title: 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.
authors: Department of Ophthalmology, Second Xiangya Hospital, Central South University, Changsha, China.
authors: Jing
authors: J
authors: Luo
authors: Ling
authors: L
authors: Zhao
authors: Aaron Yun
authors: AY
authors: Chen
authors: Xiaohui
authors: X
authors: Zhang
authors: Jin
authors: J
authors: Zhu
authors: Jiagang
authors: J
authors: Zhao
authors: Hong
authors: H
authors: Ouyang
authors: Hongrong
authors: H
authors: Luo
authors: Yaojun
authors: Y
authors: Song
authors: Janet
authors: J
authors: Lee
authors: Sherrina H
authors: SH
authors: Patel
authors: Peter X
authors: PX
authors: Shaw
authors: Srinivas
authors: S
authors: Sadda
authors: Yehong
authors: Y
authors: Zhuo
authors: Michael G
authors: MG
authors: Rosenfeld
authors: Kang
authors: K
authors: Zhang
mesh_terms: D000483:Alleles; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D003930:Diabetic Retinopathy / Q000235:genetics*; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D051379:Mice; D020641:Polymorphism, Single Nucleotide; D015861:Retinal Neovascularization / Q000235:genetics; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A