TCF7L2 rs7903146 polymorphism association with diabetes and obesity in an elderly cohort from Brazil

Abstract

Background Type 2 diabetes mellitus (T2DM) and obesity are complex pandemic diseases in the 21st century. Worldwide, the T allele rs7903146 in the TCF7L2 gene is recognized as a strong GWAS signal associated with T2DM. However, the association between the C allele and obesity is still poorly explored and needs to be replicated in other populations. Thus, the primary objectives of this study were to evaluate the TCF7L2 rs7903146 association with T2DM according to BMI status and to determine if this variant is related to obesity and BMI variation in a cohort of elderly Brazilians. Methods A total of 1,023 participants from an elderly census-based cohort called SABE (Saúde, Bem Estar e Envelhecimento—Health, Well-Being and Aging) were stratified by BMI status and type 2 diabetes presence. The TCF7L2 genotypes were filtered from the Online Archive of Brazilian Mutations (ABraOM—Online Archive of Brazilian Mutations) database, a web-based public database with sequencing data of samples of the SABE’s participants. Logistic regression models and interaction analyses were performed. The BMI variation (∆BMI) was calculated from anthropometric data collected in up to two time-points with a ten-year-assessment interval. Results The association between the rs7903146 T allele and T2DM was inversely proportional to the BMI status, with an increased risk in the normal weight group (OR 3.36; 95% CI [1.46–7.74]; P = 0.004). We confirmed the T allele association with risk for T2DM after adjusting for possible confound ing variables (OR 2.35; 95% CI [1.28–4.32]; P = 0.006). Interaction analysis showed that the increased risk for T2DM conferred by the T allele is modified by BMI (Pinteraction = 0.008), age (Pinteraction = 0.005) and gender (Pinteraction = 0.026). A T allele protective effect against obesity was observed (OR 0.71; 95% CI [0.54–0.94]; P = 0.016). The C allele increased obesity risk (OR 1.40; 95% CI [1.06–1.84]; P = 0.017) and the CC genotype showed a borderline association with abdominal obesity risk (OR 1.28; 95% CI [1.06–1.67]; P = 0.045). The CC genotype increased the obesity risk factor after adjusting for possible confounding variables (OR 1.41; 95% CI [1.06–1.86]; P = 0.017). An increase of the TT genotype in the second tertile of ∆BMI values was observed in participants without type 2 diabetes (OR 5.13; 95% CI [1.40–18.93]; P = 0.009) in the recessive genetic model. Conclusion We confirmed that the rs7903146 is both associated with T2DM and obesity. The TCF7L2 rs7903146 T allele increased T2DM risk in the normal weight group and interacted with sex, age and BMI, while the C allele increased obesity risk. The TT genotype was associated with a lesser extent of BMI variation over the SABE study’s 10-year period.

Association of TCF7L2, CASC8 and GREM1 Polymorphisms in Patients with Colorectal Cancer and Type II Diabetes Mellitus

“…It contains a DNA- binding domain, is implicated in the regulation of cell proliferation and differentiation, and maintains the stability of plasma glucose [ 28 , 29 ]. TCF7L2 is related with T2DM risk and DM complications such as diabetic nephropathy, and is also a susceptibility locus for CRC [ 12 , 15 , 30 ]. In the present study, the genotype distribution of the TCF7L2 rs7903146 polymorphism was correlated with susceptibility for CRC and DM in our population.…”

“…The transcription factor 7-like 2 ( TCF7L2 ) gene, 10q25.2–q25.3, is a transcription factor and β-catenin transcription partner in the Wnt signaling pathway that represses gene transcription in the absence of β-catenin after DNA-binding and also promotes miR-21 expression [ 9 , 10 , 11 ]. There are studies that have confirmed an association between TCF7L2 rs7903146 and T2DM [ 12 , 13 , 14 , 15 ], and a weak association with CRC [ 16 , 17 , 18 ]. Another polymorphism, rs6983267, is located in Cancer Susceptibility Candidate 8 Noncoding (CASC8) 8q24.21 and the risk allele promote stronger TCF7L2 binding, facilitating Wnt signaling [ 9 , 19 ].…”

A Review of the Impact of Pharmacogenetics and Metabolomics on the Efficacy of Metformin in Type 2 Diabetes

“…Furthermore, TCF7L2 variants were also linked to a faster decline in pancreatic ß-cell function, higher glycemic levels, and lower insulin production, all of which are linked to familial history of T2D 66 . Other studies have shown that the TCF7L2 rs 7903146T genotype is associated with both T2D and obesity, and that carriers may have changes in their plasma metabolic profiles due to phospholipids, suggesting that phospholipids may cause metabolic abnormalities prior to the onset of glucose intolerance 67 , 68 . These effects were recently brought to light by research demonstrating that the TCF7L2 gene controls a number of processes, including adipogenesis and disorders like T2D, as a downstream effector of the Wnt/ß-catenin signaling system 69 .…”

Interactions between genetic and lifestyle factors on cardiometabolic disease-related outcomes in Latin American and Caribbean populations: A systematic review

“…The search string results had an output of 29,092 articles and from these, 101 articles were identified as potential studies. After the full-text screening, 27 articles were excluded for the following reasons: six studies were not based on LACP (35)(36)(37)(38)(39)(40), five studies aimed to identify the effect of genomic ancestry (41)(42)(43)(44)(45), six studies focused only on genetic associations (46)(47)(48)(49)(50)(51), eight studies did not include cardiometabolic diseases (52)(53)(54)(55)(56)(57)(58)(59), and two studies investigated gene x phenotype interactions (60,61) as shown in Figure 5. Finally, after excluding the irrelevant articles based on the exclusion criteria, 74 studies were included in this systematic review as shown in Table 1.…”