TCF7L2 variants have been associated with type 2 diabetes in multiple ethnic groups.1,2,3,4,5,6,7 Specific associated variants increase risk of type 2 diabetes 1.5-fold in heterozygotes and 2.41-fold in homozygotes, corresponding to a population attributable risk of 21%. This makes TCF7L2 variants the strongest known genetic risk factor for type 2 diabetes.8
TCF7L2 is a transcription factor and key component of the Wnt signaling pathway, and is involved in the development of a wide variety of cell lineages and organs.9 Potential mechanisms by which TCF7L2 variants influence type 2 diabetes include its role in adipogenesis, myogenesis, and pancreatic islet development, as well transcription of the genes for proglucagon and the glucagon-like-peptides GLP-1 and GLP-2, which play a role in post-prandial insulin secretion.10 Additionally, TCF7L2 polymorphisms have been associated with impaired insulin secretion, glucose production, and glucose tolerance via direct effects on pancreatic islet beta-cells.11,12 Thus, while the specific mechanism driving the development of type 2 diabetes remains unclear, there is sufficient evidence to demonstrate that TCF7L2 variants strongly predict the development of type 2 diabetes and/or the progression to diabetes from impaired glucose tolerance.12,13
Although genetic tests for TCF7L2 could help predict the incidence of type 2 diabetes, the strongest predictors continue to be positive family history, increased body mass index, increased blood pressure, and increased serum levels of triglycerides, apolipoprotein A-1, and liver enzymes, all of which precede inception of metabolic syndrome.14 In fact, the predictive power of TCF7L2 variants disappears with lifestyle modifications or metformin treatment, while the improved insulin sensitivity resulting from these changes directly oppose the pathological influence of TCF7L2 variants.15 These data suggest that genetic susceptibility to type 2 diabetes as determined by TCF7L2 variants might prove an actionable indicator for early intervention and disease prevention.13
Researchers are also exploring whether TCF7L2 variants might serve as markers for tailoring customized therapeutic regimens. For example, DPP4 is a peptidase that degrades incretins such as GLP-1.16 DPP4 inhibitors enhance incretin-stimulated insulin secretion and inhibit glucagon release, thereby helping to normalize blood glucose levels. If a negative influence on incretin secretion is confirmed as a major pathological axis in TCF7L2 -driven type 2 diabetes, DPP4 inhibitors could potentially serve as a counterbalance and reverse the effects of TCF7L2 variants on incretin levels.16
Obviously, the clinical utility of TCF7L2 variants is associated with some caveats. First, it is unclear what role specific TCF7L2 variants play in different ethnic backgrounds. Similar effect sizes have been observed in a number of ethnic groups for the most commonly studied TCF7L2 variants, but the research must still be expanded to larger nonwhite populations. Second, although the effect sizes of TCF7L2 variants are relatively large, a much more accurate picture of risk stratification and therapeutic personalization would be informed by a larger collection of predisposition genes rather than TCF7L2 alone. Finally, no studies have unequivocally demonstrated a role for TCF7L2 variants in the management of type 2 diabetes beyond the point of disease onset.
Ultimately, TCF7L2 could prove a promising biomarker for disease prevention for those with an elevated genetic predisposition to type 2 diabetes. In the meantime, however, there is no clinical role for routine screening for, and the presence of TCF7L2 variants that are associated with increased risk of type 2 diabetes should be considered in combination with other known predictors when assessing a patient's individual risk for type 2 diabetes.
More information about type 2 diabetes and the influence of TCF7L2 variants can be found in the eMedicine article on Diabetes Mellitus, Type 2 and in the Medscape GLP-1 and Other Incretin Hormones in Diabetes Resource Center.
Type 2 diabetes, transcription factor 7-like 2, TCF7L2