMID: 21945708 DOI: 10.1016/j.ijcard.2011.08.850] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2011] [Revised: 08/26/2011] [Accepted: 08/30/2011] [Indexed: 12/26/2022]
Abstract
BACKGROUND Fibroblast growth factor (FGF)-23 levels have been associated with impaired vasoreactivity, increased arterial stiffness, and cardiovascular morbi-mortality, whereas a protective function of KLOTHO against endothelial dysfunction has been reported. Since expression of the FGF23-KLOTHO system in human vascular tissue remains unproved, we aimed to study the expression of FGF23, FGF receptors (FGFR) and KLOTHO in human aorta. In addition, we analyzed the FGF23-KLOTHO expression in occlusive coronary thrombi. METHODS Thoracic aorta specimens from 44 patients underwent elective cardiac surgery, and thrombus material from 2 patients with acute coronary syndrome (ACS), were tested for FGF23-KLOTHO system expression. RESULTS Expression of KLOTHO (mean expression level 4.85 ± 5.43, arbitrary units) and two of the three cognate FGFR (FGFR-1 and -3) were detected and confirmed by RT-PCR, sequencing and qRT-PCR. KLOTHO expression was confirmed within occlusive coronary thrombi from patients with ACS. However, expression of FGF23 and FGFR4 was not observed. We also detected the aortic expression of membrane-anchored A Desintegrin and Metalloproteinases (ADAM)-17, the enzyme responsible for the shedding of KLOTHO from the cell surface, and the anti-inflammatory cytokine interleukin (IL)-10. Interestingly, in aortic samples there was a direct association between KLOTHO mRNA levels and those of ADAM-17 and IL-10 (r = 0.54, P<0.001; r = 0.51, P<0.01, respectively). CONCLUSIONS Human vascular tissue expresses members of the FGF23-KLOTHO system, indicating that it can be a direct target organ for FGF23. In addition, KLOTHO expression is also detected in occlusive coronary thrombi. These findings suggest a putative role of FGF23-KLOTHO axis in human vascular pathophysiology and cardiovascular disease.
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Affiliation(s)
- Javier Donate-Correa
- Research Unit, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
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Ko GJ, Lee EA, Jeon US, Pyo HJ, Chin HJ, Chae DW, Kim S, Kwon YJ. The association of Klotho polymorphism with disease progression and mortality in IgA nephropathy. Kidney Blood Press Res 2012; 36:191-9. [PMID: 23147162 DOI: 10.1159/000343408] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/07/2012] [Indexed: 12/17/2022] Open
Abstract
BACKGROUNDS IgA nephropathy (IgAN) is the most common primary glomerulonephritis causing end stage renal disease (ESRD), and vasculopathy is known to involve disease progression. Klotho, a gene related to aging, has been reported to play a role in atherosclerosis and endothelial dysfunction. We investigated whether klotho gene polymorphism affect clinical course of IgAN. METHODS The data registered for PREMIER study which enrolled the patients with biopsy proven IgAN were analyzed. Two single nucleotide polymorphisms for klotho gene, G395A of promoter region and C1818T of exon 4, were examined, and investigated the association klotho genotypes with the progression of IgAN and patient survival. RESULTS Clinical data from 973 patients confirmed about survival were analyzed. The allele frequency was 0.830 and 0.170 for allele G and A, and 0.816 and 0.184 for allele C and T, which were complied with Hardy-Weinberg equilibrium (p=0.996 and 0.531 respectively). Death was observed more frequently in A-allele carriers of G395A polymorphism (0.7 vs. 2.6 %, GG vs. GA+AA, p=0.022). Renal survival in Kaplan-Meier survival curve was also worse in same group (p=0.04). CONCLUSION Klotho gene polymorphism was associated with patient survival and disease progression of IgAN.
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Affiliation(s)
- Gang Jee Ko
- Korea University Medical school, Department of Internal Medicine, Seoul, Korea
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Abstract
A disproportionate expansion of white adipose tissue and abnormal recruitment of adipogenic precursor cells can not only lead to obesity but also impair glucose metabolism, which are both common causes of insulin resistance and diabetes mellitus. The development of novel and effective therapeutic strategies to slow the progression of obesity, diabetes mellitus and their associated complications will require improved understanding of adipogenesis and glucose metabolism. Klotho might have a role in adipocyte maturation and systemic glucose metabolism. Klotho increases adipocyte differentiation in vitro, and mice that lack Klotho activity are lean owing to reduced white adipose tissue accumulation; moreover, mice that lack the Kl gene (which encodes Klotho) are resistant to obesity induced by a high-fat diet. Knockout of Kl in leptin-deficient Lep(ob/ob) mice reduces obesity and increases insulin sensitivity, which lowers blood glucose levels. Energy metabolism might also be influenced by Klotho. However, further studies are needed to explore the possibility that Klotho could be a novel therapeutic target to reduce obesity and related complications, and to determine whether and how Klotho might influence the regulation and function of a related protein, β-Klotho, which is also involved in energy metabolism.
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Affiliation(s)
- M Shawkat Razzaque
- Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Research and Education Building, Room 304, 190 Longwood Avenue, Boston, MA 02115, USA.
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Abstract
The absence of Klotho (KL) from mice causes the development of disorders associated with human aging and decreased longevity, whereas increased expression prolongs lifespan. With age, KL protein levels decrease, and keeping levels consistent may promote healthier aging and be disease-modifying. Using the KL promoter to drive expression of luciferase, we conducted a high-throughput screen to identify compounds that activate KL transcription. Hits were identified as compounds that elevated luciferase expression at least 30%. Following validation for dose-dependent activation and lack of cytotoxicity, hit compounds were evaluated further in vitro by incubation with opossum kidney and Z310 rat choroid plexus cells, which express KL endogenously. All compounds elevated KL protein compared with control. To determine whether increased protein resulted in an in vitro functional change, we assayed FGF23 (fibroblast growth factor 23) signalling. Compounds G-I augmented ERK (extracellular-signal-regulated kinase) phosphorylation in FGFR (fibroblast growth factor receptor)-transfected cells, whereas co-transfection with KL siRNA (small interfering RNA) blocked the effect. These compounds will be useful tools to allow insight into the mechanisms of KL regulation. Further optimization will provide pharmacological tools for in vivo studies of KL.
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Abstract
Artery calcification reflects an admixture of factors such as ectopic osteochondral differentiation with primary host pathological conditions. We review how genetic factors, as identified by human genome-wide association studies, and incomplete correlations with various mouse studies, including knockout and strain analyses, fit into "pieces of the puzzle" in intimal calcification in human atherosclerosis, and artery tunica media calcification in aging, diabetes mellitus, and chronic kidney disease. We also describe in sharp contrast how ENPP1, CD73, and ABCC6 serve as "cogs in a wheel" of arterial calcification. Specifically, each is a minor component in the function of a much larger network of factors that exert balanced effects to promote and suppress arterial calcification. For the network to normally suppress spontaneous arterial calcification, the "cogs" ENPP1, CD73, and ABCC6 must be present and in working order. Monogenic ENPP1, CD73, and ABCC6 deficiencies each drive a molecular pathophysiology of closely related but phenotypically different diseases (generalized arterial calcification of infancy (GACI), pseudoxanthoma elasticum (PXE) and arterial calcification caused by CD73 deficiency (ACDC)), in which premature onset arterial calcification is a prominent but not the sole feature.
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Affiliation(s)
- Frank Rutsch
- Department of General Pediatrics, Münster University Children's Hospital, Albert-Schweitzer-Campus 1, D-48149 Münster, Germany.
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Kim WJ, Oh YM, Kim TH, Lee JH, Kim EK, Lee JH, Lee SM, Shin TR, Yoon HI, Lim SY, Lee SD. Lack of Association between theKlothoGene and COPD. Tuberc Respir Dis (Seoul) 2011. [DOI: 10.4046/trd.2011.71.4.254] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Affiliation(s)
- Woo Jin Kim
- Department of Internal Medicine, Kangwon National University, Chuncheon, Korea
| | - Yeon-Mok Oh
- Department of Pulmonary and Critical Care Medicine, and Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Tae-Hyung Kim
- Division of Pulmonology, Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea
| | - Ji-Hyun Lee
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
| | - Eun-Kyung Kim
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
| | - Jin Hwa Lee
- Department of Internal Medicine, Ewha Womans University Mokdong Hospital, Ewha Womans University College of Medicine, Seoul, Korea
| | - Sang-Min Lee
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Clinical Research Institute, Seoul National University Hospital, Lung Institute, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea
| | - Tae Rim Shin
- Department of Internal Medicine, Kangnam Sacred Heart Hospital, Hanllym University College of Medicine, Seoul, Korea
| | - Ho Il Yoon
- Respiratory Center, Seoul National University Bundang Hospital, Department of Internal Medicine, Seoul National University College of Medicine, Seongnam, Korea
| | - Seong-Yong Lim
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sang Do Lee
- Department of Pulmonary and Critical Care Medicine, and Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Wang HL, Xu Q, Wang Z, Zhang YH, Si LY, Li XJ, Yang QH, Xiao H. A potential regulatory single nucleotide polymorphism in the promoter of the Klotho gene may be associated with essential hypertension in the Chinese Han population. Clin Chim Acta 2010; 411:386-90. [DOI: 10.1016/j.cca.2009.12.004] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2009] [Revised: 11/21/2009] [Accepted: 12/04/2009] [Indexed: 02/02/2023]
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