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The KL genetic polymorphisms Associated with type 2 diabetes Mellitus

Abstract

Growing number of research studies have shown that an anti-ageing gene Klotho (KL) is closely associated with Type 2 Diabetes Mellitus (T2DM). In this study, the association is genetically analyzed with single nucleotide polymorphism (SNP) of KL found in T2DM case of an Asian cohort. KL SNP information was obtained from a big database of the Korean Association Resource (KARE) from which 20 KL SNPs were available. Statistical analyses were conducted based on the 3 genetic models, such as additive, dominant, and recessive. Of the 20 KL SNPs, 12 SNPs were found to be significantly associated with T2DM in both of additive and dominant models. Odds ratios of the KL SNPs indicate increased susceptibility to T2DM in additive and dominant models. Significant association of KL with T2DM was further analyzed using imputed KL SNPs from HapMap reference data of the Eastern population. The statistically significant KL SNPs including the imputed SNPs distributed evenly over the KL gene area. The results in this study suggest klotho is a major player in the development of T2DM and the KL SNPs found in the case could be a risk marker of T2DM in the cohort.

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References

  1. Matschinsky FM. Glucokinase, glucose homeostasis, and diabetes mellitus. Curr Diab Rep. 2005;5(3):171–6.

    CAS  Article  Google Scholar 

  2. Li C, Yang Y, Liu X, Li Z, Liu H, Tan Q. Glucose metabolism-related gene polymorphisms as the risk predictors of type 2 diabetes. Diabetol Metab Syndr. 2020;12(1):97.

    CAS  Article  Google Scholar 

  3. Kuro OM. The Klotho proteins in health and disease. Nat Rev Nephrol. 2019;15(1):27–44.

    Article  Google Scholar 

  4. 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.

    CAS  Article  Google Scholar 

  5. 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.

    CAS  Article  Google Scholar 

  6. Ito S, Fujimori T, Hayashizaki Y, Nabeshima Y. Identification of a novel mouse membrane-bound family 1 glycosidase-like protein, which carries an atypical active site structure. Biochim Biophys Acta. 2002;1576(3):341–5.

    CAS  Article  Google Scholar 

  7. Ito S, Kinoshita S, Shiraishi N, Nakagawa S, Sekine S, Fujimori T, et al. Molecular cloning and expression analyses of mouse betaklotho, which encodes a novel Klotho family protein. Mech Dev. 2000;98(1–2):115–9.

    CAS  Article  Google Scholar 

  8. 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.

    CAS  Article  Google Scholar 

  9. Hu MC, Shiizaki K, Kuro-o M, Moe OW. Fibroblast growth factor 23 and Klotho: physiology and pathophysiology of an endocrine network of mineral metabolism. Annu Rev Physiol. 2013;75:503–33.

    CAS  Article  Google Scholar 

  10. Yahata K, Mori K, Arai H, Koide S, Ogawa Y, Mukoyama M, et al. Molecular cloning and expression of a novel klotho-related protein. J Mol Med (Berl). 2000;78(7):389–94.

    CAS  Article  Google Scholar 

  11. Fon Tacer K, Bookout AL, Ding X, Kurosu H, John GB, Wang L, et al. Research resource: Comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol Endocrinol. 2010;24(10):2050–64.

    Article  Google Scholar 

  12. Kurosu H, Choi M, Ogawa Y, Dickson AS, Goetz R, Eliseenkova AV, et al. Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J Biol Chem. 2007;282(37):26687–95.

    CAS  Article  Google Scholar 

  13. Kharitonenkov A. FGFs and metabolism. Curr Opin Pharmacol. 2009;9(6):805–10.

    CAS  Article  Google Scholar 

  14. Hu MC, Shi M, Zhang J, Quinones H, Griffith C, Kuro-o M, et al. Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol. 2011;22(1):124–36.

    CAS  Article  Google Scholar 

  15. Kanbay M, Demiray A, Afsar B, Covic A, Tapoi L, Ureche C, et al. Role of Klotho in the Development of Essential Hypertension. Hypertension. 2021;77(3):740–50.

    CAS  Article  Google Scholar 

  16. Chen NX, Moe SM. Arterial calcification in diabetes. Curr Diab Rep. 2003;3(1):28–32.

    Article  Google Scholar 

  17. 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.

    CAS  Article  Google Scholar 

  18. Bloch L, Sineshchekova O, Reichenbach D, Reiss K, Saftig P, Kuro-o M, et al. Klotho is a substrate for alpha-, beta- and gamma-secretase. FEBS Lett. 2009;583(19):3221–4.

    CAS  Article  Google Scholar 

  19. Xu Y, Sun Z. Molecular basis of Klotho: from gene to function in aging. Endocr Rev. 2015;36(2):174–93.

    CAS  Article  Google Scholar 

  20. Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, Nabeshima Y. Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochem Biophys Res Commun. 1998;242(3):626–30.

    CAS  Article  Google Scholar 

  21. Dalton G, An SW, Al-Juboori SI, Nischan N, Yoon J, Dobrinskikh E, et al. Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling. Proc Natl Acad Sci U S A. 2017;114(4):752–7.

    CAS  Article  Google Scholar 

  22. Chen L, Magliano DJ, Zimmet PZ. The worldwide epidemiology of type 2 diabetes mellitus–present and future perspectives. Nat Rev Endocrinol. 2011;8(4):228–36.

    Article  Google Scholar 

  23. Takenaka T, Kobori H, Miyazaki T, Suzuki H, Nishiyama A, Ishii N, et al. Klotho protein supplementation reduces blood pressure and renal hypertrophy in db/db mice, a model of type 2 diabetes. Acta Physiol (Oxf). 2019;225(2):e13190.

    Article  Google Scholar 

  24. Lim SC, Liu JJ, Subramaniam T, Sum CF. Elevated circulating alpha-klotho by angiotensin II receptor blocker losartan is associated with reduction of albuminuria in type 2 diabetic patients. J Renin Angiotensin Aldosterone Syst. 2014;15(4):487–90.

    Article  Google Scholar 

  25. Karalliedde J, Maltese G, Hill B, Viberti G, Gnudi L. Effect of renin-angiotensin system blockade on soluble Klotho in patients with type 2 diabetes, systolic hypertension, and albuminuria. Clin J Am Soc Nephrol. 2013;8(11):1899–905.

    CAS  Article  Google Scholar 

  26. Cho YS, Go MJ, Kim YJ, Heo JY, Oh JH, Ban HJ, et al. A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat Genet. 2009;41(5):527–34.

    CAS  Article  Google Scholar 

  27. Ahmed A, Khan TE, Yasmeen T, Awan S, Islam N. Metabolic syndrome in type 2 diabetes: comparison of WHO, modified ATPIII & IDF criteria. J Pak Med Assoc. 2012;62(6):569–74.

    PubMed  Google Scholar 

  28. Rabbee N, Speed TP. A genotype calling algorithm for affymetrix SNP arrays. Bioinformatics. 2006;22(1):7–12.

    CAS  Article  Google Scholar 

  29. Li Y, Willer CJ, Ding J, Scheet P, Abecasis GR. MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol. 2010;34(8):816–34.

    Article  Google Scholar 

  30. International HapMap C. Int HapMap Project Nat. 2003;426(6968):789–96.

    Google Scholar 

  31. Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, Gliedt TP, et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics. 2010;26(18):2336–7.

    CAS  Article  Google Scholar 

  32. Shin JY. Trends in the prevalence and management of diabetes in Korea:2007–2017. Epidemiol Health. 2019;41:e2019029.

    Article  Google Scholar 

  33. Mahajan A, Taliun D, Thurner M, Robertson NR, Torres JM, Rayner NW, et al. Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps. Nat Genet. 2018;50(11):1505–13.

    CAS  Article  Google Scholar 

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Contributions

Conception: H.S.J. and D.J.J., Data Acquisition and analysis: H.S.J. and D.J.J., Drafting the work: H.S.J. and D.J.J., Final approval of the manuscript: H.S.J. and D.J.J.

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Correspondence to Dongju Jung.

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The authors have no competing interests to declare that are relevant to the content of this article.

The study was conducted with bioresources from the National Biobank of Bank of Korea, the Centers for Disease Control and Prevention, Republic of Korea (KBN-2019–004), and analyzed after approval by the Institutional Review Board (IRB) at Hoseo University (IRB approval no.:1041231–150811-BR-034-03).

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Jin, HS., Jung, D. The KL genetic polymorphisms Associated with type 2 diabetes Mellitus. Ind J Clin Biochem (2022). https://doi.org/10.1007/s12291-022-01057-5

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  • DOI: https://doi.org/10.1007/s12291-022-01057-5

Keywords

  • Diabetes Mellitus Type 2
  • Polymorphism, single nucleotide
  • Cohort studies