TCF7L2 Variation and Proliferative Diabetic Retinopathy

Abstract

Proliferative diabetic retinopathy (PDR) is the most severe vision-threatening complication of diabetes. For investigation of genetic association between TCF7L2 and PDR in Caucasian type 2 diabetes mellitus (T2DM) and its functional consequences, 383 T2DM patients with PDR (T2DM-PDR) and 756 T2DM patients without diabetic retinopathy (T2DM–no DR) were genotyped with rs7903146 in TCF7L2. We found that risk allele (T) frequency of rs7903146 was significantly higher in T2DM-PDR patients (allelic P = 2.52E-04). In lymphoblastoid cells induced to undergo endoplasmic reticulum (ER) stress by treatment of tunicamycin, higher fold change of TCF7L2 and VEGFA mRNA levels were observed in rs7903146-TT cells than in rs7903146-CC cells (P = 0.02 for TCF7L2; P = 0.004 for VEGFA), suggesting that ER stress plays a role in PDR pathogenesis. Silencing TCF7L2 resulted in decreased mRNA levels of both TCF7L2 and VEGFA (P < 0.001). Retinas of oxygen-induced retinopathy mice (a model for PDR) had higher TCF7L2 and VEGFA mRNA levels than those of controls (P = 2.9E-04 for TCF7L2; P = 1.9E-07 for VEGFA). Together, data from our study show that TCF7L2-rs7903146 is associated with PDR in Caucasian T2DM and suggest that TCF7L2 promotes pathological retinal neovascularization via ER stress–dependent upregulation of VEGFA.

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

“…An association with PDR in Caucasians with T2D and replication in an independent cohort was reported [33]. 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.…”

“…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.…”

Developments in Ocular Genetics

“…For instance, variants in the TCF7L2 gene were found to promote pathological retinal neovascularization via ER stress-dependent upregulation of VEGFA 34 . Moreover, the receptor for advanced glycation end-product ( RAGE ) gene polymorphism -2245G/A was shown to upregulate expression of NF-κB p65 , plasma MCP-1 , AOPP and pentosidine, all of which are pro-inflammatory, oxidative-glycation markers 35 .…”

Association between transcription factor 7-like 2 rs7903146 polymorphism and diabetic retinopathy in type 2 diabetes mellitus: A meta-analysis

“…9 Among these genetic variants, rs7903146 on the chromosome 10q25 region has been the most frequently reported to be strongly associated with T2DM. 8,[10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] It was also reported that TCF7L2 gene rs7903146 is linked with microvascular and macrovascular complications, such as coronary artery disease, 30,31 nephropathy, 20,32,33 retinopathy, 32,[34][35][36][37][38][39][40] and neuropathy. 37 However, some studies demonstrated that TCF7L2 rs7903146 is not consistently associated with DR, 32,34,35,38,39 while others suggested TCF7L2 genetic variability contributes to the development of DR. 36,37,40 Clarification of the actual role of TCF7L2 rs7903146 in DR process and identification of its function as a genetic risk marker will assist ophthalmologists to predict and debilitate diabetes complication.…”

“…All studies were case-control studies, of which two studies were performed on East Asian and six on Caucasian. Three studies had larger sample sizes, 36,38,39 the total cases were 1139, 1129 and 1206, respectively. Other five studies had relatively small sizes (numbers of cases < 1000).…”