Practice Essentials
Transcription factor 7-like 2 (TCF7L2) variants have been associated with type 2 diabetes mellitus (T2DM) in multiple ethnic groups. [1, 2, 3, 4, 5, 6, 7, 8] Specific associated variants increase the risk of T2DM 1.5-fold in heterozygotes and 2.4-fold in homozygotes, corresponding to a population attributable risk of 21%. This makes TCF7L2 variants the strongest known genetic risk factors for T2DM. [9, 10]
TCF7L2 was discovered as a type 2 diabetes susceptibility gene after a strong linkage signal was mapped to chromosome 10q in a Mexican-American population. This region was later fine-mapped in the Icelandic population and confirmed in US and Danish cohorts, where the risk locus was found to be located in intron 3 of the TCF7L2 gene. There are indications that this gene may play a role in cancer as well as in diabetes. [11] Subsequent studies have shown that several noncoding genetic variants of TCF7L2 are associated with T2DM risk in populations of diverse ancestries in the United Kingdom, the Netherlands, Finland, Sweden, France, India, and Japan. [12]
The TCF7L2 gene is polymorphic, and a number of loci such as the rs10749127, rs10787475, rs11196224, rs12775879, rs17130188, rs290481, rs290487, rs290489, rs3750804, rs4918792, rs6585194, rs7085532, rs7094463, rs7919409, rs966227, rs7903146, rs11196205, and rs12255372 polymorphisms have been identified. Among these single-nucleotide polymorphisms (SNPs), the TCF7L2 rs7903146 (intron 4) shows the strongest association with T2DM. [13]
The incidence of T2DM in African American women is more than twice that in white women in the United States. However, although more than 75 genetic loci for T2DM have been discovered in European, Asian, and Mexican ancestry populations, only 3 novel variants have been discovered in genome-wide association studies (GWASs) of African ancestry (AA) populations; most notable is SNP TCF7L2 rs7903146—the variant most significantly associated with T2DM to date. [14, 15]
TCF7L2 is a transcription factor and a key component of the Wnt signaling pathway; it is involved in the development of a wide variety of cell lineages and organs. [16] Potential mechanisms through which TCF7L2 variants influence T2DM include its role in adipogenesis, myogenesis, and pancreatic islet development, as well as in beta-cell survival and insulin secretory granule function. [17, 18] TCF7L2 protein is increased during adipogenesis in 3T3-L1 cells and in primary adipocyte stem cells. Inactivation of TCF7L2 protein attained by removing the high-mobility group (HMG)-box DNA binding domain in mature adipocytes in vivo leads to whole-body glucose intolerance and hepatic insulin resistance. This phenotype is associated with increased subcutaneous adipose tissue mass, adipocyte hypertrophy, and inflammation. [19] It is also involved in transcriptional regulation of genes for proglucagon and the glucagon-like peptides GLP-1 and GLP-2; these peptides play a role in postprandial insulin secretion. [20]
Finally, TCF7L2 polymorphisms have been associated with impaired insulin secretion, glucose production, and glucose tolerance via direct effects on pancreatic islet beta cells. [21, 22] Indeed, dysregulation of glucose metabolism, decreased processing of proinsulin, and elevated levels of gastric inhibitory peptide and glycated hemoglobin (HbA1c) can be observed before the onset of T2DM in normoglycemic individuals with TCF7L2 polymorphisms. [23, 24, 25]
Thus, although the specific mechanism driving the development of T2DM remains unclear, evidence is sufficient to demonstrate that TCF7L2 variants strongly predict development of T2DM and/or progression to diabetes from impaired glucose tolerance. [22, 26]
Clinical Implications
Although genetic tests for TCF7L2 could help predict the incidence and the rate of onset of T2DM, [27] 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. [28] In fact, the predictive power of TCF7L2 variants disappears with lifestyle modifications or metformin treatment, although improved insulin sensitivity resulting from these changes directly opposes the pathologic influence of TCF7L2 variants. [29] These data suggest that genetic susceptibility to T2DM as determined by TCF7L2 variants might prove an actionable indicator for early intervention and disease prevention. [26]
Researchers are also exploring whether TCF7L2 variants might serve as markers for tailoring customized therapeutic regimens. For example, dipeptidyl peptidase 4 (DPP4) is a peptidase that degrades incretins such as glucagon-like peptide 1 (GLP-1) agonists. [30] 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 pathologic axis in TCF7L2-driven T2DM, DPP4 inhibitors could potentially serve as a counterbalance and reverse the effects of TCF7L2 variants on incretin levels. [30] TCF7L2 polymorphisms have been associated with variation in response to sulfonylurea treatment, but these effects are likely too modest to guide care. [31, 32]
Obviously, the clinical utility of TCF7L2 variants is associated with some caveats. First, the specific T2DM risk variants of TCF7L2 vary from population to population. [33] Similar effect sizes have been observed in a number of ethnic groups for the most commonly studied TCF7L2 variants, but research must be expanded beyond nonwhite populations. Second, although 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.
Ultimately, TCF7L2 could prove a promising biomarker for disease prevention for those with an elevated genetic predisposition to T2DM. In the meantime, however, routine screening for TCF7L2 has no clinical role, and the presence of TCF7L2 variants that are associated with increased risk of T2DM should be considered in combination with other known predictors when a patient's individual risk for T2DM is assessed.
TCF7L2 rs12255372-T and rs7903146-T variants have been shown to modestly influence the initial therapeutic success with sulfonylureas, a class of oral hypoglycemic agents that stimulate the release of insulin. [34, 35, 36]
Researchers reported that downregulation of members of the Wnt-signaling pathway is evident in the bone of diabetic patients with and without Charcot arthropathy and that this may serve as a future therapeutic target for patients with this severe disease. In T2DM patients who developed Charcot arthropathy WNT3A and WNT5A, gene expression was downregulated by 89% and 58%, respectively, compared to healthy controls. TCF7L2 gene expression showed a significant reduction by 63% and 18%. [37]
