机构：[1]Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, China[2]Institute for Genomic Medicine and Shiley Eye Center, University of California, San Diego, La Jolla, California[3]Molecular Medicine Research Center and Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China四川大学华西医院[4]Institute of Molecular Medicine, Peking University, Beijing, China[5]Department of Medicine, Howard Hughes Medical Institute, School of Medicine, University of California, San Diego, La Jolla, California[6]Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing Tongren Hospital, Capital Medical University, Beijing, China研究所眼科研究所首都医科大学附属北京同仁医院首都医科大学附属同仁医院[7]Doheny Eye Institute, Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, California[8]State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China[9]Veterans Administration Healthcare System, San Diego, California.
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.
基金：
973 ProgramNational Basic Research Program of China [2011CB510200, 2013CB967504]; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [EY018660, EY021374, EY019270, EY014428)]; King Abdulaziz City for Science and Technology; University of California, San Diego, Center of Excellence in Nanomedicine; Burroughs Wellcome Fund Clinical Scientist Award in Translational ResearchBurroughs Wellcome Fund; Research to Prevent BlindnessResearch to Prevent Blindness (RPB); Clinical and Translational Research Institute [1TL1RR031979-01]; Cancer Training Grant [T32 CA009523]; VA Merit AwardUS Department of Veterans Affairs; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [T32CA009523] Funding Source: NIH RePORTER; NATIONAL CENTER FOR RESEARCH RESOURCESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Research Resources (NCRR) [TL1RR031979] Funding Source: NIH RePORTER; NATIONAL EYE INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Eye Institute (NEI) [R01EY021374, R01EY014428, R01EY019270, R01EY018660] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [P01DK074868] Funding Source: NIH RePORTER
第一作者机构：[1]Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, China[2]Institute for Genomic Medicine and Shiley Eye Center, University of California, San Diego, La Jolla, California[3]Molecular Medicine Research Center and Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
共同第一作者：
通讯作者：
通讯机构：[2]Institute for Genomic Medicine and Shiley Eye Center, University of California, San Diego, La Jolla, California[3]Molecular Medicine Research Center and Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China[9]Veterans Administration Healthcare System, San Diego, California.
医学