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Background: Myopia is the leading cause of refractive errors. As its pathogenesis is poorly understood, we determined if the retinal VIP-VIPR2 signalling pathway axis has a role in controlling signalling output that affects myopia development in mice., Methods: Association analysis meta-study, single-cell transcriptome, bulk RNA sequencing, pharmacological manipulation and VIPR2 gene knockout studies were used to clarify if changes in the VIP-VIPR2 signalling pathway affect refractive development in mice., Results: The SNP rs6979985 of the VIPR2 gene was associated with high myopia in a Chinese Han cohort (randomceffect model: p=0.013). After either 1 or 2 days' form deprivation (FD) retinal VIP mRNA expression was downregulated. Retinal single-cell transcriptome sequencing showed that VIPR2 was expressed mainly by bipolar cells. Furthermore, the cAMP signalling pathway axis was inhibited in some VIPR2 + clusters after 2 days of FD. The selective VIPR2 antagonist PG99-465 induced relative myopia, whereas the selective VIPR2 agonist Ro25-1553 inhibited this response. In Vipr2 knockout ( Vipr2 -KO) mice, refraction was significantly shifted towards myopia (p<0.05). The amplitudes of the bipolar cell derived b-waves in 7-week-old Vipr2 -KO mice were significantly larger than those in their WT littermates (p<0.05)., Conclusions: Loss of VIPR2 function likely compromises bipolar cell function based on presumed changes in signal transduction due to altered signature electrical wave activity output in these mice. As these effects correspond with increases in form deprivation myopia (FDM), the VIP-VIPR2 signalling pathway axis is a viable novel target to control the development of this condition., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: To study the effects of posterior chamber phakic intraocular lens (IOL) on axial length (AL) measurements and whether a correction factor for later IOL power calculation before cataract surgery is necessary., Methods: Twenty-two high myopic patients (39 eyes) with mean spherical equivalent -19.00 +/- 4.03 D received phakic refractive lens (PRL) implantation, and 24 patients (40 eyes) with mean spherical equivalent (-13.10 +/- 2.53) D received implantable Collamer lens (ICL) implantation. Pre-and postoperative AL measurements with the IOLMaster were compared. Results The pre-and postoperative ALs were (30.87 +/- 2.18) mm and (30.94 +/- 2.16) mm, respectively (t = -2.635, P = 0.012) in the PRL group, and (28.35 +/- 1.20) mm and (28.45 +/- 1.22) mm, respectively ( t = -3.97, P < 0.001) in the ICL group. Linear regression analysis showed: in the PRL group, preoperative AL = 1.01 x postoperative AL-0.24 (R2 = 0.99, P < 0.001), or postoperative AL--preoperative AL = 0.24-0.0055 x postoperative AL; in the ICL group, preoperative AL = 0.96 x postoperative AL +1.17 (R2 = 0.99, P < 0.001), or postoperative AL--preoperative AL = 0.0154 x postoperative AL -0.3763. The mean differences between pre-and postoperative ALs in the PRL and, ICL groups were 0.075 mm and 0.054 mm, respectively., Conclusions: Based on the SRK formula, a < 0.1 mm AL difference would result in a <0.25 D change in the calculated IOL power, possibly a < 0.20 D change in manifest refraction. Furthermore, for PRL, the longer the AL, the smaller the difference between pre-and postoperative ALs. These differences are so small that it is unnecessary to correct IOL power calculation.

Myopia is a refractive error of the eye that is prevalent worldwide. The most extreme form, high myopia, is usually associated with other ocular disorders such as retinal detachment, macular degeneration, cataract, and glaucoma, and is one of leading causes of blindness. The etiology is complex and has not been fully elucidated. In this study, we identified a novel missense variant of the CCDC111 gene (NM&#95;152683.2: c.265T > G; p.Y89D) in a high myopia family by exome sequencing. The variant was identified in 4 patients from an additional 270 sporadic high myopia patients, but not found in 270 controls. The amino acid is highly conserved across species, and variants giving rise to amino acid substitutions are predicted to be functionally damaging. The CCDC111 gene was ubiquitously expressed in primary cell cultures from human eye tissue, including corneal epithelial cells, choroidal melanoma cells, scleral fibroblasts, retinal epithelial cells, retinal Müller cells, and lens capsule epithelial cells. In summary, our results suggested that the CCDC111 may be a susceptibility gene for high myopia.

Purpose: To investigate the changes in axial length and retinal thickness and their relationships with myopia in highly myopic anisometropia., Methods: A total of 87 Chinese subjects (25.28±11.98 years, mean±SD) were divided into two groups: anisometropia (n=38) and nonanisometropia (n=49). All eyes were measured for axial length, refractive status, and macular thickness (optical coherence tomography). Ocular biometric results were compared between eyes of subgroups. Linear correlation between refractive error and other biometric results was performed., Results: In the anisometropic group, the inner ring macula and part of the outer ring macula (nasal and inferior quadrants) in the higher myopic eyes were significantly thinner than in the fellow eyes (P≤0.007), but the foveal thickness (minimum and average) was similar (P≥0.050) between the two eyes. However, the minimum and average foveal thicknesses were found to be significantly thicker in the highly myopic eyes than those in the emmetropic to moderate myopic eyes (P≤0.016) in the nonanisometropic group. Among the eyes ranging from emmetropia to high myopia, the refractive error was negatively correlated to the axial length of the eye (P<0.001) and the thinning of inner ring macula is consistent with the increase in both myopia and axial length. There was a negative correlation in refractive error and axial length but no correlation in parafoveal thickness between eyes of the same subjects (P<0.001) in the anisometropic group., Conclusions: In people with myopic anisometropia, the higher myopic eye has a longer axial length but a thinner parafoveal region than its fellow eye. The axial growth in the development of high myopia seems to be centrally regulated; however, the changes in parafoveal thickness are likely manipulated by local mechanisms within the eye.

High myopia, which is extremely prevalent in the Chinese population, is one of the leading causes of blindness in the world. Genetic factors play a critical role in the development of the condition. To identify the genetic variants associated with high myopia in the Han Chinese, we conducted a genome-wide association study (GWAS) of 493,947 SNPs in 1088 individuals (419 cases and 669 controls) from a Han Chinese cohort and followed up on signals that were associated with p < 1.0 × 10(-4) in three independent cohorts (combined, 2803 cases and 5642 controls). We identified a significant association between high myopia and a variant at 13q12.12 (rs9318086, combined p = 1.91 × 10(-16), heterozygous odds ratio = 1.32, and homozygous odds ratio = 1.64). Furthermore, five additional SNPs (rs9510902, rs3794338, rs1886970, rs7325450, and rs7331047) in the same linkage disequilibrium (LD) block with rs9318086 also proved to be significantly associated with high myopia in the Han Chinese population; p values ranged from 5.46 × 10(-11) to 6.16 × 10(-16). This associated locus contains three genes-MIPEP, C1QTNF9B-AS1, and C1QTNF9B. MIPEP and C1QTNF9B were found to be expressed in the retina and retinal pigment epithelium (RPE) and are more likely than C1QTNF9B-AS1 to be associated with high myopia given the evidence of retinal signaling that controls eye growth. Our results suggest that the variants at 13q12.12 are associated with high myopia., (Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Purpose: The adenosine A(2A) receptor (A(2A)R) modulates collagen synthesis and extracellular matrix production in ocular tissues that contribute to eye growth and the development of myopia. We aimed to determine if single nucleotide polymorphisms (SNPs) in A(2A)R exons associates with high myopia found in Chinese subjects., Methods: DNA samples were prepared from venous lymphocytes of 175 Chinese subjects with high myopia of less than -8.00 diopters (D) correction and 101 ethnically similar controls with between -1.00 D and +1.00 D correction. The coding region sequences of A(2A)R were amplified by PCR and analyzed by Sanger sequencing. The detected variations were confirmed by reverse sequencing. Allelic frequencies of all detected common SNPs were assessed for Hardy-Weinberg equilibrium., Results: Five variations in A(2A)R exons, 5675 A>G, 5765 C>T, 13325 G>A, 13448 C>T, and 14000 T>A, were detected in controls at a low frequency (<1%). However, one SNP, 13772 T>C (rs5751876), showed its polymorphism in 53.3% of the total study population. The rs5751876 is a synonymous substitution located in a tyrosine codon of exon 2. Despite no significant difference in genotype distribution between cases and controls, the frequency of heterozygotes with the rs5751876 genotype was significantly lower in subjects with high myopia., Conclusions: The reduced frequency of the heterozygote rs5751876 genotype in subjects suggests a possible association of A(2A)R with high myopia in a Chinese population.

Purpose: BH3-like motif containing, cell death inducer (BLID) and LOC399959 are two genes associated with the single nucleotide polymorphism (SNP) rs577948, which is a susceptibility locus for high myopia in Japanese subjects. The purpose of this study was to determine if BLID and LOC399959 are associated with high myopia in Chinese Han subjects., Methods: High myopia subjects (n=476) had a spherical refractive error of less than -6.00 D in at least one eye and/or an axial length greater than 26 mm. Genomic DNA was extracted and genotyped from peripheral blood leukocytes of high myopes and controls (n=275). Using a case-control association study of candidate regions, linkage disequilibrium blocks for 19 tag SNPs (tSNPs), including rs577948, harbored within and surrounding the BLID and LOC399959 genes were analyzed on a MassArray platform using iPlex chemistry. Each of the tSNPs had an r(2)>0.8 and minor allele frequency >10% in the Chinese Han population. Haplotype association analysis was performed on Haploview 4.1 using Chi-square (χ(2)) tests., Results: None of the 19 tSNPs were statistically associated with high myopia., Conclusions: While rs577948 may be associated with high myopia in Japanese subjects, it and the other tSNPs near the BLID and LOC399959 genes are not susceptibility loci for high myopia in the Chinese Han population. Thus, associations of SNPs with high myopia as determined by Genome-Wide Association Study (GWAS) may be restricted to certain ethnic or genetically distinct populations. Without systematic replication in other populations, the results of GWAS associations should be interpreted with great caution.

Purpose: High myopia or pathological myopia is a common refractive error. Individuals with high myopia are subject to increased risk of serious eye complications. Accumulating evidence has demonstrated the role for heritability in ocular growth and in the development of high myopia. Retinoic acid and retinoic acid receptors play important roles in ocular development and in experimentally induced myopia. The purpose of this study was to determine if high myopia is associated with single nucleotide polymorphism (SNP) variants in the retinoic acid receptor beta (RARbeta) gene in Chinese subjects., Methods: DNA samples were purified from venous lymphocytes of 175 unrelated Chinese patients with high myopia (less than -8.00 diopters) and 101 Chinese control subjects without high myopia (+/-1.00 diopters). Direct nucleotide sequence analysis in the RARbeta gene was performed, and the detected variations were further confirmed by reverse sequencing. Allelic frequencies of all detected SNPs were assessed for Hardy-Weinberg equilibrium., Results: Five variations in RARbeta were detected in Chinese subjects with high myopia, including 32574G>A, 32629G>A, 32645C>T, 32647T>G, and 151973C>T, of which only 32647T>G (NCBI notes as rs58244688 and rs2067964) had already been reported. The majority of SNP genotypes were heterozygous. While 32647T>G, 32629G>A, and 32645C>T were located in introns and 32574G>A and 151973C>T were located in coding regions, none of the SNPs affected the amino acid sequence. In the present study, no evidence of association was found between variations in the nucleotide sequence of RARbeta and high myopia., Conclusions: Five SNP variants in RARbeta were detected in Chinese subjects with high myopia, none of them were associated significantly with high myopia. Further studies are needed to identify which genes are responsible for high myopia.

Purpose: To investigate the relationship between myopia and changes in ocular biometry and macular thickness in young adults., Methods: Two hundred sixteen eyes from 108 adults (23.3 +/- 6.3 years old, mean +/- SD) were measured for refractive status, corneal curvature, and axial components of the eye. Macular thickness was measured in 118 eyes (59 subjects) by optical coherence tomography. All eyes were categorized into emmetropia, low, moderate, or high myopia based on the refractive status. Biometric results from right eyes of all subjects were compared between sub-groups with the linear correlation analyzed between refraction and other parameters for each group., Results: The vitreous chamber depth was longest in high myopia, followed by the moderate myopia group, the low myopia group and finally the emmetropic group (p < or = 0.004). Average thickness of the inner and outer ring macula in all the myopia groups was significantly thinner than in the emmetropia group (p < or = 0.021). Among different macular regions, the inferior quadrant of the outer ring was consistently the thinnest in myopia. Corneal curvature, anterior chamber depth, and lens thickness measures were not associated with myopia., Conclusions: Myopia in young adults is associated with an increase in vitreous length and a decrease in para-foveal thickness. The thinness in the retinal region inferior to the fovea appears to be more highly correlated with myopia than any other retinal region.

Purpose: To determine corneal biomechanical properties in patients with high myopia., Design: Observational study., Methods: High myopia patients (n=45, age: 37.0+/-12.6 years) with refractive errors of spherical equivalent (SE) greater than -9.00D were recruited in this study along with healthy subjects (n=90, age: 33.7+/-12.4 years) with refractive errors of SE ranging from 0D to -3.00D. Only the right eye was studied. Central corneal thickness (CCT) was measured by optical coherence tomography (OCT). Metrics of corneal biomechanical properties, including corneal hysteresis (CH) and corneal resistance factor (CRF), were measured with the Ocular Response Analyzer (ORA). The ORA also determined the values of intraocular pressure (IOP(g)) and corneal compensated IOP (IOP(cc))., Results: No significant differences of CCT and CRF were present between the two groups (P=.15 and 0.35 for CCT and CRF, respectively); however, CH in the high myope group was lower than that in the controls (P<.01). IOP(g) and IOP(cc) were both significantly higher in the high myopes compared to the controls. In both groups, there were significant correlations between CH and CCT and between CRF and CCT. CH was not significantly correlated with age in either the control group or the high myope group (P>.05). There was a significant correlation between CH and SE when the two groups were combined for analysis., Conclusion: CH, but not CRF, was significantly lower in high myopia patients compared to that in normal subjects. The results indicate that some compromised aspects of the biomechanical properties of cornea may exist in people with high myopia.

Purpose: To evaluate the effects of angle-supported, iris-fixated and posterior chamber phakic intraocular lens (PIOL) implantation on contrast sensitivity (CS)., Methods: This prospective study included 69 eyes of 41 consecutive cases of high myopia which received an angle-supported (Phakic-6H; 26 eyes), iris-fixated (Verisyse; 23 eyes) or posterior chamber PIOL [phakic refractive lens (PRL); 20 eyes]. Photopic, mesopic and mesopic with glare CS were evaluated preoperatively and at least 6 months postoperatively., Results: In the PRL group, the mean postoperative CS at all frequencies and across all lighting conditions increased. These changes were significant for 6, 12 and 18 cycles per degree (cpd) under both photopic and mesopic conditions (p < 0.01) and for all the tested frequencies under mesopic with glare condition (p < or = 0.01). The average CS was relatively low in the PRL group. These changes were significant for 6 and 12 cpd between the Verisyse and PRL group under photopic condition (p < 0.05), for 3 and 6 cpd under mesopic condition (p < 0.01, p = 0.01) and under mesopic with glare condition (p < 0.01, p < 0.05)., Conclusions: Improvements in postoperative CS confirm that PIOL implantation is a promising alternative for correction of high myopia. In comparison to posterior chamber PIOLs, angle-supported and iris-fixated PIOLs seem to produce a better visual quality in terms of CS, which needs to be warranted by further investigations., ((c) 2007 S. Karger AG, Basel.)

Background: This study aimed to investigate the clinical effectiveness of posterior scleral reinforcement(PSR) for the treatment of myopic traction maculopathy (MTM).Methods: This was a prospective study of 32 eyes from 20 patients with MTM treated with PSR using genipin-cross-linked donor sclera. The length of the scleral strip used for the surgery was designed to be 1.5-times the axial length of the eye, whereas its width was 0.4-times the axial length of the eye. The optical coherence tomography images, spherical equivalent of refractive error, axial length, best corrected visual acuity, electroretinogram findings, and intraocular pressure of the patients were assessed postoperatively.Results: The mean duration of follow-up was 17.80 ± 8.74 months. The differences between the spherical equivalent of refractive error, best corrected visual acuity, axial length, and electroretinogram findings recorded preoperatively and those measured postoperatively were statistically significant (p < 0.05). The final reduction in axial length was 1.64 ± 0.85 mm. At the end of the follow-up, optical coherence tomography showed essential foveal reattachment in 30 eyes (93.75%), partial reattachment in two eyes (6.25%), and closure of macular holes in seven eyes (77.78%). No retinal detachment, vitreous haemorrhage, or other serious complications occurred following the surgery.Conclusions: Posterior scleral reinforcement with genipin-cross-linked sclera showed safe and effective outcomes for the treatment of MTM during a follow-up period of at least one year.Trial Registration: 11\12\2018, ChiCTR1800020012 . [ABSTRACT FROM AUTHOR]

Myopia is the most common cause of refractive error worldwide. High myopia is a severe type of myopia, which usually accompanies pathological changes in the fundus. To identify high myopia susceptibility genes, DNA-pooling based genome-wide association analysis was used to search for a correlation between single nucleotide polymorphisms and high myopia in a Han Chinese cohort (cases vs. controls in discovery stage: 507 vs. 294; replication stage 1: 991 vs. 1,025; replication stage 2: 1,021 vs. 52,708). Three variants (rs10889602T/G, rs2193015T/C, rs9676191A/C) were identified as being significantly associated with high myopia in the discovery, and replication stage. rs10889602T/G is located at the third intron of phosphodiesterase 4B (PDE4B), whose functional assays were performed by comparing the effects of rs10889602T/T deletion of this risk allele on PDE4B and COL1A1 gene and protein expression levels in the rs10889602T/Tdel/del, rs10889602T/Tdel/wt, and normal control A549 cell lines. The declines in the PDE4B and COL1A1 gene expression levels were larger in the rs10889602T/T deleted A549 cells than in the normal control A549 cells (one-way ANOVA, p < 0.001). The knockdown of PDE4B by siRNA in human scleral fibroblasts led to downregulation of COL1A1. This correspondence between the declines in rs10889602 of the PDE4B gene, PDE4B knockdown, and COL1A1 protein expression levels suggest that PDE4B may be a novel high myopia susceptibility gene, which regulates myopia progression through controlling scleral collagen I expression levels. More studies are needed to determine if there is a correlation between PDE4B and high myopia in other larger sample sized cohorts. [ABSTRACT FROM AUTHOR]