Association of Soluble α-Klotho and Klotho Polymorphisms (KL-VS and G-395A) with Essential Hypertension in Indian Population
Klotho, a novel anti-aging gene, is known to ameliorate aging phenotypes and extend lifespan. Recent studies have highlighted arterial aging as a risk factor for hypertension. Thus, Klotho appears to be a link between aging and cardiovascular diseases (CVD) including hypertension. KL-VS and G-395A polymorphisms of Klotho and its soluble levels have been associated with CVD incidence. We analyzed the prevalence of α-Klotho polymorphisms – KL-VS and G-395A and their influence on soluble α-Klotho levels in essential hypertension (EH) patients in Indian population. One-hundred-twelve EH patients and age, BMI-matched 103 normotensive controls were recruited. Soluble α-Klotho levels were measured by Enzyme-Linked-Immunosorbent-Assay. Genotyping of single nucleotide polymorphisms (SNP) was performed using TaqMan assays. Soluble α-Klotho levels in patients were significantly lower (26.9%,p=0.001) than controls. ROC curve analysis for soluble α-Klotho showed a cut-off of 580pg/ml with AUC 0.798(SE=0.031, 95%CI=0.737-0.859). Genotype distributions for both polymorphisms did not differ between the groups. Distribution of soluble α-Klotho levels in both groups did not vary across KL-VS genotypes. In patient group, GA and AA genotypes of G-395A polymorphism were associated with significantly lower (15.4%,p=0.014) soluble α-Klotho levels compared to GG genotype. Soluble α-Klotho levels were significantly lower in EH patients as compared to healthy normotensive individuals.
Beevers G, Lip GYH, O’Brien E. The pathophysiology of hypertension. BMJ 2001; 322(7291): 912-6.
Global Health Observatory (GHO) data, World Health Organization. Available from: http://www.who.int/gho/ncd/risk_factors/blood_pressure_prevalence_text/en/
Mills KT, Bundy JD, Kelly TN, Reed JE, Kearney PM, Reynolds K, et al. Global Disparities of Hypertension Prevalence and Control: A Systematic Analysis of Population-Based Studies from 90 Countries. Circulation 2016; 134(6):441-50.
Sun Z. Aging, Arterial Stiffness and Hypertension. Hypertension 2015; 65(2): 252-6.
Harvey A, Montezano AC, Touyz RM. Vascular biology of ageing—Implications in hypertension. J Mol Cell Cardiol 2015; 83: 112-21.
Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing.Nature 1997; 390(6655):45-51.
Zhou X, Chen K, Lei H, Sun Z. Klotho Gene Deficiency Causes Salt-Sensitive Hypertension via Monocyte Chemotactic Protein-1/CC Chemokine Receptor 2–Mediated Inflammation. J Am Soc Nephrol 2015; 26(1):121-32.
Shiraki-Iida T, Aizawa H, Matsumura Y, Sekine S, Iida A, Anazawa H, et al. Structure of the mouse klotho gene and its two transcripts encoding membrane and secreted protein. FEBS Lett 1998;424(1-2):6-10.
Zhang H, Shi Y, Ma F, Wang L, Hou Y, Zhu Z. Association of Klotho single nucleotide polymorphisms with cardiovascular diseases: a systematic review and meta-analysis. Int J Clin Exp Med 2017; 10(3): 5721-41.
Donate‐Correa J, Martín‐Núñez E, Martínez‐Sanz R, Muros‐de‐Fuentes M, Mora‐Fernández C, Pérez‐Delgado N, et al. Influence of Klotho gene polymorphisms on vascular gene expression and its relationship to cardiovascular disease. J Cell Mol Med 2016; 20(1):128-33.
Arking DE, Krebsova A, Macek M Sr, Macek M Jr, Arking A, Mian IS, et al. Association of human aging with a functional variant of klotho. Proc Natl Acad Sci U S A 2002; 99(2):856-61.
Freathy RM, Weedon MN, Melzer D, Shields B, Hitman GA, Walker M, et al. The functional “KL-VS” variant of KLOTHO is not associated with type 2 diabetes in 5028 UK Caucasians. BMC Med Genet 2006; 7:51.
Kato Y, Arakawa E, Kinoshita S, Shirai A, Furuya A, Yamano K, et al. Establishment of the anti-Klotho monoclonal antibodies and detection of Klotho protein in kidneys. Biochem Biophys Res Commun 2000; 267(2): 597-602.
Krajisnik T, Olauson H, Mirza MA, Hellman P, Akerström G, Westin G, et al. Parathyroid Klotho and FGF-receptor 1 expression decline with renal function in hyperparathyroid patients with chronic kidney disease and kidney transplant recipients. Kidney Int 2010;78(10):1024-32.
Li SA, Watanabe M, Yamada H, Nagai A, Kinuta M, Takei K. Immunohistochemical localization of Klotho protein in brain, kidney, and reproductive organs of mice. Cell Struct Funct 2004; 29(4):91-9.
Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, et al. Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 2006; 281(10):6120-3.
Imura A, Iwano A, Tohyama O, Tsuji Y, Nozaki K, Hashimoto N, et al. Secreted Klotho protein in sera and CSF: implication for post-translational cleavage in release of Klotho protein from cell membrane. FEBS Lett 2004; 565(1-3):143-7.
Gigante M, Lucarelli G, Divella C, Netti GS, Pontrelli P, Cafiero C, et al. Soluble Serum αKlotho Is a Potential Predictive Marker of Disease Progression in Clear Cell Renal Cell Carcinoma. Medicine 2015; 94(45): e1917.
Saito Y, Nakamura T, Ohyama Y, Suzuki T, Iida A, Shiraki-Iida T, et al. In vivo klotho gene delivery protects against endothelial dysfunction in multiple risk factor syndrome. Biochem Biophys Res Commun 2000; 276(2):767-72.
Semba RD, Cappola AR, Sun K, Bandinelli S, Dalal M, Crasto C, et al. Plasma klotho and cardiovascular disease in adults. J Am Geriatr Soc 2011; 59(9):1596-601.
Nabeshima Y. Discovery of alpha-Klotho unveiled new insights into calcium and phosphate homeostasis. Proc Jpn Acad Ser B Phys Biol Sci. 2009; 85(3):125-41.
Chang Q, Hoefs S, van der Kemp AW, Topala CN, Bindels RJ, Hoenderop JG. The beta-glucuronidase klotho hydrolyzes and activates the TRPV5 channel. Science 2005; 310(5747):490-3.
Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, et al. Suppression of aging in mice by the hormone Klotho. Science 2005; 309(5742):1829-33.
Wang Y, Sun Z. Klotho gene delivery prevents the progression of spontaneous hypertension and renal damage. Hypertension 2009; 54(4):810-7.
Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289(19):2560-72.
Su X-M, Yang W. Klotho protein lowered in elderly hypertension. Int J Clin Exp Med 2014; 7(8): 2347–50.
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(1):34-40.
Kitagawa M, Sugiyama H, Morinaga H, Inoue T, Takiue K, Ogawa A, et al. A decreased level of serum soluble Klotho is an independent biomarker associated with arterial stiffness in patients with chronic kidney disease. PLoS One 2013; 8(2):e56695.
Majumdar V, Nagaraja D, Christopher R. Association of the functional KL-VS variant of Klotho gene with early-onset ischemic stroke. Biochem Biophys Res Commun 2010; 403(3-4):412-6.
Sivaraman S, Halankar A, Shalia K. Klotho in chronic kidney disease in Indian population. International Journal of Current Research 2016;8(11):42477-85
Riancho JA, Valero C, Hernández JL, Ortiz F, Zarrabeitia A, Alonso MA, et al. Association of the F352V variant of the Klotho gene with bone mineral density. Biogerontology 2007; 8(2):121-7.
Invidia L, Salvioli S, Altilia S, Pierini M, Panourgia MP, Monti D, et al. The frequency of Klotho KL-VS polymorphism in a large Italian population, from young subjects to centenarians, suggests the presence of specific time windows for its effect. Biogerontology 2010; 11(1):67-73.
Nzietchueng R, El Shamieh S, Benachour H, Labat C, Herbeth B, Ndiaye NC, et al. Klotho KL-VS genotype is involved in blood pressure regulation. Clin Chim Acta 2011; 412(19-20):1773-7.
Kim HK, Jeong BH. Lack of functional KL-VS polymorphism of the KLOTHO gene in the Korean population. Genet Mol Biol 2016; 39(3):370-3.
Rhee EJ, Oh KW, Lee WY, Kim SY, Jung CH, Kim BJ, et al. The differential effects of age on the association of KLOTHO gene polymorphisms with coronary artery disease. Metabolism 2006; 55(10): 1344-51.
Arking DE, Becker DM, Yanek LR, Fallin D, Judge DP, Moy TF, et al. KLOTHO allele status and the risk of early-onset occult coronary artery disease. Am J Hum Genet. 2003; 72(5):1154-61.
Arking DE, Atzmon G, Arking A, Barzilai N, Dietz HC. Association between a functional variant of the KLOTHO gene and high-density lipoprotein cholesterol, blood pressure, stroke, and longevity. Circ Res 2005; 96(4):412-8.
Jo SH, Kim SG, Choi YJ, Joo NR, Cho GY, Choi SR, et al. KLOTHO gene polymorphism is associated with coronary artery stenosis but not with coronary calcification in a Korean population. Int Heart J 2009; 50(1): 23-32.
Kim Y, Jeong SJ, Lee HS, Kim EJ, Song YR, Kim SG, et al. Polymorphism in the promoter region of the klotho gene (G-395A) is associated with early dysfunction in vascular access in hemodialysis patients. Korean J Intern Med 2008; 23(4):201-7.
Wang HL, Xu Q, Wang Z, Zhang YH, Si LY, Li XJ, et al. 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(5-6):386-90. doi: 10.1016/j.cca.2009.12.004.
Imamura A, Okumura K, Ogawa Y, Murakami R, Torigoe M, Numaguchi Y, et al. Klotho gene polymorphism may be a genetic risk factor for atherosclerotic coronary artery disease but not for vasospastic angina in Japanese. Clin Chim Acta 2006; 371(1-2):66-70.
Rhee EJ, Oh KW, Yun EJ, Jung CH, Lee WY, Kim SW, et al. Relationship between polymorphisms G395A in promoter and C1818T in exon 4 of the KLOTHO gene with glucose metabolism and cardiovascular risk factors in Korean women. J Endocrinol Invest 2006; 29(7):613-8.
Kim Y, Kim JH, Nam YJ, Kong M, Kim YJ, Yu KH, et al. Klotho is a genetic risk factor for ischemic stroke caused by cardioembolism in Korean females. Neurosci Lett 2006; 407(3):189-94.
Gao LL, Ding X, Xie DM, Yang M, Dong BR. G-395A polymorphism in the promoter region of the KLOTHO gene and hypertension among elderly (90 years and older) Chinese individuals. Genet Mol Res 2015; 14(4):15444-52.
Luo L, Hao Q, Dong B, Yang M. The Klotho gene G-395A polymorphism and metabolic syndrome in very elderly people. BMC Geriatr 2016; 16:46.
Dąbrowska AM, Tarach JS. Soluble Klotho protein as a novel serum biomarker in patients with acromegaly. Arch Med Sci 2016; 12(1): 222-6. doi: 10.5114/aoms.2014.45050.
Cho NJ, Han DJ, Lee JH, Jang SH, Kang JS, Gil HW, et al. Soluble klotho as a marker of renal fibrosis and podocyte injuries in human kidneys. PLoS One 2018; 13(3): e0194617.
Pathare G, Shah VK, Shalia K. Emerging Roles of Klotho in Cardiovascular Diseases. J Cardiol Curr Res 2016; 6(6):00228.
Cai H, Lu R, Zhang M, Pang H, Zhu M, Zhang W, et al. Serum Soluble Klotho Level Is Associated with Abdominal Aortic Calcification in Patients on Maintenance Hemodialysis. Blood Purif 2015; 40(2):120-6.
Copyright (c) 2018 International Journal of Biomedical and Advance Research
This work is licensed under a Creative Commons Attribution 4.0 International License.
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (SeeThe Effect of Open Access).