Commentary

Nearwork and myopia

Myopia is a good model for understanding the interaction between genetics and environmental stimuli. Here we dissect the biological processes affecting myopia progression.

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.

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.

Our study implicated the HIF-1α signaling pathway in promoting human myopia through mediating interactions between genetic and environmental factors.

National Natural Science Foundation of China grants; Natural Science Foundation of Zhejiang Province.

Myopia is a highly prevalent eye disease. There is limited information suggesting a relationship between myopia and inflammation. We found children with allergic conjunctivitis (AC) had the highest adjusted odds ratio (1.75, 95% confidence interval [CI], 1.72–1.77) for myopia among the four allergic diseases. A cohort study was conducted and confirmed that children with AC had a higher incidence and subsequent risk of myopia (hazard ratio 2.35, 95%CI 2.29–2.40) compared to those without AC. Lower refractive error and longer axial length were observed in an AC animal model. Myopia progression was enhanced by tumor necrosis factor (TNF)-α or interleukin (IL)-6 administration, two cytokines secreted by mast cell degranulation. The TNF-α or IL-6 weakened the tight junction formed by corneal epithelial (CEP) cells and inflammatory cytokines across the layer of CEP cells, which increased the levels of TNF-α, IL-6, and IL-8 secreted by retinal pigment epithelial cells. The expression levels of TNF-α, IL-6, IL-8, monocyte chemoattractant protein-1, and nuclear factor kappa B were up-regulated in eyes with AC, whereas IL-10 and the inhibitor of kappa B were down-regulated. In conclusion, the experimental findings in mice corroborate the epidemiological data showing that allergic inflammation influences the development of myopia.

To determine the effectiveness of different interventions to slow down the progression of myopia in children.

We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov from inception to August 2014. We selected randomized controlled trials (RCTs) involving interventions for controlling the progression of myopia in children with a treatment duration of at least 1 year for analysis.

The primary outcomes were mean annual change in refraction (diopters/year) and mean annual change in axial length (millimeters/year).

Thirty RCTs (involving 5422 eyes) were identified. Network meta-analysis showed that in comparison with placebo or single vision spectacle lenses, high-dose atropine (refraction change: 0.68 [0.52–0.84]; axial length change: −0.21 [−0.28 to −0.16]), moderate-dose atropine (refraction change: 0.53 [0.28–0.77]; axial length change: −0.21 [−0.32 to −0.12]), and low-dose atropine (refraction change: 0.53 [0.21–0.85]; axial length change: −0.15 [−0.25 to −0.05]) markedly slowed myopia progression. Pirenzepine (refraction change: 0.29 [0.05–0.52]; axial length change: −0.09 [−0.17 to −0.01]), orthokeratology (axial length change: −0.15 [−0.22 to −0.08]), and peripheral defocus modifying contact lenses (axial length change: −0.11 [−0.20 to −0.03]) showed moderate effects. Progressive addition spectacle lenses (refraction change: 0.14 [0.02–0.26]; axial length change: −0.04 [−0.09 to −0.01]) showed slight effects.

This network analysis indicates that a range of interventions can significantly reduce myopia progression when compared with single vision spectacle lenses or placebo. In terms of refraction, atropine, pirenzepine, and progressive addition spectacle lenses were effective. In terms of axial length, atropine, orthokeratology, peripheral defocus modifying contact lenses, pirenzepine, and progressive addition spectacle lenses were effective. The most effective interventions were pharmacologic, that is, muscarinic antagonists such as atropine and pirenzepine. Certain specially designed contact lenses, including orthokeratology and peripheral defocus modifying contact lenses, had moderate effects, whereas specially designed spectacle lenses showed minimal effect.