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

Autor: Yi Shi, Wenjuan Zhuang, Dake Zhang, Xiaotong Han, Changqing Zeng, Yingying Wen, Shiming Jiao, Fuxin Zhao, Tianzi Liu, Zhenglin Yang, Jia Qu, Yun Zhu, Fei Zhao, Mingguang He, Anquan Xue, Nethrajeith Srinivasalu, Wei Chen, Yingxiang Li, Yaqiang Hong, Yongchao Su, Qinkang Lu, Jing Tang, Jiaofeng Yan, Qiongsi Wang, Deng Wu, Guoyun Zhang, Lulin Huang, Qingyi Zhou, Ying Zhai, Xiangtian Zhou
Rok vydání: 2020
Předmět:
Male
0301 basic medicine
Research paper
AL
Axial length
ChT
Choroidal thickness
genetic structures
AAV8-Vector
AAV8-packaged empty vector
DNMs
De novo mutations
lcsh:Medicine
Genome-wide association study
Mice
0302 clinical medicine
Myopia
Myopia risk genes
Genetics
lcsh:R5-920
siRNAs
Small interfering RNAs
General Medicine
EOHM
Early onset high myopia
ChBP
Choroidal blood perfusion
030220 oncology & carcinogenesis
HIF-1α
Hypoxia-inducible factor 1α
Female
GSA
Gene set analysis
FD-T
Form deprived eyes
Signal transduction
lcsh:Medicine (General)
Sclera
Signal Transduction
PPI
Protein-protein interaction
FD-F
Untreated fellow eyes in FD-mice
HIF-1α
Biology
KEGG
Kyoto Encyclopedia of Genes and Genomes
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
ECM
Extracellular matrix
VCD
Vitreous chamber depth
Downregulation and upregulation
WGS
Whole genome sequencing
FD
Form deprivation
Animals
Humans
Gene silencing
Genetic Predisposition to Disease
KEGG
Gene
GWAS
Genome wide association study
FDM
Form deprivation myopia
Genetic and environmental interactions
Near work
lcsh:R
Hypoxia-Inducible Factor 1
alpha Subunit
Actin cytoskeleton
eye diseases
AAV8-Cre
AAV8-packaged Cre-overexpressing vector
Disease Models
Animal
HSFs
Human scleral fibroblasts
ORA
Over-representation analysis
030104 developmental biology
HIF1A
Gene-Environment Interaction
sense organs
qRT-PCR
Quantitative real-time polymerase chain reaction
Genome-Wide Association Study
Zdroj: EBioMedicine, Vol 57, Iss, Pp 102878-(2020)
EBioMedicine
ISSN: 2352-3964
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: