KLOTHO and VDR Gene Polymorphisms and Clinical Phenotype in Chronic Kidney Disease Patients

  • Kuyaş Hekimler Öztürk Süleyman Demirel Üniversitesi Tıp Fakültesi Tıbbi Genetik AD.
  • Saliha Handan Yıldız
  • Necat İmirzalıoğlu
  • Serap Demir
  • Tülay Köken
  • Memnune Sena Ulu
Keywords: Chronic Kidney Disease, KLOTHO, VDR, Polymorphism

Abstract

Objective: With an increasing incidence and prevalence, Chronic Kidney Disease (CKD), is a bad prognosed and high cost common public health problem. KLOTHO gene which is defined as aging suppressor gene is highly expressed in kidneys. Decreased Vitamin D receptor (VDR) activation plays a role in CKD morbidity and mortality. The aim of this study is to examine the association between CKD and polymorphisms of KLOTHO (G395A and C1818T) and VDR (ApaI and TaqI) genes as well as investigating the effects of these polymorphisms on different clinical phenotype of the disease. Methods: In 104 cases diagnosed to have CKD and 104 healthy controls, KLOTHO gene G395A, C1818T polymorphisms were studied by DNA sequence analysis and VDR gene ApaI and TaqI polymorphisms were studied by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) method. Results: No statistical difference was found in genotype and allele frequencies for KLOTHO gene G395A, C1818T and VDR gene TaqI polymorphisms between the groups. VDR gene ApaI polymorphism was found to be significantly higher in the patient group than in the control group (p=0.018). Conclusion: Our results demonstrated that VDR gene ApaI polymorphism may be related to CKD and may be a risk factor for the development of the disease.

References

Akpolat T, Utaş C, Süleymanlar G. Nefroloji el kitabı. 3. Baskı, İstanbul, Turkey: Nobel Tıp Kitabevi; 2000.

Yoshida T, Kato K, Fujimaki T, Yokoi K, Oguri M, Watanabe S, et al. Association of genetic variants with chronic kidney disease in Japanese individuals. Clin J Am Soc Nephrol 2009, 24:883-90.

Kuro-O M. Klotho. Eur J Physiol 2010;459:333-43.

Shimoyama Y, Nishio K, Hamajima N, Niwa T. KLOTHO gene polymorphisms G-395A and C1818T are associated with lipid and glucose metabolism, bone mineral density and systolic blood pressure in Japanese healthy subjects. Clin Chim Acta 2009;406:134-8.

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;55:1344-1351.

Kawano K, Ogata N, Chiano M, Molloy H, Kleyn P, Spector TD, et al. Klotho gene polymorphisms associated with bone density of aged postmenopausal women. J Bone Miner Res 2002;17:1744-51.

Valdivielso JM, Fernandez E. Vitamin D receptor polymorphisms and diseases. Clin Chim Acta 2006;371:1-12.

Martin RJ, Mcknight AJ, Patterson CC, Sadlier DM, Maxwell AP, Warren 3/UK GoKinD Study Group. A rare haplotype of the vitamin D receptor gene is protective against diabetic nephropathy. Nephrol Dial Transplant 2010;25:497-503.

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;411:386-90.

Dilmec F, Uzer E, Akkafa F, Kose E, Van Kuilenburg AB. Detection of VDR gene ApaI and TaqI polymorphisms in patients with type 2 diabetes mellitus using PCR-RFLP method in a Turkish population. J Diabetes Complication 2010;24:186-91.

Skrabic V, Zemunik T, Situm M, Terzic J. Vitamin D receptor polymorphism and susceptibility to type 1 diabetes in the Dalmatian population. Diabetes Res Clin Pract 2003;59:31-5.

Langdahl BL, Gravholt CH, Brixen K, Eriksen EF. Polymorphisms in the vitamin D receptor gene and bone mass, bone turnover and osteoporotic fractures. Eur J Clin Invest 2000;30:608-17.

Oh JY, Barrett-Connor E. Association between vitamin D receptor polymorphism and type 2 diabetes or metabolic syndrome in community-dwelling older adults: The Rancho Bernardo Study. Metabolism 2002;51:356-9.

Buyru N, Tezol A, Yosunkaya-Fenerci E, Dalay N. Vitamin D receptor gene polymorphisms in breast cancer. Exp Mol Med 2004;35:550-5.

Lurie G, Wilkens LR, Thompson PJ, McDuffie KE, Carney ME, Terada KY, et al. Vitamin D receptor gene polymorphisms and epithelial ovarian cancer risk. Cancer Epidemiol Biomarkers Prev 2007;16:2566-71.

Yokoyama K, Shigematsu T, Tsukada T, Ogura Y, Takemoto F, Hara S, et al. Apa I polymorphism in the vitamin D receptor gene may affect the parathyroid response in Japanese with end-stage renal disease. Kidney Int 1998;53:454-8.

Ko GJ, Lee EA, Jeon US, Pyo HJ, Chin HJ, Chae DW, et al. The association of Klotho polymorphism with disease progression and mortality in IgA nephropathy. Kidney Blood Press Res 2012;36:191-9.

Lee EY, Kim SS, Lee JS, Kim IJ, Song SH, Cha SK, et al. Soluble α-klotho as a novel biomarker in the early stage of nephropathy in patients with type 2 diabetes. PLoS One 2014;9:e102984.

Sezer S, Külah E, Özdemir FN. Hipertansiyonun renal komplikasyonlar ve böbrek hastalığının progresyonundaki rolü. Turk Neph Dial Transpl 2003;12:67-73.

Süleymanlar G, Serdengeçti K, Erek E. Türkiye’de son dönem böbrek yetmezliğin etyolojisi. Turkiye Klinikleri J Int Med Sci 2005;1:1-8.

Razzaque MS. Role of Klotho in energy metabolism. Nat Rev Endocrinol 2012;8:579-87.

Semba RD, Cappola AR, Sun K, Bandinelli S, Dalal M, Crasto C, et al. Plasma klotho and mortality risk in older community-dwelling adults. J Gerontol A Biol Sci Med Sci 2011;66:794-800.

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;309:1829-33.

Williams S, Malatesta K, Norris K. Vitamin D and Chronic Kidney Disease. Ethn Dis 2009;19 (4 Suppl 5):5–8-11.

Swapna N, Mohana Vamsi U, Usha G, Padma T. Risk conferred by FokI polymorphism of vitamin D receptor (VDR) gene for essential hypertension. Indian J Hum Genet 2011;17:201-6.

Vural HC, Maltas E. RT-qPCR assay on the vitamin D receptor gene in type 2 diabetes and hypertension patients in Turkey. Genet Mol Res 2012;11:582-90.

Malecki MT, Frey J, Moczulski D, Klupa T, Kozek E, Sieradzki J. Vitamin D receptor gene polymorphisms and association with Type 2 diabetes mellitus in a Polish population. Exp Clin Endocrinol Diabetes 2003;111:505-9.

Ye WZ, Reis AF, Dubois-Laforgue D, Bellanné-Chantelot C, Timsit J, Velho G. Vitamin D receptor gene polymorphisms are associated with obesity in Type 2 diabetic subjects with early age of onset. Eur J Endocrinol 2001;145:181-6.

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;23:201-7.

Rhee EJ, Oh KW, Yun EJ, Jung CH, Lee WY, Kim SW, et al. Relationship between polymorphisms G-395A 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;29:613-8.

Published
2018-12-20
Section
Original Research