Transcription Factor 7 Like, 2 (TCF7L2) is, as the name suggests, a transcription factor involved in glucose homeostasis. Certain polymorphisms in this gene have been consistently associated with type 2 diabetes (T2D). Although the exact mechanism of this effect is under study, it probably involves impairment in insulin secretion. In addition, at least one frameshift mutation in the gene has been linked to colon cancer.
The TCF7L2 gene is located on chromosome 10, where it spans a total length of 215 kb. The gene product consists of 619 amino acids and weighs approximately 70 kDa. This protein is a member of the Wnt signaling pathway. It heterodimerizes with beta-catenin, thereby, activating several genes many of them involved in cell cycle regulation. Intestinal proglucagon is one of the important genes regulated by this transcription factor. The TCF7L2 protein also plays a role in the maintenance of the small intestinal epithelium. Not surprisingly, the protein shows maximum expression in this tissue.
Cauchi et al. (2007) investigated the association between the TCF7L2 rs7903146 polymorphism and T2D in Moroccans (406 normoglycemic individuals and 504 T2D subjects) and in white Austrians. The allelic odds ratios (ORs) for T2D were 1.56 and 1.52 in Moroccans and Austrians, respectively. No heterogeneity was found between these two different populations by Woolf test. Later, Cauchi et al. (2008) included this study group into a larger analysis to validate possible markers that could be highly associated with type 2 diabetes (T2D) in other European and non-European populations. The T2D risk increased strongly when risk alleles, including the T2D-associated TCF7L2 rs7903146 SNP, were combined. Cauchi et al. (2008) concluded that TCF7L2, SLC30A8, HHEX, CDKAL1, IGFBP2, and CDKN2A/2B genes strongly associate with T2D in French individuals, and mostly in populations of Central European descent, but not in Moroccan subjects.
A study by Alsmadi et al. (2008) was set to determine the role of two variants of the TCF7L2 gene in Arabs in the context of type 2 diabetes (T2D); these variants are rs7903146 and rs12255372. The latter variants have been strongly associated with T2D risk in many populations around the world. Saudi T2D patients (522 individuals), and controls (346 individuals) aged over 60, with fasting plasma glucose < 7 mmol/L were included in a case-control association study. The results indicated weak or no association of T2D in Arabs with the abovementioned TCF7L2 variants.
Saadi et al. (2008) studied the association of the two TCF7L2 SNPs, rs12255372 and rs7903146, with diabetes mellitus (DM), metabolic syndrome, and insulin resistance in 368 adult Emiratis. Diabetes disease stage was found to be marginally significantly associated with the rs12255372 SNP, while subjects with DM or pre-diabetes were found to be significantly associated with the rs7903146 SNP. Results, thus, showed an association of these TCF7L2 variants with DM in the Emirati population. However, no such association was found with insulin levels or metabolic syndrome.
Al-Safar et al. (2015) carried out a case-control study to evaluate the association between TCF7L2 and PPAR-𝛾2 SNPs with Type 2 Diabetes Mellitus (T2DM) in the Emirati population. The authors genotyped 272 Emirati T2DM patients along with 216 healthy controls for the SNPs rs10885409 (TCF7L2) and rs1801282 (PPAR-𝛾2 Pro12Ala). No association was found between these two SNPs and T2DM in this cohort. The patients were then stratified based on obesity status wherein individuals with a BMI greater than 30 were considered obese. It was found that patients in the non-obese group with the TCF7L2 rs10885409 CC genotypes were at an approximately two-fold higher risk of T2DM than those with CT or TT genotypes [OR 1.975 (95% CI 1.127-3.461), p=0.017]. No such association was seen in the obese group. The authors thus identified the rs10885409 C allele as a T2DM risk factor which is modulated by obesity status in the Emirati population.
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