TCF7L2 gene polymorphisms and type 2 diabetes: association with diabetic retinopathy and cardiovascular autonomic neuropathy

Abstract

Type 2 diabetes (T2DM) is a complex disease resulting from the contribution of both environmental and genetic factors. Recently, the list of genes implicated in the susceptibility to T2DM has substantially grown, also as a consequence of the great development of the genome-wide association studies in the last decade. Common polymorphisms in TCF7L2 gene have shown to have a strong effect with respect to many other involved genes. The aims of our study were to confirm the role of TCF7L2 in the susceptibility to T2DM in the Italian population and to investigate whether TCF7L2 genotypes also contribute to the clinical phenotypes variability and to diabetic complications development. Three TCF7L2 polymorphisms (rs7903146, rs7901695 and rs12255372) have been analyzed by allelic discrimination assays in a cohort of 154 Italian patients with T2DM and 171 healthy controls. A case-control association study and a genotype-phenotype correlation study have been carried out. Consistent with previous studies, all three SNPs showed a strong association with susceptibility to T2DM, both at genotypic (P = 0.003, P = 0.004 and P = 0.012) and at allelic level (P = 0.0004, P = 0.0004 and P = 0.003). Moreover, we observed associations between TCF7L2 variants and the following diabetic complications: diabetic retinopathy, cardiovascular disease and coronary artery disease. We also found a strong correlation between the rs7903146 and the presence of cardiovascular autonomic neuropathy (P = 0.02 with a high OR = 8.28). In conclusion, our study, in addition to confirming the involvement of TCF7L2 gene in the T2DM susceptibility, has shown that TCF7L2 genetic variability also contributes to the development of diabetic complications such as retinopathy and cardiovascular autonomic neuropathy.

Meta-analysis of variant rs 7903146 of TCF7L2 gene with secondary complications of Type 2 Diabetes Mellitus

“…Buraczynska et al [12] reported association of rs 7903146 with nephropathy, diabetic retinopathy and Cardiomyopathy, while Ciccacci et al [13] Egger's test for intercept showed no evidence of publication bias (intercept = -0.76, SE = 1.50, 95% CI = -4.44 to 2.90, p 2 tailed = 0.62). Classic Fail safe 'N' = 223, missing from the analysis for every published study included, which further supports absence of publication bias.…”

Exploring the association between diabetes mellitus and hearing loss: Genetic mutation, neuropathy and microangiopathy

“…Among the most common diabetic complications, some susceptible genes have been proposed to be independent factors, despite the duration of diabetes and HbA1c level. For instances, in a cohort, case-control and genotype-phenotype correlation study involving over 320 patients, TCF7L2 gene was significantly associated with diabetic retinopathy and autonomic neuropathy of cardiovascular diseases (Ciccacci et al, 2013). In addition, genetic linkage and characteristic analyses resulted that genes responsible for lipoprotein metabolism, PPARs (Peroxisome proliferator-activated receptors), cytokines, chemokines, and KLFs (Krüppel-like family of transcription factors) associated type 2 DM and coronary heart disease (Akbar, 2015).…”

Novel Genetic Actors of Diabetes-Associated Microvascular Complications: Retinopathy, Kidney Disease and Neuropathy

“…This study had a reasonable sample size (n = 1,139 in the discovery and replication cohorts combined), used the PDR phenotype, and defined controls stringently with a minimum diabetes duration of 15 years. TCF7L2 had already been studied in DR with both positive [33,34] and negative results [32,35]. Further investigation in other T2D populations is warranted.…”

“…The T allele frequency in the diabetic peripheral neuropathy group was lower than in T2D control (p = 0.001). In 154 Italian patients with T2D and 171 healthy controls, an association between the TCF7L2 rs7903146 variant and the presence of cardiovascular autonomic neuropathy has been reported (p = 0.02) [34]. Samples from subjects with diabetic neuropathy have also been evaluated for mutations in the AKR1B1 gene (exon 1) [97].…”