TCF7L2 Variation and Proliferative Diabetic Retinopathy

  1. Kang Zhang2,3,9
  1. 1Department of Ophthalmology, Second Xiangya Hospital, Central South University, Changsha, China
  2. 2Institute for Genomic Medicine and Shiley Eye Center, University of California, San Diego, La Jolla, California
  3. 3Molecular Medicine Research Center and Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
  4. 4Institute of Molecular Medicine, Peking University, Beijing, China
  5. 5Department of Medicine, Howard Hughes Medical Institute, School of Medicine, University of California, San Diego, La Jolla, California
  6. 6Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing Tongren Hospital, Capital Medical University, Beijing, China
  7. 7Doheny Eye Institute, Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, California
  8. 8State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
  9. 9Veterans Administration Healthcare System, San Diego, California
  1. Corresponding author: Yehong Zhuo, zhuoyh{at}mail.sysu.edu.cn, or Kang Zhang, kang.zhang{at}gmail.com.
  1. J.Lu., L.Z., and A.Y.C. contributed equally to this work.

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.

Footnotes

  • Received August 13, 2012.
  • Accepted February 16, 2013.

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  1. Diabetes vol. 62 no. 7 2613-2617
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