Objective. Genetic variants in the transcription factor 7-like 2 (TCF7L2) gene have been described as the most noteworthy ones regarding the type 2 diabetes mellitus (T2DM) liability. This work is aimed to evaluate the association between rs12255372 and rs7903146 polymorphisms and T2DM in patients with cardiovascular disease (CAD) risk.
Methods. A sample of six hundred and forty-seven patients that underwent the coronary angiography in a Cardiac Catheterization Lab was evaluated. The patients were investigated for the presence of T2DM and coronary stenosis. The TCF7L2 polymorphisms were genotyped by real-time PCR and the haplotype analysis was performed with the MLOCUS software. All genetic tests were carried out by considering the haplotype combinations in patients divided into three groups: 0 – carrying none disease risk allele, 1 – carrying one or two risk alleles and 2 – carrying three or four risk alleles.
Results. No significant associations between TCF7L2 risk haplotypes and the presence of T2DM or CAD were detected.
Conclusions. Our results indicate that the TCF7L2 rs12255372 and rs7903146 polymorphisms do not influence T2DM in Brazilian patients with the high risk for CAD. Therefore, we assume that these variants may only be relevant for a specific subgroup of T2DM patients or some particular human population.
Ali O. Genetics of type 2 diabetes. World J Diabetes 4,114–123, 2013.
American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 36, S67–S74, 2013.
Assmann TS, Duarte GCK, Rheinheimer J, Cruz LA, Canani LH and Crispim D. The TCF7L2 rs7903146 (C/T) polymorphism is associated with risk to type 2 diabetes mellitus in Southern-Brazil. Arq Bras Endocrinol Metabol 58, 918–925, 2014.
Barros CMAR, Araujo-Neto AP, Lopes TR, Barros MAL, Motta FJN, Canalle R, Nunes LCC, Rey JA, Burbano RR, Lima-Barros MA, Yoshioka FK, Pinto GR. Association of the rs7903146 and rs12255372 polymorphisms in the TCF7L2 gene with type 2 diabetes in a population from northeastern Brazil. Genet Mol Res 13, 7889–7898, 2014.
Bielinski SJ, Pankow JS, Folsom AR, North KE and Boerwinkle E. TCF7L2 single nucleotide polymorphisms, cardiovascular disease and all-cause mortality: the Atherosclerosis Risk in Communities (ARIC) study. Diabetologia 51, 968–970, 2008.
Cauchi S, El Achhab Y, Choquet H, Dina C, Krempler F, Weitgasser R, Nejjari C, Patsch W, Chikri M, Meyre D, Froguel P. TCF7L2 is reproducibly associated with type 2 diabetes in various ethnic groups: a global meta-analysis. J Mol Med 85, 777–782, 2007.
Chauhan G, Spurgeon CJ, Tabassum R, Bhaskar S, Kulkarni SR, Mahajan A, Chavali S, Kumar MV, Prakash S, Dwivedi OP, Ghosh S, Yajnik CS, Tandon N, Bharadwaj D, Chandak GR. Impact of common variants of PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2A, IGF2BP2, and CDKAL1 on the risk of type 2 diabetes in 5,164 Indians. Diabetes 59, 2068–2074, 2010.
Dawson K, Aflaki M, Nattel S. Role of the Wnt-Frizzled system in cardiac pathophysiology: a rapidly developing, poorly understood area with enormous potential. J Physiol 591, 1409–1432, 2013.
de Melo SF, Frigeri HR, dos Santos-Weiss ICR, Rea RR, de Souza EM, Alberton D, Gomes de Moraes Rego F, Picheth
G. Polymorphisms in FTO and TCF7L2 genes of Euro-Brazilian women with gestational diabetes. Clin Biochem 48, 1064–1067, 2015.
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. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 38, 320–323, 2006.
Jin T. The WNT signalling pathway and diabetes mellitus. Diabetologia 51, 1771–1780, 2008.
Lahiri DK, Nurnberger JI Jr. A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res 19, 5444, 1991.
Long J, Edwards T, Signorello LB, Cai Q, Zheng W, Shu XO, Blot WJ. Evaluation of genome-wide association study-identified type 2 diabetes loci in African Americans. Am J Epidemiol 176, 995–1001, 2012.
Lyssenko V, Lupi R, Marchetti P, Del Guerra S, Orho-Melander M, Almgren P, Sjogren M, Ling C, Eriksson KF, Lethagen AL, Mancarella R, Berglund G, Tuomi T, Nilsson P, Del Prato S, Groop L. Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J Clin Invest 117, 2155–2163, 2007.
MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 17, 9–26, 2009.
Marquezine G, Pereira A, Sousa A, Mill J, Hueb W, Krieger J. TCF7L2 variant genotypes and type 2 diabetes risk in Brazil: significant association, but not a significant tool for risk stratification in the general population. BMC Med Genet 9, 106, 2008.
Muendlein A, Saely CH, Geller-Rhomberg S, Sonderegger G, Rein P, Winder T, Beer S, Vonbank A, Drexel H. Single nucleotide polymorphisms of TCF7L2 are linked to diabetic coronary atherosclerosis. PLoS One 6, e17978, 2011.
Palsgaard J, Emanuelli B, Winnay JN, Sumara G, Karsenty G, Kahn CR. Cross-talk between insulin and Wnt signaling in preadipocytes: role of Wnt co-receptor low density lipoprotein receptor-related protein-5 (LRP5). J Biol Chem 287, 12016–12026, 2012.
Rulifson IC, Karnik SK, Heiser PW, ten Berge D, Chen H, Gu X, Taketo MM, Nusse R, Hebrok M, Kim SK. Wnt signaling regulates pancreatic beta cell proliferation. Proc Natl Acad Sci 104, 6247–6252, 2007.
Schafer SA, Tschritter O, Machicao F, Thamer C, Stefan N, Gallwitz B, Holst JJ, Dekker JM, ‘t Hart LM, Nijpels G, van
Haeften TW, Haring HU, Fritsche A. Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms. Diabetologia 50, 2443–2450, 2007.
Schinner S, Ulgen F, Papewalis C, Schott M, Woelk A, Vidal-Puig A, Scherbaum WA. Regulation of insulin secretion, glucokinase gene transcription and beta cell proliferation by adipocyte-derived Wnt signalling molecules. Diabetologia 51, 147–154, 2007.
Scott LJ, Mohlke KL, Bonnycastle LL, Willer CJ, Li Y, Duren WL, Erdos MR, Stringham HM, Chines PS, Jackson AU, Prokunina-Olsson L, Ding CJ, Swift AJ, Narisu N, Hu T, Pruim R, Xiao R, Li XY, Conneely KN, Riebow NL, Sprau AG, Tong M, White PP, Hetrick KN, Barnhart MW, Bark CW, Goldstein JL, Watkins L, Xiang F, Saramies J, Buchanan TA, Watanabe RM, Valle TT, Kinnunen L, Abecasis GR, Pugh EW, Doheny KF, Bergman RN, Tuomilehto J, Collins FS, Boehnke M. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316, 1341–1345, 2007.
Sousa AGP, Marquezine GF, Lemos PA, Martinez E, Lopes N, Hueb WA, Krieger JE, Pereira AC. TCF7L2 polymorphism rs7903146 is associated with coronary artery disease severity and mortality. PLoS One 4, e7697, 2009.
Szabo M, Mate B, Csep K, Benedek T. Genetic approaches to the study of gene variants and their impact on the patho-physiology of type 2 diabetes. Biochem Genet 56, 22–55, 2018.
Tong Y, Lin Y, Zhang Y, Yang J, Zhang Y, Liu H, Zhang B. 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, 2009.
Travers ME, McCarthy MI. Type 2 diabetes and obesity: genomics and the clinic. Hum Genet 130, 41–58, 2011.
Turki A, Al-Zaben GS, Mtiraoui N, Marmmuoch H, Mahjoub T, Almawi WY. Transcription factor-7-like 2 gene variants are strongly associated with type 2 diabetes in Tunisian Arab subjects. Gene 513, 244–248, 2013.
Wang J, Zhang J, Li L, Wang Y, Wang Q, Zhai Y, You H, Hu D. Association of rs12255372 in the TCF7L2 gene with type 2 diabetes mellitus: a meta-analysis. Brazilian J Med Biol Res 46, 382–393, 2013.
Weedon MN. The importance of TCF7L2. Diabet Med 24, 1062–1066, 2007.
Xavier HT, Izar MC, Faria Neto JR, Assad MH, Rocha VZ, Sposito AC, Fonseca FA, Santos JE dos, Santos RD, Bertolami MC, Faludi AA, Martinez TLR, Diament J, Guimaraes A, Forti NA, Moriguchi E, Chagas ACP, Coelho OR, Ramires JAF. V Diretriz Brasileira de Dislipidemias e Prevencao da Aterosclerose. Arq Bras Cardiol 101, 1–22, 2013.