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      Is Open Access

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

      research-article
      Author(s): a , b , 1 , c , d , 1 , a , b , a , b , e , f , g , h , a , b , a , b , a , b , a , b , a , b , a , b , e , h , a , b , d , i , h , d , d , j , k , c , d , a , b , a , b , a , b , a , b , d , a , b , a , b , *
      Publication date (Electronic):
      Journal: EBioMedicine
      Publisher: Elsevier
      Keywords: Genetic and environmental interactions, Myopia, Sclera, Near work, Myopia risk genes, HIF-1α, AAV8-Cre, AAV8-packaged Cre-overexpressing vector, AAV8-Vector, AAV8-packaged empty vector, AL, Axial length, ChT, Choroidal thickness, ChBP, Choroidal blood perfusion, DNMs, De novo mutations, EOHM, Early onset high myopia, ECM, Extracellular matrix, FD, Form deprivation, FD-T, Form deprived eyes, FDM, Form deprivation myopia, GSA, Gene set analysis, GWAS, Genome wide association study, HSFs, Human scleral fibroblasts, HIF-1α, Hypoxia-inducible factor 1α, KEGG, Kyoto Encyclopedia of Genes and Genomes, ORA, Over-representation analysis, PPI, Protein-protein interaction, qRT-PCR, Quantitative real-time polymerase chain reaction, siRNAs, Small interfering RNAs, FD-F, Untreated fellow eyes in FD-mice, VCD, Vitreous chamber depth, WGS, Whole genome sequencing

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          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.

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          Most cited references42

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          Homeostasis of eye growth and the question of myopia.

          Josh Wallman, Jonathan Winawer (2004)
          As with other organs, the eye's growth is regulated by homeostatic control mechanisms. Unlike other organs, the eye relies on vision as a principal input to guide growth. In this review, we consider several implications of this visual guidance. First, we compare the regulation of eye growth to that of other organs. Second, we ask how the visual system derives signals that distinguish the blur of an eye too large from one too small. Third, we ask what cascade of chemical signals constitutes this growth control system. Finally, if the match between the length and optics of the eye is under homeostatic control, why do children so commonly develop myopia, and why does the myopia not limit itself? Long-neglected studies may provide an answer to this last question.
          Article 0 comments Cited 234 times – based on 0 reviews     Review now
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            Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia.

            Virginie J M Verhoeven, Pirro G. Hysi, Robert Wojciechowski … (2013)
            Refractive error is the most common eye disorder worldwide and is a prominent cause of blindness. Myopia affects over 30% of Western populations and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses, including 37,382 individuals from 27 studies of European ancestry and 8,376 from 5 Asian cohorts. We identified 16 new loci for refractive error in individuals of European ancestry, of which 8 were shared with Asians. Combined analysis identified 8 additional associated loci. The new loci include candidate genes with functions in neurotransmission (GRIA4), ion transport (KCNQ5), retinoic acid metabolism (RDH5), extracellular matrix remodeling (LAMA2 and BMP2) and eye development (SIX6 and PRSS56). We also confirmed previously reported associations with GJD2 and RASGRF1. Risk score analysis using associated SNPs showed a tenfold increased risk of myopia for individuals carrying the highest genetic load. Our results, based on a large meta-analysis across independent multiancestry studies, considerably advance understanding of the mechanisms involved in refractive error and myopia.
            Article 0 comments Cited 194 times – based on 0 reviews     Review now
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              Hypoxia-inducible factor-1alpha is a positive factor in solid tumor growth.

              W McNulty, M Gassmann, M Poloni … (2000)
              Deficiencies in oxygenation are widespread in solid tumors. The transcription factor hypoxia-inducible factor (HIF)-1alpha is an important mediator of the hypoxic response of tumor cells and controls the up-regulation of a number of factors important for solid tumor expansion, including the angiogenic factor vascular endothelial growth factor (VEGF). We have isolated two cell lines nullizygous for HIF-1alpha, one from embryos genetically null for HIF-1alpha, and the other from embryos carrying loxP-flanked alleles of the gene, which allows for cre-mediated excision. The loss of HIF-1alpha negatively affects tumor growth in these two sets of H-ras-transformed cell lines, and this negative effect is not due to deficient vascularization. Despite differences in VEGF expression, vascular density is similar in wild-type and HIF-1alpha-null tumors. The evidence from these experiments indicates that hypoxic response via HIF-1alpha is an important positive factor in solid tumor growth and that HIF-1alpha affects tumor expansion in ways unrelated to its regulation of VEGF expression.
              Article 0 comments Cited 159 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Xiangtian Zhou
                Journal
                Journal ID (nlm-ta): EBioMedicine
                Journal ID (iso-abbrev): EBioMedicine
                Title: EBioMedicine
                Publisher: Elsevier
                ISSN (Electronic): 2352-3964
                Publication date PMC-release: 08 July 2020
                Publication date Collection: July 2020
                Publication date (Electronic): 08 July 2020
                Volume: 57
                Electronic Location Identifier: 102878
                Affiliations
                [a ]School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
                [b ]The State Key Laboratory of Optometry, Ophthalmology and Vision Science, Wenzhou, Zhejiang, China
                [c ]Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
                [d ]Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, The Chinese Academy of Sciences, Beijing, China
                [e ]State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, China
                [f ]Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia
                [g ]Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, Australia
                [h ]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
                [i ]People's Hospital of Ningxia Hui Autonomous Region, Ningxia Eye Hospital (First Affiliated Hospital of Northwest University For Nationalities), Yinchuan, Ningxia, China
                [j ]WeGene, Inc, Shenzhen, Guangdong, China
                [k ]Ophthalmology Center of Yinzhou People's Hospital, Ningbo, Zhejiang, China
                Author notes
                [* ]Corresponding author at: School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, 270 Xueyuan Road, Wenzhou, Zhejiang 325027, China. zxt@ 123456mail.eye.ac.cn
                [1]

                These authors contributed equally to this article.

                Article
                Publisher ID: S2352-3964(20)30253-X Publisher ID: 102878
                DOI: 10.1016/j.ebiom.2020.102878
                PMC ID: 7348000
                PubMed ID: 32652319
                SO-VID: 7540fbd0-1d88-443c-b34e-b65a19336bed
                Copyright © © 2020 The Author(s)
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 18 February 2020
                Date revision received : 8 June 2020
                Date accepted : 22 June 2020
                Categories
                Subject: Research paper

                Keywords: genetic and environmental interactions,myopia,sclera,near work,myopia risk genes,hif-1α,aav8-cre, aav8-packaged cre-overexpressing vector,aav8-vector, aav8-packaged empty vector,al, axial length,cht, choroidal thickness,chbp, choroidal blood perfusion,dnms, de novo mutations,eohm, early onset high myopia,ecm, extracellular matrix,fd, form deprivation,fd-t, form deprived eyes,fdm, form deprivation myopia,gsa, gene set analysis,gwas, genome wide association study,hsfs, human scleral fibroblasts,hif-1α, hypoxia-inducible factor 1α,kegg, kyoto encyclopedia of genes and genomes,ora, over-representation analysis,ppi, protein-protein interaction,qrt-pcr, quantitative real-time polymerase chain reaction,sirnas, small interfering rnas,fd-f, untreated fellow eyes in fd-mice,vcd, vitreous chamber depth,wgs, whole genome sequencing
                Data availability:
                Keywords: genetic and environmental interactions, myopia, sclera, near work, myopia risk genes, hif-1α, aav8-cre, aav8-packaged cre-overexpressing vector, aav8-vector, aav8-packaged empty vector, al, axial length, cht, choroidal thickness, chbp, choroidal blood perfusion, dnms, de novo mutations, eohm, early onset high myopia, ecm, extracellular matrix, fd, form deprivation, fd-t, form deprived eyes, fdm, form deprivation myopia, gsa, gene set analysis, gwas, genome wide association study, hsfs, human scleral fibroblasts, hif-1α, hypoxia-inducible factor 1α, kegg, kyoto encyclopedia of genes and genomes, ora, over-representation analysis, ppi, protein-protein interaction, qrt-pcr, quantitative real-time polymerase chain reaction, sirnas, small interfering rnas, fd-f, untreated fellow eyes in fd-mice, vcd, vitreous chamber depth, wgs, whole genome sequencing

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