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

doi:10.1016/j.ebiom.2020.102878

Scleral HIF-1α is a prominent regulatory candidate for genetic and environmental interactions in human myopia pathogenesis

EBioMedicine. 2020 Jul:57:102878. doi: 10.1016/j.ebiom.2020.102878. Epub 2020 Jul 8.

Authors

Fei Zhao¹, Dake Zhang², Qingyi Zhou¹, Fuxin Zhao¹, Mingguang He³, Zhenglin Yang⁴, Yongchao Su¹, Ying Zhai¹, Jiaofeng Yan¹, Guoyun Zhang¹, Anquan Xue¹, Jing Tang¹, Xiaotong Han⁵, Yi Shi⁴, Yun Zhu¹, Tianzi Liu⁶, Wenjuan Zhuang⁷, Lulin Huang⁴, Yaqiang Hong⁶, Deng Wu⁶, Yingxiang Li⁸, Qinkang Lu⁹, Wei Chen², Shiming Jiao¹, Qiongsi Wang¹, Nethrajeith Srinivasalu¹, Yingying Wen¹, Changqing Zeng⁶, Jia Qu¹, Xiangtian Zhou¹⁰

Affiliations

¹ 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.
² 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.
³ 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.
⁴ 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.
⁵ State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, China.
⁶ Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, The Chinese Academy of Sciences, Beijing, China.
⁷ People's Hospital of Ningxia Hui Autonomous Region, Ningxia Eye Hospital (First Affiliated Hospital of Northwest University For Nationalities), Yinchuan, Ningxia, China.
⁸ WeGene, Inc, Shenzhen, Guangdong, China.
⁹ Ophthalmology Center of Yinzhou People's Hospital, Ningbo, Zhejiang, China.
¹⁰ 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. Electronic address: [email protected].

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.

Keywords: Genetic and environmental interactions; HIF-1α; Myopia; Myopia risk genes; Near work; Sclera.

MeSH terms

Animals
Disease Models, Animal
Female
Gene-Environment Interaction*
Genetic Predisposition to Disease*
Genome-Wide Association Study
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
Male
Mice
Myopia / genetics*
Myopia / metabolism
Myopia / pathology
Sclera / metabolism
Sclera / pathology
Signal Transduction

Substances

HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit