TCF7L2 Variation and Proliferative Diabetic Retinopathy
- Jing Luo1,2,3,
- Ling Zhao2,4,
- Aaron Yun Chen5,
- Xiaohui Zhang2,6,
- Jin Zhu2,
- Jiagang Zhao2,
- Hong Ouyang2,
- Hongrong Luo2,3,
- Yaojun Song2,
- Janet Lee2,
- Sherrina H. Patel2,
- Peter X. Shaw2,
- Srinivas Sadda7,
- Yehong Zhuo8⇑,
- Michael G. Rosenfeld5 and
- Kang Zhang2,3,9⇑
- 1Department of Ophthalmology, Second Xiangya Hospital, Central South University, Changsha, China
- 2Institute for Genomic Medicine and Shiley Eye Center, University of California, San Diego, La Jolla, California
- 3Molecular Medicine Research Center and Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
- 4Institute of Molecular Medicine, Peking University, Beijing, China
- 5Department of Medicine, Howard Hughes Medical Institute, School of Medicine, University of California, San Diego, La Jolla, California
- 6Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing Tongren Hospital, Capital Medical University, Beijing, China
- 7Doheny Eye Institute, Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, California
- 8State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
- 9Veterans Administration Healthcare System, San Diego, California
- Corresponding author: Yehong Zhuo, , or Kang Zhang, .
J.Lu., L.Z., and A.Y.C. contributed equally to this work.
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-1093/-/DC1.
- Received August 13, 2012.
- Accepted February 16, 2013.
- © 2013 by the American Diabetes Association.
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