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Association of resistin (rs3745367) and urotensin II (rs228648 and rs2890565) gene polymorphisms with risk of type 2 diabetes mellitus in Indian population

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Abstract

Insulin resistance may become the most powerful predictor of future development of type 2 diabetes mellitus (T2DM) and a therapeutic target for the treatment of the same. Both Resistin, an adipose derived peptide hormone and Urotensin II a potent vasoconstrictor, are reported to be involved in the development of insulin resistance and T2DM but the results remain contradictory. Therefore, investigations were carried out to study the association of T2DM and single nucleotide polymorphism (SNP) in Resistin (RETN) gene at rs3745367 (+ 299 G > A) and Urotensin II (UTS2) gene at rs228648 (+ 143 G > A) and rs2890565 (+ 3836 C > T) in a North Indian population. Method: The present case–control study, conducted from August 2017 to July 2020, involved 168 T2DM patients and 102 healthy controls. SNPs rs3745367, rs228648 and rs2890565 were amplified from genomic DNA in the studied samples by polymerase chain reaction (PCR) using specific primers. The amplified products were genotyped by restriction fragment length polymorphism (RFLP) using particular restriction endonucleases. Clinical parameters viz. glycosylated haemoglobin (HbA1c), fasting blood glucose (FBG), high density lipoprotein cholesterol (HDL-C), triglycerides (TG), total cholesterol (CHL) and fasting insulin were determined by enzymatic methods. Result and conclusion: A statistically significant association between T2DM and RETN gene at SNP rs3745367 (p = 0.001) and UTS2 gene at SNP rs2890565 (p = 0.001) was observed. In RETN gene SNP rs3745367, insulin and homeostasis model assessment of insulin resistance (HOMA-IR) were found to be higher in GA + AA combined genotype than in GG genotype for T2DM subjects. Regression analysis revealed that SNP rs2890565 and HOMA-IR were independently associated with the risk of development of T2DM when three SNPs were taken as independent variable adjusted for clinical variables. Among four haplotypes, A/T was found associated with increased risk of T2DM as determined for rs228648 and rs2890565 of UTS2 gene. It can be concluded from these results that polymorphism at rs3745367 of RETN gene and at rs2890565 of UTS2 gene are associated with risk of T2DM in North Indian population.

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References

  1. Adeghate E, Schattner P, Dunn E (2006) An update on the etiology and epidemiology of diabetes mellitus. Ann NY Acad Sci 1084(1):1–29

    Article  Google Scholar 

  2. IDF (2018) International Diabetes Federation Diabetes Atlas, 8th edn. IDF

  3. Kubaszek A, Pihlajamäki J, Komarovski V et al (2003) Promoter polymorphisms of the TNF-α (G-308A) and IL-6 (C-174G) genes predict the conversion from impaired glucose tolerance to type 2 diabetes: the Finnish Diabetes Prevention Study. Diabetes 52(7):1872–1876

  4. Solaleh E, Arash HN, Azam N et al (2009) Promoter resistin gene polymorphism in patients with type 2 diabetes and its influence on concerned metabolic phenotypes. J Diabetes Metab Disord 8:17

  5. Arababadi MK, Mirzaei MR, Sajadi SM et al (2012) Interleukin (IL)-10 gene polymorphisms are associated with type 2 diabetes with and without nephropathy: a study of patients from the southeast region of Iran. Inflammation 35(3):797–802

  6. Saxena M, Srivastava N, Banerjee M (2013) Association of IL-6, TNF-α and IL-10 gene polymorphisms with type 2 diabetes mellitus. Mol Bio Rep 40(11):6271–6279

    Article  CAS  Google Scholar 

  7. Wang H, Chu WS, Hemphill C et al (2002) Human resistin gene: molecular scanning and evaluation of association with insulin sensitivity and type 2 diabetes in Caucasians. J Clin Endo Meta 87(6):2520–2524

  8. Patel L, Buckels AC, Kinghorn IJ et al (2003) Resistin is expressed in human macrophages and directly regulated by PPARγ activators. Bio Bio Res Comm 300(2):472–476

    Article  CAS  Google Scholar 

  9. Jung HS, Park KH, Cho YM et al (2006) Resistin is secreted from macrophages in atheromas and promotes atherosclerosis. Cardio Res 69(1):76–85

    Article  CAS  Google Scholar 

  10. Sadashiv ST, Paul BN, Kumar S et al (2012) Over expression of resistin in adipose tissue of the obese induces insulin resistance. World J Diabetes 3(7):135

    Article  CAS  Google Scholar 

  11. Lee TS, Lin CY, Tsai JY et al (2009) Resistin increases lipid accumulation by affecting class A scavenger receptor, CD36 and ATP-binding cassette transporter-A1 in macrophages. Life Sci 84(3–4):97–104

  12. Ikeda Y, Tsuchiya H, Hama S et al (2013) Resistin affects lipid metabolism during adipocyte maturation of 3T3‐L1 cells. FEBS J 280(22):5884–5895

  13. Wen F, Zhang H, Bao C et al (2015) Resistin increases ectopic deposition of lipids through miR-696 in C2C12 cells. Biochem Genet 53(4–6):63–71

  14. McTernan PG, Fisher FM, Valsamakis G et al (2003) Resistin and type 2 diabetes: regulation of resistin expression by insulin and rosiglitazone and the effects of recombinant resistin on lipid and glucose metabolism in human differentiated adipocytes. J Clin Endo Meta 88(12):6098–6106

  15. Degawa-Yamauchi M, Bovenkerk JE, Juliar BE et al (2003) Serum resistin (FIZZ3) protein is increased in obese humans. J Clin Endo Meta 88(11):5452–5455

  16. Lee JH, Chan JL, Yiannakouris N et al (2003) Circulating resistin levels are not associated with obesity or insulin resistance in humans and are not regulated by fasting or leptin administration: cross-sectional and interventional studies in normal, insulin-resistant, and diabetic subjects. J Clin Endo Meta 88(10):4848–4856

  17. Utzschneider KM, Carr DB, Tong J et al (2005) Resistin is not associated with insulin sensitivity or the metabolic syndrome in humans. Diabetologia 48(11):2330–2333

  18. Gerber M, Boettner A, Seidel B et al (2005) Serum resistin levels of obese and lean children and adolescents: biochemical analysis and clinical relevance. J Clin Endo Metab 90(8):4503–4509

    Article  CAS  Google Scholar 

  19. Chung CM, Lin TH, Chen JW et al (2014) Common quantitative trait locus downstream of RETN gene identified by genome‐wide association study is associated with risk of type 2 diabetes mellitus in Han Chinese: a Mendelian randomization effect. Diabetes Metab Res Rev 30(3): 232–240

  20. Conneely KN, Silander K, Scott LJ et al (2004) Variation in the resistin gene is associated with obesity and insulin-related phenotypes in Finnish subjects. Diabetologia 47(10):1782–1788

    Article  CAS  Google Scholar 

  21. Suriyaprom K, Phonrat B, Namjuntra P et al (2009) The+ 299 (G> A) resistin gene polymorphism and susceptibility to type 2 diabetes in Thais. J Clin Bio Nutr 44(1):104–110

  22. Al-Hilali HA, Abduljaleel AK (2015) The role of TNF and Resistin Gene+ 299 (G/A) polymorphism in the development of insulin resistance in non-obese Type 2 Diabetes Mellitus Iraqi patients. Int J Curr Microbiol App Sci 4(10):475–486

  23. Kaur H, Kapoor R, Singh N (2016) Circulating levels of resistin and +299 (G>A) Resistin gene polymorphism in type 2 diabetes mellitus, a study from North India. Int J Curr Res 8(07):34692–34696

  24. Montiel-Tellez BS, Nieva-Vazquez A, Porchia LM et al (2016) + 62G> A and g.-420C> G RETNPolymorphisms and the risk of developing type 2 diabetes and obesity: original research on a Mexican population and meta-analysis. Endocrinol Metab Syndr 5(228). https://doi.org/10.4172/2161-1017.1000228

  25. Ames RS, Sarau HM, Chambers JK et al (1999) Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14. Nature 401(6750):282–286

  26. Douglas SA, Sulpizio AC, Piercy V et al (2000) Differential vasoconstrictor activity of human urotensin‐II in vascular tissue isolated from the rat, mouse, dog, pig, marmoset and cynomolgus monkey. British J Pharma 131(7):1262–1274

  27. Böhm F, Pernow J (2002) Urotensin II evokes potent vasoconstriction in humans in vivo. British J Pharma 135(1):25–27

    Article  Google Scholar 

  28. Baron AD (2002) Insulin resistance and vascular function. J Dia Comp 16(1):92–102

    Article  Google Scholar 

  29. Jiang Z, Michal JJ, Tobey DJ et al (2008) Comparative understanding of UTS2 and UTS2R genes for their involvement in type 2 diabetes mellitus. Int J Biol Sci 4(2):96

  30. Silvestre RA, Rodriguez-Gallardo J, Egido EM et al (2001) Inhibition of insulin release by urotensin II-a study on the perfused rat pancreas. Hormon Meta Res 33(06):379–381

    Article  CAS  Google Scholar 

  31. Wenyi Z, Suzuki S, Hirai M et al (2003) Role of urotensin II gene in genetic susceptibility to Type 2 diabetes mellitus in Japanese subjects. Diabetologia 46(7):972–976

  32. Suzuki S, Wenyi Z, Hirai M et al (2004) Genetic variations at urotensin II and urotensin II receptor genes and risk of type 2 diabetes mellitus in Japanese. Peptides 25(10):1803–1808

    Article  CAS  Google Scholar 

  33. Ong KL, Wong LY, Man YB et al (2006) Haplotypes in the urotensin II gene and urotensin II receptor gene are associated with insulin resistance and impaired glucose tolerance. Peptides 27(7):1659–1667

    Article  CAS  Google Scholar 

  34. McTernan CL, McTernan PG, Harte AL et al (2002) Resistin, central obesity, and type 2 diabetes. Lancet 359(9300):46–47

  35. Rajala MW, Obici S, Scherer PE et al (2003) Adipose-derived resistin and gut-derived resistin-like molecule–β selectively impair insulin action on glucose production. J Clin Invest 111(2):225–230

  36. Pesole G, Mignone F, Gissi C et al (2001) Structural and functional features of eukaryotic mRNA untranslated regions. Gene 276(1–2):73–81

    Article  CAS  Google Scholar 

  37. Ma X, Warram JH, Trischitta V et al (2002) Genetic variants at the resistin locus and risk of type 2 diabetes in Caucasians. J Clin Endo Meta 87(9):4407–4410

  38. Lau CH, Muniandy S (2011) Adiponectin and resistin gene polymorphisms in association with their respective adipokine levels. Ann Hum Genet 75(3):370–382

    Article  CAS  Google Scholar 

  39. Bouchard L, Weisnagel SJ, Engert JC et al (2004) Human resistin gene polymorphism is associated with visceral obesity and fasting and oral glucose stimulated C-peptide in the Quebec Family Study. J Endo Invest 27(11):1003–1009

    Article  CAS  Google Scholar 

  40. Osawa H, Onuma H, Ochi M et al (2005) Resistin SNP-420 determines its monocyte mRNA and serum levels inducing type 2 diabetes. Biochem Bio Res Comm 335(2):596–602

  41. Nakashima E, Watarai A, Tsukahara T et al (2010) Association of resistin polymorphism, its serum levels and prevalence of stroke in Japanese type 2 diabetic patients. J Diabetes Invest 1(4):154–158

  42. Kapłon‐Cieślicka A, Tymińska A, Rosiak M et al (2019) Resistin is a prognostic factor for death in type 2 diabetes. Diabetes Meta Res Rev 35(2):e3098

  43. Kumar V, Singh J, Aneja A et al (2019) Association of RETN gene polymorphism at+ 299 G> A with type 2 diabetes mellitus: a meta-analysis. Int J Diabetes Dev Count 40:1–9

  44. Osawa H, Onuma H, Murakami A et al (2002) Systematic search for single nucleotide polymorphisms in the resistin gene: the absence of evidence for the association of three identified single nucleotide polymorphisms with Japanese type 2 diabetes. Diabetes 51(3):863–866

  45. Gouni‐Berthold I, Giannakidou E, Faust M, et al (2005) Resistin gene 3′‐untranslated region+ 62G→ A polymorphism is associated with hypertension but not diabetes mellitus type 2 in a German population. J Intern Med 258(6):518–526

  46. Khalil O, Alnahal A, Ghonium M et al (2014) Does resistin gene polymorphisms+ 299 (G> A) participate in insulin resistance in Egyption non-obese type 2 diabetes? Int J Genet Med 2:117

  47. Jiang B, Liu Y, Liu Y et al (2014) Association of four insulin resistance genes with type 2 diabetes mellitus and hypertension in the Chinese Han population. Mol Bio Rep 41(2):925–933

  48. Ong KL, Wong LY, Cheung BM (2008) The role of urotensin II in the metabolic syndrome. Peptides 29(5):859–867

    Article  CAS  Google Scholar 

  49. Gruson D, Rousseau MF, Ketelslegers JM et al (2010) Raised plasma urotensin II in type 2 diabetes patients is associated with the metabolic syndrome phenotype. J Clin Hypertension 12(8):653–660

  50. Calan M, Arkan T, Kume T et al (2019) The relationship between urotensin II and insulin resistance in women with gestational diabetes mellitus. Hormones 18(1):91–97

    Article  Google Scholar 

  51. Yilmaz Ö, Calan O, Kume T et al (2013) The relationship of urotensin II with insulin resistance and hs-CRP in patients having PCOS. Gyneco Endo 29(11):970–973

    Article  CAS  Google Scholar 

  52. Sun HX, Du WN, Zuo J et al (2002) The association of two single nucleotide polymorphisms in PRKCZ and UTS2 respectively with type 2 diabetes in Han people of northern China. Zhongguo yi xue ke xue yuan xue bao. Acta Acad Med Sinicae 24(3):223–227

  53. Zhu F, Ji L, Luo B (2002) The role of urotensin II gene in the genetic susceptibility to type 2 diabetes in Chinese population. Zhonghua Yi Xue Za Zhi 82(21):1473–1475

  54. Okumus S, Igci YZ, Taskin T et al (2012) Association between Thr21Met and Ser89Asn polymorphisms of the urotensin-II (UTS2) gene, diabetes mellitus, and diabetic retinopathy. Curr Eye Res 37(10):921–929

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Acknowledgement

The authors are thankful to Dr. Ashok Chaudhary and Dr. Sapna Grewal, Bio and Nano Technology Department, Guru Jambheshwar University of Science and Technology (G.J.U), Hisar, Haryana, for providing access to instruments, which have been used in present research work, in their laboratory.

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Correspondence to Jasbir Singh.

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The research work was approved by the Ethical committee of Kurukshetra University, Kurukshetra and all the subjects who participated in the study had signed the informed consent form.

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Kumar, V., Singh, J., Bala, K. et al. Association of resistin (rs3745367) and urotensin II (rs228648 and rs2890565) gene polymorphisms with risk of type 2 diabetes mellitus in Indian population. Mol Biol Rep 47, 9489–9497 (2020). https://doi.org/10.1007/s11033-020-05991-6

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