Current Diabetes Reports

, 8:149

TCF7L2 genetic defect and type 2 diabetes



After two decades of limited success, the genetic architecture of type 2 diabetes (T2D) is finally being revealed. Within only 2 years, an avalanche of studies identified several genes expressed in pancreatic β cells and involved in the control of insulin secretion, such as transcription factor 7-like 2 (TCF7L2), a key element of the Wnt signaling pathway. In Europeans, genome-wide association scans showed that TCF7L2 has been the most important locus predisposing to T2D so far. For the first time, a gene is consistently involved in T2D susceptibility in all major ethnic groups. At the individual level, carrying the TCF7L2 risk allele increases T2D risk 50%. However, at the population level, the attributable risk is lower than 25% and varies with the allele frequency. The presence of the TCF7L2 rs7903146 risk allele increases TCF7L2 gene expression in β cells, possibly impairing glucagon-like peptide-1-induced insulin secretion and/or the production of new mature β cells. The tremendous association of TCF7L2 polymorphisms with T2D provides new insights into future genetic predisposition tests but remains the tip of the T2D genetic iceberg.

References and Recommended Reading

  1. 1.
    Deeb SS, Fajas L, Nemoto M, et al.: A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet 1998, 20:284–287.PubMedCrossRefGoogle Scholar
  2. 2.
    Altshuler D, Hirschhorn JN, Klannemark M, et al.: The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 2000, 26:76–80.PubMedCrossRefGoogle Scholar
  3. 3.
    Hani EH, Boutin P, Durand E, et al.: Missense mutations in the pancreatic islet beta cell inwardly rectifying K+ channel gene (KIR6.2/BIR): a meta-analysis suggests a role in the polygenic basis of type II diabetes mellitus in Caucasians. Diabetologia 1998, 41:1511–1515.PubMedCrossRefGoogle Scholar
  4. 4.
    Nielsen EM, Hansen L, Carstensen B, et al.: The E23K variant of Kir6.2 associates with impaired post-OGTT serum insulin response and increased risk of type 2 diabetes. Diabetes 2003, 52:573–577.PubMedCrossRefGoogle Scholar
  5. 5.
    Barroso I, Gurnell M, Crowley VE, et al.: Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 1999, 402:880–883.PubMedGoogle Scholar
  6. 6.
    Gloyn AL, Pearson ER, Antcliff JF, et al.: Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med 2004, 350:1838–1849.PubMedCrossRefGoogle Scholar
  7. 7.
    Tsuchiya T, Schwarz PE, Bosque-Plata LD, et al.: Association of the calpain-10 gene with type 2 diabetes in Europeans: results of pooled and meta-analyses. Mol Genet Metab 2006, 89:174–184.PubMedCrossRefGoogle Scholar
  8. 8.
    Osawa H, Yamada K, Onuma H, et al.: The G/G genotype of a resistin single-nucleotide polymorphism at −420 increases type 2 diabetes mellitus susceptibility by inducing promoter activity through specific binding of Sp1/3. Am J Hum Genet 2004, 75:678–686.PubMedCrossRefGoogle Scholar
  9. 9.
    Silander K, Mohlke KL, Scott LJ, et al.: Genetic variation near the hepatocyte nuclear factor-4 alpha gene predicts susceptibility to type 2 diabetes. Diabetes 2004, 53:1141–1149.PubMedCrossRefGoogle Scholar
  10. 10.
    Winckler W, Weedon MN, Graham RR, et al.: Evaluation of common variants in the six known maturity-onset diabetes of the young (MODY) genes for association with type 2 diabetes. Diabetes 2007, 56:685–693.PubMedCrossRefGoogle Scholar
  11. 11.
    Vasseur F, Helbecque N, Lobbens S, et al.: Hypoadiponectinaemia and high risk of type 2 diabetes are associated with adiponectin-encoding (ACDC) gene promoter variants in morbid obesity: evidence for a role of ACDC in diabesity. Diabetologia 2005, 48:892–899.PubMedCrossRefGoogle Scholar
  12. 12.
    Holmkvist J, Cervin C, Lyssenko V, et al.: Common variants in HNF-1 alpha and risk of type 2 diabetes. Diabetologia 2006, 49:2882–2891.PubMedCrossRefGoogle Scholar
  13. 13.
    Meyre D, Bouatia-Naji N, Tounian A, et al.: Variants of ENPP1 are associated with childhood and adult obesity and increase the risk of glucose intolerance and type 2 diabetes. Nat Genet 2005, 37:863–867.PubMedCrossRefGoogle Scholar
  14. 14.
    Grant SF, Thorleifsson G, Reynisdottir I, et al.: Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 2006, 38:320–323.PubMedCrossRefGoogle Scholar
  15. 15.
    Scott LJ, Bonnycastle LL, Willer CJ, et al.: Association of transcription factor 7-like 2 (TCF7L2) variants with type 2 diabetes in a Finnish sample. Diabetes 2006, 55:2649–2653.PubMedCrossRefGoogle Scholar
  16. 16.
    Groves CJ, Zeggini E, Minton J, et al.: 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 2006, 55:2640–2644.PubMedCrossRefGoogle Scholar
  17. 17.
    Saxena R, Gianniny L, Burtt NP, et al.: Common single nucleotide polymorphisms in TCF7L2 are reproducibly associated with type 2 diabetes and reduce the insulin response to glucose in nondiabetic individuals. Diabetes 2006, 55:2890–2895.PubMedCrossRefGoogle Scholar
  18. 18.
    Cauchi S, Meyre D, Dina C, et al.: 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 2006, 55:2903–2908.PubMedCrossRefGoogle Scholar
  19. 19.
    van Vliet-Ostaptchouk JV, Shiri-Sverdlov R, Zhernakova A, et al.: Association of variants of transcription factor 7-like 2 (TCF7L2) with susceptibility to type 2 diabetes in the Dutch Breda cohort. Diabetologia 2007, 50:59–62.PubMedCrossRefGoogle Scholar
  20. 20.
    Humphries SE, Gable D, Cooper JA, et al.: Common variants in the TCF7L2 gene and predisposition to type 2 diabetes in UK European Whites, Indian Asians and Afro-Caribbean men and women. J Mol Med 2006, 84:1–10.PubMedCrossRefGoogle Scholar
  21. 21.
    Damcott CM, Pollin TI, Reinhart LJ, et al.: Polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes in the Amish: replication and evidence for a role in both insulin secretion and insulin resistance. Diabetes 2006, 55:2654–2659.PubMedCrossRefGoogle Scholar
  22. 22.
    Florez JC, Jablonski KA, Bayley N, et al.: TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N Engl J Med 2006, 355:241–250.PubMedCrossRefGoogle Scholar
  23. 23.
    Zhang C, Qi L, Hunter DJ, et al.: 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 2006, 55:2645–2648.PubMedCrossRefGoogle Scholar
  24. 24.
    Marzi C, Huth C, Kolz M, et al.: 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 2007, 39:46–52.PubMedCrossRefGoogle Scholar
  25. 25.
    Melzer D, Murray A, Hurst AJ, et al.: Effects of the diabetes linked TCF7L2 polymorphism in a representative older population. BMC Med 2006, 4:34.PubMedCrossRefGoogle Scholar
  26. 26.
    Mayans S, Lackovic K, Lindgren P, et al.: TCF7L2 polymorphisms are associated with type 2 diabetes in northern Sweden. Eur J Hum Genet 2007, 15:342–346.PubMedCrossRefGoogle Scholar
  27. 27.
    Helgason A, Palsson S, Thorleifsson G, et al.: Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution. Nat Genet 2007, 39:218–225.PubMedCrossRefGoogle Scholar
  28. 28.
    Lehman DM, Hunt KJ, Leach RJ, et al.: Haplotypes of transcription factor 7-like 2 (TCF7L2) gene and its upstream region are associated with type 2 diabetes and age of onset in Mexican Americans. Diabetes 2007, 56:389–393.PubMedCrossRefGoogle Scholar
  29. 29.
    Chandak GR, Janipalli CS, Bhaskar S, et al.: Common variants in the TCF7L2 gene are strongly associated with type 2 diabetes mellitus in the Indian population. Diabetologia 2007, 50:63–67.PubMedCrossRefGoogle Scholar
  30. 30.
    Horikoshi M, Hara K, Ito C, et al.: A genetic variation of the transcription factor 7-like 2 gene is associated with risk of type 2 diabetes in the Japanese population. Diabetologia 2007, 50:747–751.PubMedCrossRefGoogle Scholar
  31. 31.
    Hayashi T, Iwamoto Y, Kaku K, et al.: Replication study for the association of TCF7L2 with susceptibility to type 2 diabetes in a Japanese population. Diabetologia 2007, 50:980–984.PubMedCrossRefGoogle Scholar
  32. 32.
    Cauchi S, El Achhab Y, Choquet H, et al.: TCF7L2 is reproducibly associated with type 2 diabetes in various ethnic groups: a global meta-analysis. J Mol Med 2007, 85:777–782.PubMedCrossRefGoogle Scholar
  33. 33.
    Barroso I, Luan J, Sandhu MS, et al.: Meta-analysis of the Gly482Ser variant in PPARGC1A in type 2 diabetes and related phenotypes. Diabetologia 2006, 49:501–505.PubMedCrossRefGoogle Scholar
  34. 34.
    Gloyn AL, Weedon MN, Owen KR, et al.: Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes 2003, 52:568–572.PubMedCrossRefGoogle Scholar
  35. 35.
    Love-Gregory L, Wasson J, Lin J, et al.: E23K single nucleotide polymorphism in the islet ATP-sensitive potassium channel gene (Kir6.2) contributes as much to the risk of type II diabetes in Caucasians as the PPARgamma Pro12Ala variant. Diabetologia 2003, 46:136–137.PubMedGoogle Scholar
  36. 36.
    Weedon MN, Schwarz PE, Horikawa Y, et al.: Meta-analysis and a large association study confirm a role for calpain-10 variation in type 2 diabetes susceptibility. Am J Hum Genet 2003, 73:1208–1212.PubMedCrossRefGoogle Scholar
  37. 37.
    Weedon MN, Owen KR, Shields B, et al.: A large-scale association analysis of common variation of the HNF1alpha gene with type 2 diabetes in the U.K. Caucasian population. Diabetes 2005, 54:2487–2491.PubMedCrossRefGoogle Scholar
  38. 38.
    Weedon MN, Shields B, Hitman G, et al.: No evidence of association of ENPP1 variants with type 2 diabetes or obesity in a study of 8,089 U.K. Caucasians. Diabetes 2006, 55:3175–3179.PubMedCrossRefGoogle Scholar
  39. 39.
    Qi L, van Dam RM, Meigs JB, et al.: Genetic variation in IL6 gene and type 2 diabetes: tagging-SNP haplotype analysis in large-scale case-control study and meta-analysis. Hum Mol Genet 2006, 15:1914–1920.PubMedCrossRefGoogle Scholar
  40. 40.
    Huth C, Heid IM, Vollmert C, et al.: IL6 gene promoter polymorphisms and type 2 diabetes: joint analysis of individual participants’ data from 21 studies. Diabetes 2006, 55:2915–2921.PubMedCrossRefGoogle Scholar
  41. 41.
    Cauchi S, Meyre D, Choquet H, et al.: TCF7L2 variation predicts hyperglycemia incidence in a French general population: the data from an epidemiological study on the Insulin Resistance Syndrome (DESIR) study. Diabetes 2006, 55:3189–3192.PubMedCrossRefGoogle Scholar
  42. 42.
    Ng MC, Tam CH, Lam VK, et al.: Replication and identification of novel variants at TCF7L2 associated with type 2 diabetes in Hong Kong Chinese. J Clin Endocrinol Metab 2007, 92:3733–3737.PubMedCrossRefGoogle Scholar
  43. 43.
    Chang YC, Chang TJ, Jiang YD, et al.: Association study of the genetic polymorphisms of the transcription factor 7-like 2 (TCF7L2) gene and type 2 diabetes in the Chinese population. Diabetes 2007, 56:2631–2637.PubMedCrossRefGoogle Scholar
  44. 44.
    Frazer KA, Ballinger DG, Cox DR, et al.: A second generation human haplotype map of over 3.1 million SNPs. Nature 2007, 449:851–861.PubMedCrossRefGoogle Scholar
  45. 45.
    Sladek R, Rocheleau G, Rung J, et al.: A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 2007, 445:881–885.PubMedCrossRefGoogle Scholar
  46. 46.
    Zeggini E, Weedon MN, Lindgren CM, et al.: Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 2007, 316:1336–1341.PubMedCrossRefGoogle Scholar
  47. 47.
    Scott LJ, Mohlke KL, Bonnycastle LL, et al.: A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 2007, 316:1341–1345.PubMedCrossRefGoogle Scholar
  48. 48.
    Saxena R, Voight BF, Lyssenko V, et al.: Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 2007, 316:1331–1336.PubMedCrossRefGoogle Scholar
  49. 49.
    Steinthorsdottir V, Thorleifsson G, Reynisdottir I, et al.: A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet 2007, 39:770–775.PubMedCrossRefGoogle Scholar
  50. 50.
    Barker N, Morin PJ, Clevers H: The Yin-Yang of TCF/beta-catenin signaling. Adv Cancer Res 2000, 77:1–24.PubMedCrossRefGoogle Scholar
  51. 51.
    Logan CY, Nusse R: The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 2004, 20:781–810.PubMedCrossRefGoogle Scholar
  52. 52.
    Munemitsu S, Albert I, Souza B, et al.: Regulation of intra-cellular beta-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein. Proc Natl Acad Sci U S A 1995, 92:3046–3050.PubMedCrossRefGoogle Scholar
  53. 53.
    Rubinfeld B, Souza B, Albert I, et al.: Association of the APC gene product with beta-catenin. Science 1993, 262:1731–1734.PubMedCrossRefGoogle Scholar
  54. 54.
    Su LK, Vogelstein B, Kinzler KW: Association of the APC tumor suppressor protein with catenins. Science 1993, 262:1734–1737.PubMedCrossRefGoogle Scholar
  55. 55.
    Behrens J, von Kries JP, Kuhl M, et al.: Functional interaction of beta-catenin with the transcription factor LEF-1. Nature 1996, 382:638–642.PubMedCrossRefGoogle Scholar
  56. 56.
    Korinek V, Barker N, Morin PJ, et al.: Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/-colon carcinoma. Science 1997, 275:1784–1787.PubMedCrossRefGoogle Scholar
  57. 57.
    Clevers H: Wnt/beta-catenin signaling in development and disease. Cell 2006, 127:469–480.PubMedCrossRefGoogle Scholar
  58. 58.
    Papadopoulou S, Edlund H: Attenuated Wnt signaling perturbs pancreatic growth but not pancreatic function. Diabetes 2005, 54:2844–2851.PubMedCrossRefGoogle Scholar
  59. 59.
    Apelqvist A, Ahlgren U, Edlund H: Sonic hedgehog directs specialised mesoderm differentiation in the intestine and pancreas. Curr Biol 1997, 7:801–804.PubMedCrossRefGoogle Scholar
  60. 60.
    Thomas MK, Rastalsky N, Lee JH, Habener JF: Hedgehog signaling regulation of insulin production by pancreatic beta-cells. Diabetes 2000, 49:2039–2047.PubMedCrossRefGoogle Scholar
  61. 61.
    Nusse R: Wnts and Hedgehogs: lipid-modified proteins and similarities in signaling mechanisms at the cell surface. Development 2003, 130:5297–5305.PubMedCrossRefGoogle Scholar
  62. 62.
    Kalderon D: Similarities between the hedgehog and Wnt signaling pathways. Trends Cell Biol 2002, 12: 523–531.PubMedCrossRefGoogle Scholar
  63. 63.
    Luo Y, Cai J, Xue H, et al.: SDF1alpha/CXCR4 signaling stimulates beta-catenin transcriptional activity in rat neural progenitors. Neurosci Lett 2006, 398:291–295.PubMedCrossRefGoogle Scholar
  64. 64.
    Cauchi S, Vaxillaire M, Choquet H, et al.: No major contribution of TCF7L2 sequence variants to maturity onset of diabetes of the young (MODY) or neonatal diabetes mellitus in French white subjects. Diabetologia 2007, 50:214–216.PubMedCrossRefGoogle Scholar
  65. 65.
    Duval A, Rolland S, Tubacher E, et al.: The human T-cell transcription factor-4 gene: structure, extensive characterization of alternative splicings, and mutational analysis in colorectal cancer cell lines. Cancer Res 2000, 60:3872–3879.PubMedGoogle Scholar
  66. 66.
    Cauchi S, Choquet H, Gutiérrez-Aguilar R, et al.: Effects of TCF7L2 polymorphisms on obesity in European populations. Obesity (Silver Spring) 2008, In press.Google Scholar
  67. 67.
    Vidal-Puig AJ, Considine RV, Jimenez-Linan M, et al.: Peroxisome proliferator-activated receptor gene expression in human tissues. Effects of obesity, weight loss, and regulation by insulin and glucocorticoids. J Clin Invest 1997, 99:2416–2422.PubMedCrossRefGoogle Scholar
  68. 68.
    Wang J, Kuusisto J, Vanttinen M, et al.: 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 2007, 50:1192–1200.PubMedCrossRefGoogle Scholar
  69. 69.
    Watanabe RM, Allayee H, Xiang AH, et al.: Transcription factor 7-like 2 (TCF7L2) is associated with gestational diabetes mellitus and interacts with adiposity to alter insulin secretion in Mexican Americans. Diabetes 2007, 56:1481–1485.PubMedCrossRefGoogle Scholar
  70. 70.
    Loos RJ, Franks PW, Francis RW, et al.: TCF7L2 polymorphisms modulate proinsulin levels and beta-cell function in a British Europid population. Diabetes 2007, 56:1943–1947.PubMedCrossRefGoogle Scholar
  71. 71.
    Munoz J, Lok KH, Gower BA, et al.: Polymorphism in the transcription factor 7-like 2 (TCF7L2) gene is associated with reduced insulin secretion in nondiabetic women. Diabetes 2006, 55:3630–3634.PubMedCrossRefGoogle Scholar
  72. 72.
    Korinek V, Barker N, Moerer P, et al.: Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat Genet 1998, 19:379–383.PubMedCrossRefGoogle Scholar
  73. 73.
    Schafer SA, Tschritter O, Machicao F, et al.: Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms. Diabetologia 2007, 50:2443–2450.PubMedCrossRefGoogle Scholar
  74. 74.
    Lyssenko V, Lupi R, Marchetti P, et al.: Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J Clin Invest 2007, 117:2155–2163.PubMedCrossRefGoogle Scholar
  75. 75.
    Nauck MA, Meier JJ: The enteroinsular axis may mediate the diabetogenic effects of TCF7L2 polymorphisms. Diabetologia 2007, 50:2413–2416.PubMedCrossRefGoogle Scholar
  76. 76.
    Pearson ER, Donnelly LA, Kimber C, et al.: Variation in TCF7L2 influences therapeutic response to sulfonylureas: a GoDARTs study. Diabetes 2007, 56:2178–2182.PubMedCrossRefGoogle Scholar
  77. 77.
    Ross SE, Hemati N, Longo KA, et al.: Inhibition of adipogenesis by Wnt signaling. Science 2000, 289:950–953.PubMedCrossRefGoogle Scholar
  78. 78.
    Cawthorn WP, Heyd F, Hegyi K, Sethi JK: Tumour necrosis factor-alpha inhibits adipogenesis via a beta-catenin/TCF(TCF7L2)-dependent pathway. Cell Death Differ 2007, 14:1361–1373.PubMedCrossRefGoogle Scholar
  79. 79.
    Bennett CN, Ross SE, Longo KA, et al.: Regulation of Wnt signaling during adipogenesis. J Biol Chem 2002, 277:30998–31004.PubMedCrossRefGoogle Scholar
  80. 80.
    Cauchi S, Meyre D, Choquet H, et al.: TCF7L2 rs7903146 variant does not associate with smallness for gestational age in the French population. BMC Med Genet 2007, 8:37.PubMedCrossRefGoogle Scholar
  81. 81.
    Freathy RM, Weedon MN, Bennett A, et al.: Type 2 diabates TCF7L2 risk genotypes alter birth weight: a study of 24,053 individuals. Am J Hum Genet 2007, 80:1150–1161.PubMedCrossRefGoogle Scholar
  82. 82.
    Butler PC, Meier JJ, Butler AE, Bhushan A: The replication of beta cells in normal physiology, in disease and for therapy. Nat Clin Pract Endocrinol Metab 2007, 3:758–768.PubMedCrossRefGoogle Scholar
  83. 83.
    Janssens AC, Gwinn M, Valdez R, et al.: Predictive genetic testing for type 2 diabetes. BMJ 2006, 333:509–510.PubMedCrossRefGoogle Scholar
  84. 84.
    Weedon MN, McCarthy MI, Hitman G, et al.: Combining information from common type 2 diabetes risk polymorphisms improves disease prediction. PLoS Med 2006, 3:e374.PubMedCrossRefGoogle Scholar
  85. 85.
    Yang Q, Khoury MJ, Friedman J, et al.: How many genes underlie the occurrence of common complex diseases in the population? Int J Epidemiol 2005, 34:1129–1137.PubMedCrossRefGoogle Scholar
  86. 86.
    Mokdad AH, Ford ES, Bowman BA, et al.: Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 2003, 289:76–79.PubMedCrossRefGoogle Scholar

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© Current Medicine Group LLC 2008

Authors and Affiliations

  1. 1.Imperial College, Section of Genomic Medicine, Imperial College LondonHammersmith HospitalLondonUK

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