TCF7L2 Test # 2219

TRANSCRIPTION FACTOR 7-LIKE 2 (TCF7L2) implicated in blood glucose homeostasis. TCF7L2 variants have been associated with type 2 diabetes in multiple ethnic groups. Associated variants increase the risk of type 2 diabetes 1.5-fold in heterozygotes and 2.4-fold in homozygotes, corresponding to a population attributable risk of 31%. TCF7L2 variants are the strongest known genetic risk factors for type 2 diabetes and gestational diabetes. [1,2,3] Signal mapped to chromosome 10q in a Mexican-American population.[6] This region was later fine-mapped in the Icelandic population and confirmed in United States and Danish cohorts, where the risk locus was found to be located in intron 3 of the TCF7L2 gene. In intron 4 rs11196218 polymorphism in TCF7L2 with type 2 diabetes mellitus in Asian population(8). Potential mechanisms through which TCF7L2 variants influence type 2 diabetes include its role in adipogenesis, myogenesis, and pancreatic islet development, as well as in beta-cell survival and insulin secretory granule function. [4, 5] It is also involved in the transcriptional regulation of the genes for proglucagon and the glucagon-like peptides GLP-1 and GLP-2; these peptides play a role in postprandial insulin secretion.

Table 1 TCF7L2 Mutations
Mutation Name Codon Position dbSNP
c.382-41435 C>T Intron 3 rs7903146
c.483+9017 G>T Intron 4 rs12255372
c.483+7162 G>C Intron 4 rs11196205

Mechanisms by which TCF7L2 silencing reduces glucose-stimulated insulin secretion. A: Stimulus-secretion coupling of the β-cell. Glucose, via mitochondrial (mitoch.) production of ATP and an increased ATP-to-ADP ratio, causes closure of ATP-sensitive K+ (KATP) channels and elicits action potentials (APs) that are associated with the opening of voltage-gated Ca2+ channels. The increase in [Ca2+]i stimulates exocytosis of insulin-containing secretory granules (SGs). B: The insulin granules belong to different functional pools, which differ with regard to release competence. The vast majority of granules did not attain release competence and belong to a reserve pool (red granules). A small fraction of the granules are immediately available for release: the readily releasable pool (RRP) (green granules). Many readily releasable pool granules are situated in close proximity of the voltage-gated Ca2+ channels (i). In the absence of TCF7L2, the Ca2+ channels may detach from the secretory granules and [Ca2+]i increases in the wrong part of the β-cell (ii). C: Localized increases in [Ca2+]i (gray zones) close to the Ca2+ channels during brief action potential–like stimulation (i) and the global elevation produced during protracted (e.g., high K+) stimulation (ii).[7]

Abnormal Sample Report

Test Description:

The analysis of common variants in the TCF7L2 gene is detected by automated DNA sequencing. The gene is analyzed by PCR-based double-stranded automated sequencing in the sense and antisense directions.

Another important genes involved in Diabetes: ABCC8,CAPN10.

ABCC8: the protein functions are a modulator of ATP-sensitive potassium channels and insulin release. Mutations and deficiencies in this protein have been observed in patients with hyperinsulinemic hypoglycemia of infancy, an autosomal recessive disorder of unregulated and high insulin secretion. Mutations have also been associated with non-insulin-dependent diabetes mellitus type II, an autosomal dominant disease of defective insulin secretion.

CAPN10:This gene is associated with type 2 or non-insulin-dependent diabetes mellitus (NIDDM), and is located within the NIDDM1 region.

Specimen Requirements:

  • Specimen and Volume: Buccal epithelial cells collected on standard cotton tip swabs. Alternative acceptable specimens include 3-5 cc of blood in EDTA or ACD BD Vacutainer tubes guide. Other types of tissue may be accepted (please call 818-789-1033 to verify before sending).
  • Contact your doctor's office or FirmaLab for buccal swab kits. Buccal Swab Kit Instructions
  • Temperature: can be at room temperature the specimen needs to be at the laboratory no more then 72hrs. Do not freeze whole blood.
  • Turn around time: 5-7 days

Specimen Rejection Criteria: Below are general rejection criteria. If the specimen must be rejected based on the following criteria, or specific criteria for the requested test:

  1. The test requisition form has missing information. Requisition must contain the required information including:
    • Requesting party and referring authority, usually a healthcare professional.
    • Patient identifying information - Name or alias if anonymous;
    • Test requested, Clinical indication for testing;
    • Date and time of specimen collection;
    • Type of sample (e.g. whole blood or epithelial cells obtained by buccal swab);
    • All other identifying information (e.g. social security number, telephone number, hospital ID, sex … etc.) is optional, but useful for accurate differentiating between patients with similar names.
  2. Label is unclear;
  3. Blood specimen is from a recipient of bone marrow transplant;
  4. Specimen is inappropriate for test requested;
  5. Blood sample is clotted or hemolyzed;
  6. Incorrect container or Vacutainer used;


1. 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 Oct. 55(10):2903-8.

2. Sale MM, Smith SG, Mychaleckyj JC, et al. Variants of the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes in an African-American population enriched for nephropathy. Diabetes. 2007 Oct. 56(10):2638-42.

3. Lin P-C, Lin W-T, Yeh Y-H, Wung S-F. Transcription Factor 7-Like 2 (TCF7L2) rs7903146 Polymorphism as a Risk Factor for Gestational Diabetes Mellitus: A Meta-Analysis. Hribal ML, ed. PLoS ONE. 2016;11(4):e0153044.

4. Da Silva Xavier G, Mondragon A, Mourougavelou V, Cruciani-Guglielmacci C, Denom J, Herrera PL, Magnan C, Rutter GA.Pancreatic alpha cell-selective deletion of Tcf7l2 impairs glucagon secretion and counter-regulatory responses to hypoglycaemia.Diabetologia. 2017 Mar 25. doi:10.1007/s00125-017-4242-2.

5. Engelbrechtsen L, Hansen TH, Mahendran Y, Pyl P, Andersson E, Jonsson A, Gjesing A, Linneberg A, Jørgensen T, Hansen T, Vestergaard H.Homozygous carriers of the TCF7L2 rs7903146 T-allele show altered postprandial response in triglycerides and triglyceride-rich lipoproteins. Sci Rep. 2017 Feb 21;7:43128. doi: 10.1038/srep43128.

6. Gallardo-Blanco HL.Genetic variants in KCNJ11, TCF7L2 and HNF4A are associated with type 2 diabetes, BMI and dyslipidemia in families of Northeastern Mexico: A pilot study.Exp Ther Med. 2017 Feb;13(2):523-529.

7. Gloyn AL, Braun M, Rorsman P. Type 2 Diabetes Susceptibility Gene TCF7L2 and Its Role in β-Cell Function. Diabetes. 2009;58(4):800-802. doi:10.2337/db09-0099.

8. Yujia Zhai a,1, Jingzhi Zhao b et all. Association of the rs11196218 polymorphism in TCF7L2 with type 2 diabetes mellitus in Asian population.

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