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TCF7L2 gene variants predispose to the development of type 2 diabetes mellitus among individuals with metabolic syndrome

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Abstract

Introduction

Transcription factor 7-like 2 (TCF7L2) gene variants rs12255372 and rs7903146 have been consistently shown to raise genetic risk for type 2 diabetes mellitus (T2DM). The aim of this study was to investigate the possible role of these variants in the development of impaired glucose metabolism (IGM), including impaired fasting glucose (IFG) or T2DM, in patients with metabolic syndrome (MS).

Patients and methods

The study population consisted of 228 patients with MS who were divided into two groups. The first group consisted of 148 patients with MS and IGM [39M/109F, 59.8 ± 14.6 (mean ± SD) years] and the second group of 80 patients with MS and normoglycemia (NGM) (16M/64F, 56.1 ± 15.8 years). The diagnosis of MS was based on the criteria proposed by the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) Scientific Statement. Anthropometric parameters including BMI and waist circumference were recorded and blood samples were obtained after overnight fasting for biochemical tests. The rs12255372 and rs7903146 TCF7L2 polymorphisms were genotyped in peripheral blood leucocytes.

Results

Analysis of the distribution of the TCF7L2 polymorphic alleles revealed that the frequency of the T allele of the TCF7L2 variant rs12255372 was 38.2% in the study population, while the frequency of the T allele of the TCF7L2 rs7903146 variant was 35.3%. The T allele of the rs12255372 variant was more frequently present in patients with MS and IGM (48.3%) compared to patients with MS and NGM (19.4%, p < 0.001). Also, the T allele of rs7903146 was more frequently present in patients with MS and IGM (44.6%) compared to patients with MS and NGM (18.1%, p < 0.001). Logistic regression analysis followed and revealed that the presence of the T allele for both rs12255372 and rs7903146 TCF7L2 gene variants is a very powerful predictor of the presence of glucose disorders, increasing the risk more than fourfold in patients with MS and after adjustment for potential confounders, such as age, gender, BMI, and waist circumference (TCF7L2 rs12255372: Exp(B) 4.917, p < 0.001 and TCF7L2 rs7903146: Exp(B) 5.460, p < 0.001).

Conclusion

The presence of the rs12255372 and rs7903146 TCF7L2 gene variants plays an important role in the development of T2DM among individuals with MS. These findings support the notion that among subjects with MS, those who finally develop T2DM have a genetic predisposition to β-cell dysfunction.

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Abbreviations

MS:

Metabolic syndrome

T2DM:

Type 2 diabetes mellitus

IGM:

Impaired glucose metabolism

NGM:

Normal glucose metabolism

IFG:

Impaired fasting glucose

IGT:

Impaired glucose tolerance

PCR:

Polymerase chain reaction

References

  1. Tsatsoulis A, Mantzaris MD, Bellou S, Andrikoula M (2013) Insulin resistance: an adaptive mechanism becomes maladaptive in the current environment—an evolutionary perspective. Metabolism 62:622–633

    Article  PubMed  CAS  Google Scholar 

  2. The IDF consensus worldwide definition of the metabolic syndrome, (2006) International Diabetes Federation

  3. Rabe K, Lehrke M, Parhofer KG, Broedl UC (2008) Adipokines and insulin resistance. Mol Med 14:741–751

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, Helgason A, Stefansson H, Emilsson V, Helgadottir A, Styrkarsdottir U, Magnusson KP, Walters GB, Palsdottir E, Jonsdottir T, Gudmundsdottir T, Gylfason A, Saemundsdottir J, Wilensky RL, Reilly MP, Rader DJ, Bagger Y, Christiansen C, Gudnason V, Sigurdsson G, Thorsteinsdottir U, Gulcher JR, Kong A, Stefansson K (2006) Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 38:320–323

    Article  PubMed  CAS  Google Scholar 

  5. Chandak GR, Janipalli CS, Bhaskar S, Kulkarni SR, Mohankrishna P, Hattersley AT, Frayling TM, Yajnik CS (2007) Common variants in the TCF7L2 gene are strongly associated with type 2 diabetes mellitus in the Indian population. Diabetologia 50:63–67

    Article  PubMed  CAS  Google Scholar 

  6. Palizban A, Nikpour M, Salehi R, Maracy MR (2012) Association of a common variant in TCF7L2 gene with type 2 diabetes mellitus in a Persian population. Clin Exp Med 12:115–119

    Article  PubMed  CAS  Google Scholar 

  7. Mayans S, Lackovic K, Lindgren P, Ruikka K, Agren A, Eliasson M, Holmberg D (2007) TCF7L2 polymorphisms are associated with type 2 diabetes in northern Sweden. Eur J Hum Genet 15:342–346

    Article  PubMed  CAS  Google Scholar 

  8. Cauchi S, Meyre D, Dina C, Choquet H, Samson C, Gallina S, Balkau B, Charpentier G, Pattou F, Stetsyuk V, Scharfmann R, Staels B, Frühbeck G, Froguel P (2006) Transcription factor TCF7L2 genetic study in the French population: expression in human beta-cells and adipose tissue and strong association with type 2 diabetes. Diabetes 55:2903–2908

    Article  PubMed  CAS  Google Scholar 

  9. Tong Y, Lin Y, Zhang Y, Yang J, Zhang Y, Liu H, Zhang B (2009) Association between TCF7L2 gene polymorphisms and susceptibility to type 2 diabetes mellitus: a large Human Genome Epidemiology (HuGE) review and meta-analysis. BMC Med Genet 10:15

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Kimber CH, Doney AS, Pearson ER, McCarthy MI, Hattersley AT, Leese GP, Morris AD, Palmer CN (2007) TCF7L2 in the Go-DARTS study: evidence for a gene dose effect on both diabetes susceptibility and control of glucose levels. Diabetologia 50:1186–1191

    Article  PubMed  CAS  Google Scholar 

  11. Delgado-Lista J, Perez-Martinez P, García-Rios A, Phillips CM, Williams CM, Gulseth HL, Helal O, Blaak EE, Kiec-Wilk B, Basu S, Drevon CA, Defoort C, Saris WH, Wybranska I, Riserus U, Lovegrove JA, Roche HM, Lopez-Miranda J (2011) Pleiotropic effects of TCF7L2 gene variants and its modulation in the metabolic syndrome: from the LIPGENE study. Atherosclerosis 214:110–116

    Article  PubMed  CAS  Google Scholar 

  12. Perez-Martinez P, Perez-Caballero AI, Garcia-Rios A, Yubero-Serrano EM, Camargo A, Gomez-Luna MJ, Marin C, Gomez-Luna P, Dembinska-Kiec A, Rodriguez-Cantalejo F, Tinahones FJ, Roche HM, Perez-Jimenez F, Lopez-Miranda J, Delgado-Lista J (2012) Effects of rs7903146 variation in the Tcf7l2 gene in the lipid metabolism of three different populations. PLoS One 7:e43390

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Povel CM, Boer JM, Reiling E, Feskens EJ (2011) Genetic variants and the metabolic syndrome: a systematic review. Obes Rev 12:952–967

    Article  PubMed  CAS  Google Scholar 

  14. Phillips CM, Goumidi L, Bertrais S, Field MR, McManus R, Hercberg S, Lairon D, Planells R, Roche HM (2012) Dietary saturated fat, gender and genetic variation at the TCF7L2 locus predict the development of metabolic syndrome. J Nutr Biochem 23(3):239–244

    Article  PubMed  CAS  Google Scholar 

  15. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC Jr, Spertus JA, Fernando Costa. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005; 112: 2735–2752

  16. van Vliet-Ostaptchouk JV, Shiri-Sverdlov R, Zhernakova A, Strengman E, van Haeften TW, Hofker MH, Wijmenga C (2007) Association of variants of transcription factor 7-like 2 (TCF7L2) with susceptibility to type 2 diabetes in the Dutch Breda cohort. Diabetologia 50:59–62

    Article  PubMed  CAS  Google Scholar 

  17. Zhang C, Qi L, Hunter DJ, Meigs JB, Manson JE, van Dam RM, Hu FB (2006) Variant of transcription factor 7-like 2 (TCF7L2) gene and the risk of type 2 diabetes in large cohorts of U.S. women and men. Diabetes 55(9):2645–2648

    Article  PubMed  CAS  Google Scholar 

  18. Marzi C, Huth C, Kolz M, Grallert H, Meisinger C, Wichmann H-E, Rathman W, Herder C, Illig T (2007) Variants of the transcription factor 7-like 2 gene (TCF7L2) are strongly associated with type 2 diabetes but not with the metabolic syndrome in the MONICA/KORA surveys. Horm Metab Res 39(1):46–52

    Article  PubMed  CAS  Google Scholar 

  19. Cruz M, Valladares-Salgado A, Garcia-Mena J, Ross K, Edwards M, Angeles-Martinez J, Ortega-Camarillo C, de la Peña JE, Burguete-Garcia AI, Wacher-Rodarte N, Ambriz R, Rivera R, D'artote AL, Peralta J, Parra EJ, Kumate J (2010) Candidate gene association study conditioning on individual ancestry in patients with type 2 diabetes and metabolic syndrome from Mexico City. Diabetes Metab Res Rev 26(4):261–270

    Article  PubMed  CAS  Google Scholar 

  20. Hayashi T, Iwamoto Y, Kaku K, Hirose H, Maeda S (2007) Replication study for the association of TCF7L2 with susceptibility to type 2 diabetes in a Japanese population. Diabetologia 50(5):980–984

    Article  PubMed  CAS  Google Scholar 

  21. Groves CJ, Zeggini E, Minton J, Frayling TM, Weedon MN, Rayner NW, Hitman GA, Walker M, Wiltshire S, Hattersley AT, McCarthy MI (2006) Association analysis of 6,736 U.K. subjects provides replication and confirms TCF7L2 as a type 2 diabetes susceptibility gene with a substantial effect on individual risk. Diabetes 55(9):2640–2644

    Article  PubMed  CAS  Google Scholar 

  22. Ng MC, Tam CH, Lam VK, So WY, Ma RC, Chan JC (2007) Replication and identification of novel variants at TCF7L2 associated with type 2 diabetes in Hong Kong Chinese. J Clin Endocrinol Metab 92(9):3733–3737

    Article  PubMed  CAS  Google Scholar 

  23. Lyssenko V, Lupi R, Marchetti P, Del Guerra S, Orho-Melander M, Almgren P, Sjögren M, Ling C, Eriksson KF, Lethagen AL, Mancarella R, Berglund G, Tuomi T, Nilsson P, Del Prato S, Groop L (2007) Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J Clin Invest 117(8):2155–2163

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Sjögren M, Lyssenko V, Jonsson A, Berglund G, Nilsson P, Groop L, Orho-Melander M (2008) The search for putative unifying genetic factors for components of the metabolic syndrome. Diabetologia 51(12):2242–2251

    Article  PubMed  CAS  Google Scholar 

  25. Carty CL, Bhattacharjee S, Haessler J, Cheng I, Hindorff LA, Aroda V, Carlson CS, Hsu CN, Wilkens L, Liu S, Selvin E, Jackson R, North KE, Peters U, Pankow JS, Chatterjee N, Kooperberg C (2014) Analysis of metabolic syndrome components in >15000 African Americans identifies pleiotropic variants: results from the population architecture using genomics and epidemiology study. Circ Cardiovasc Genet 7(4):505–513

    Article  PubMed  PubMed Central  Google Scholar 

  26. Florez JC, Jablonski KA, Bayley N, Pollin TI, de Bakker PI, Shuldiner AR, Knowler WC, Nathan DM, Altshuler D, Diabetes Prevention Program Research Group (2006) TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N Engl J Med 355(3):241–250

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Saxena R, Gianniny L, Burtt NP, Lyssenko V, Giuducci C, Sjögren M, Florez JC, Almgren P, Isomaa B, Orho-Melander M, Lindblad U, Daly MJ, Tuomi T, Hirschhorn JN, Ardlie KG, Groop LC, Altshuler D (2006) Common single nucleotide polymorphisms in TCF7L2 are reproducibly associated with type 2 diabetes and reduce the insulin response to glucose in nondiabetic individuals. Diabetes 55(10):2890–2895

    Article  PubMed  CAS  Google Scholar 

  28. Wang J, Kuusisto J, Vänttinen M, Kuulasmaa T, Lindström J, Tuomilehto J, Uusitupa M, Laakso M (2007) Variants of transcription factor 7-like 2 (TCF7L2) gene predict conversion to type 2 diabetes in the Finnish Diabetes Prevention Study and are associated with impaired glucose regulation and impaired insulin secretion. Diabetologia 50(6):1192–1200

    Article  PubMed  CAS  Google Scholar 

  29. Dahlgren A, Zethelius B, Jensevik K, Syvänen AC, Berne C (2007) Variants of the TCF7L2 gene are associated with beta cell dysfunction and confer an increased risk of type 2 diabetes mellitus in the ULSAM cohort of Swedish elderly men. Diabetologia 50(9):1852

    Article  PubMed  CAS  Google Scholar 

  30. Melzer D, Murray A, Hurst AJ, Weedon MN, Bandinelli S, Corsi AM, Ferrucci L, Paolisso G, Guralnik JM, Frayling TM (2006) Effects of the diabetes linked TCF7L2 polymorphism in a representative older population. BMC Med 20(4):34

    Article  CAS  Google Scholar 

  31. Palmer ND, Lehtinen AB, Langefeld CD, Campbell JK, Haffner SM, Norris JM, Bergman RN, Goodarzi MO, Rotter JI, Bowden DW (2008) Association of TCF7L2 gene polymorphisms with reduced acute insulin response in Hispanic Americans. J Clin Endocrinol Metab 93(1):304–309

    Article  PubMed  CAS  Google Scholar 

  32. Villareal DT, Robertson H, Bell GI, Patterson BW, Tran H, Wice B, Polonsky KS (2010) TCF7L2 variant rs7903146 affects the risk of type 2 diabetes by modulating incretin action. Diabetes 59:479–485

    Article  PubMed  CAS  Google Scholar 

  33. Pilgaard K, Jensen CB, Schou JH, Lyssenko V, Wegner L, Brøns C, Vilsbøll T, Hansen T, Madsbad S, Holst JJ, Vølund A, Poulsen P, Groop L, Pedersen O, Vaag AA (2009) The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men. Diabetologia 52:1298–1307

    Article  PubMed  CAS  Google Scholar 

  34. Schäfer SA, Tschritter O, Machicao F, Thamer C, Stefan N, Gallwitz B, Holst JJ, Dekker JM, 't Hart LM, Nijpels G, van Haeften TW, Häring HU, Fritsche A. Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms. Diabetologia 2007;50:2443–2450

  35. Pearson ER (2009) Translating TCF7L2: from gene to function. Diabetologia 52:1227–1230

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Endocrinology and Diabetes, Medical School, University of Ioannina, 45110, Ioannina, Greece

    Konstantinos Katsoulis, Stavroula A. Paschou, Stelios Tigas & Agathocles Tsatsoulis

  2. Division of Endocrinology and Diabetes, “Aghia Sophia” Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece

    Stavroula A. Paschou

  3. Laboratory of Human Reproductive Genetics, University of Ioannina, Ioannina, Greece

    Elissavet Hatzi & Ioannis Georgiou

Authors
  1. Konstantinos Katsoulis
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  2. Stavroula A. Paschou
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  3. Elissavet Hatzi
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  5. Ioannis Georgiou
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  6. Agathocles Tsatsoulis
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Contributions

K.K. contributed in the acquisition, statistical analysis, and interpretation of the data and in drafting the paper. S.A.P contributed in the acquisition, statistical analysis, and interpretation of the data and in drafting the paper. E.H. contributed in the acquisition, analysis, and interpretation of the data. S.T. contributed in the conception and design of the work, in the analysis and interpretation of the data, and in revising the paper critically with regard to its scientific content. I.G. contributed in the conception and design of the work, in the analysis and interpretation of the data, and in revising the paper critically with regard to its scientific content. A.T. contributed in the conception and design of the work, in the analysis and interpretation of the data, and in revising the paper critically with regard to its scientific content. All authors approved the final version of the paper to be published.

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Correspondence to Agathocles Tsatsoulis.

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Research was carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki). Informed consent was obtained from participants.

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The authors declare that they have no conflict of interest.

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This work has not been published previously and it is not under consideration for publication elsewhere. The publication is approved by all authors and, if accepted, will not be published elsewhere in the same form, in English or in any other language, including electronically, without the written consent of the copyright holder.

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Katsoulis, K., Paschou, S.A., Hatzi, E. et al. TCF7L2 gene variants predispose to the development of type 2 diabetes mellitus among individuals with metabolic syndrome. Hormones 17, 359–365 (2018). https://doi.org/10.1007/s42000-018-0047-z

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