EBioMedicine (Jul 2020)
Scleral HIF-1α is a prominent regulatory candidate for genetic and environmental interactions in human myopia pathogenesis
- Fei Zhao,
- Dake Zhang,
- Qingyi Zhou,
- Fuxin Zhao,
- Mingguang He,
- Zhenglin Yang,
- Yongchao Su,
- Ying Zhai,
- Jiaofeng Yan,
- Guoyun Zhang,
- Anquan Xue,
- Jing Tang,
- Xiaotong Han,
- Yi Shi,
- Yun Zhu,
- Tianzi Liu,
- Wenjuan Zhuang,
- Lulin Huang,
- Yaqiang Hong,
- Deng Wu,
- Yingxiang Li,
- Qinkang Lu,
- Wei Chen,
- Shiming Jiao,
- Qiongsi Wang,
- Nethrajeith Srinivasalu,
- Yingying Wen,
- Changqing Zeng,
- Jia Qu,
- Xiangtian Zhou
Affiliations
- Fei Zhao
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; The State Key Laboratory of Optometry, Ophthalmology and Vision Science, Wenzhou, Zhejiang, China
- Dake Zhang
- Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China; Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, The Chinese Academy of Sciences, Beijing, China
- Qingyi Zhou
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; The State Key Laboratory of Optometry, Ophthalmology and Vision Science, Wenzhou, Zhejiang, China
- Fuxin Zhao
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; The State Key Laboratory of Optometry, Ophthalmology and Vision Science, Wenzhou, Zhejiang, China
- Mingguang He
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, China; Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia; Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, Australia
- Zhenglin Yang
- The Key Laboratory for Human Disease Gene Study of Sichuan Province, Department of Clinical Laboratory, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
- Yongchao Su
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; The State Key Laboratory of Optometry, Ophthalmology and Vision Science, Wenzhou, Zhejiang, China
- Ying Zhai
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; The State Key Laboratory of Optometry, Ophthalmology and Vision Science, Wenzhou, Zhejiang, China
- Jiaofeng Yan
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; The State Key Laboratory of Optometry, Ophthalmology and Vision Science, Wenzhou, Zhejiang, China
- Guoyun Zhang
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; The State Key Laboratory of Optometry, Ophthalmology and Vision Science, Wenzhou, Zhejiang, China
- Anquan Xue
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; The State Key Laboratory of Optometry, Ophthalmology and Vision Science, Wenzhou, Zhejiang, China
- Jing Tang
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; The State Key Laboratory of Optometry, Ophthalmology and Vision Science, Wenzhou, Zhejiang, China
- Xiaotong Han
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, China
- Yi Shi
- The Key Laboratory for Human Disease Gene Study of Sichuan Province, Department of Clinical Laboratory, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
- Yun Zhu
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; The State Key Laboratory of Optometry, Ophthalmology and Vision Science, Wenzhou, Zhejiang, China
- Tianzi Liu
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, The Chinese Academy of Sciences, Beijing, China
- Wenjuan Zhuang
- People's Hospital of Ningxia Hui Autonomous Region, Ningxia Eye Hospital (First Affiliated Hospital of Northwest University For Nationalities), Yinchuan, Ningxia, China
- Lulin Huang
- The Key Laboratory for Human Disease Gene Study of Sichuan Province, Department of Clinical Laboratory, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
- Yaqiang Hong
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, The Chinese Academy of Sciences, Beijing, China
- Deng Wu
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, The Chinese Academy of Sciences, Beijing, China
- Yingxiang Li
- WeGene, Inc, Shenzhen, Guangdong, China
- Qinkang Lu
- Ophthalmology Center of Yinzhou People's Hospital, Ningbo, Zhejiang, China
- Wei Chen
- Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China; Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, The Chinese Academy of Sciences, Beijing, China
- Shiming Jiao
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; The State Key Laboratory of Optometry, Ophthalmology and Vision Science, Wenzhou, Zhejiang, China
- Qiongsi Wang
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; The State Key Laboratory of Optometry, Ophthalmology and Vision Science, Wenzhou, Zhejiang, China
- Nethrajeith Srinivasalu
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; The State Key Laboratory of Optometry, Ophthalmology and Vision Science, Wenzhou, Zhejiang, China
- Yingying Wen
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; The State Key Laboratory of Optometry, Ophthalmology and Vision Science, Wenzhou, Zhejiang, China
- Changqing Zeng
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, The Chinese Academy of Sciences, Beijing, China
- Jia Qu
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; The State Key Laboratory of Optometry, Ophthalmology and Vision Science, Wenzhou, Zhejiang, China
- Xiangtian Zhou
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; The State Key Laboratory of Optometry, Ophthalmology and Vision Science, Wenzhou, Zhejiang, China; Corresponding author at: School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, 270 Xueyuan Road, Wenzhou, Zhejiang 325027, China.
- Journal volume & issue
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Vol. 57
p. 102878
Abstract
Background: Myopia is a good model for understanding the interaction between genetics and environmental stimuli. Here we dissect the biological processes affecting myopia progression. Methods: Human Genetic Analyses: (1) gene set analysis (GSA) of new genome wide association study (GWAS) data for 593 individuals with high myopia (refraction ≤ -6 diopters [D]); (2) over-representation analysis (ORA) of 196 genes with de novo mutations, identified by whole genome sequencing of 45 high-myopia trio families, and (3) ORA of 284 previously reported myopia risk genes. Contributions of the enriched signaling pathways in mediating the genetic and environmental interactions during myopia development were investigated in vivo and in vitro. Results: All three genetic analyses showed significant enrichment of four KEGG signaling pathways, including amphetamine addiction, extracellular matrix (ECM) receptor interaction, neuroactive ligand-receptor interaction, and regulation of actin cytoskeleton pathways. In individuals with extremely high myopia (refraction ≤ -10 D), the GSA of GWAS data revealed significant enrichment of the HIF-1α signaling pathway. Using human scleral fibroblasts, silencing the key nodal genes within protein-protein interaction networks for the enriched pathways antagonized the hypoxia-induced increase in myofibroblast transdifferentiation. In mice, scleral HIF-1α downregulation led to hyperopia, whereas upregulation resulted in myopia. In human subjects, near work, a risk factor for myopia, significantly decreased choroidal blood perfusion, which might cause scleral hypoxia. Interpretation: Our study implicated the HIF-1α signaling pathway in promoting human myopia through mediating interactions between genetic and environmental factors. Funding: National Natural Science Foundation of China grants; Natural Science Foundation of Zhejiang Province.
