Three-Year Clinical Trial of Low-Concentration Atropine for Myopia Progression (LAMP) Study: Continued Versus Washout: Phase 3 Report.

PURPOSE: (1) To compare the efficacy of continued and stopping treatment for 0.05%, 0.025%, and 0.01% atropine during the third year. (2) To evaluate the efficacy of continued treatment over 3 years. (3) To investigate the rebound phenomenon and its determinants after cessation of treatment. DESIGN: A randomized, double-masked extended trial. PARTICIPANTS: A total of 350 of 438 children aged 4 to 12 years originally recruited into the Low-Concentration Atropine for Myopia Progression (LAMP) study. METHODS: At the beginning of the third year, children in each group were randomized at a 1:1 ratio to continued treatment and washout subgroups. Cycloplegic spherical equivalent (SE) refraction and axial length (AL) were measured at 4-month intervals. MAIN OUTCOME MEASURES: Changes in SE and AL between groups. RESULTS: A total of 326 children completed 3 years of follow-up. During the third year, SE progression and AL elongation were faster in the washout subgroups than in the continued treatment groups across all concentrations: -0.68 ± 0.49 diopters (D) versus -0.28 ± 0.42 D (P < 0.001) and 0.33 ± 0.17 mm versus 0.17 ± 0.14 mm (P < 0.001) for the 0.05%; -0.57 ± 0.38 D versus -0.35 ± 0.37 D (P = 0.004) and 0.29 ± 0.14 mm versus 0.20 ± 0.15 mm (P = 0.001) for the 0.025%; -0.56 ± 0.40 D versus -0.38 ± 0.49 D (P = 0.04) and 0.29 ± 0.15 mm versus 0.24 ± 0.18 mm (P = 0.13) for the 0.01%. Over the 3-year period, SE progressions were -0.73 ± 1.04 D, -1.31 ± 0.92 D, and -1.60 ± 1.32 D (P = 0.001) for the 0.05%, 0.025%, and 0.01% groups in the continued treatment subgroups, respectively, and -1.15 ± 1.13 D, -1.47 ± 0.77 D, and -1.81 ± 1.10 D (P = 0.03), respectively, in the washout subgroup. The respective AL elongations were 0.50 ± 0.40 mm, 0.74 ± 0.41 mm, and 0.89 ± 0.53 mm (P < 0.001) for the continued treatment subgroups and 0.70 ± 0.47 mm, 0.82 ± 0.37 mm, and 0.98 ± 0.48 mm (P = 0.04) for the washout subgroup. The rebound SE progressions during washout were concentration dependent, but their differences were clinically small (P = 0.15). Older age and lower concentration were associated with smaller rebound effects in both SE progression (P < 0.001) and AL elongation (P < 0.001). CONCLUSIONS: During the third year, continued atropine treatment achieved a better effect across all concentrations compared with the washout regimen. 0.05% atropine remained the optimal concentration over 3 years in Chinese children. The differences in rebound effects were clinically small across all 3 studied atropine concentrations. Stopping treatment at an older age and lower concentration are associated with a smaller rebound.

Age Effect on Treatment Responses to 0.05%, 0.025%, and 0.01% Atropine: Low-Concentration Atropine for Myopia Progression Study.

PURPOSE: To investigate the effect of age at treatment and other factors on treatment response to atropine in the Low-Concentration Atropine for Myopia Progression (LAMP) Study. DESIGN: Secondary analysis from a randomized trial. PARTICIPANTS: Three hundred fifty children aged 4 to 12 years who originally were assigned to receive 0.05%, 0.025%, or 0.01% atropine or placebo once daily, and who completed 2 years of the LAMP Study, were included. In the second year, the placebo group was switched to the 0.05% atropine group. METHODS: Potential predictive factors for change in spherical equivalent (SE) and axial length (AL) over 2 years were evaluated by generalized estimating equations in each treatment group. Evaluated factors included age at treatment, gender, baseline refraction, parental myopia, time outdoors, diopter hours of near work, and treatment compliance. Estimated mean values and 95% confidence intervals (CIs) of change in SE and AL over 2 years also were generated. MAIN OUTCOME MEASURES: Factors associated with SE change and AL change over 2 years were the primary outcome measures. Associated factors during the first year were secondary outcome measures. RESULTS: In 0.05%, 0.025%, and 0.01% atropine groups, younger age was the only factor associated with SE progression (coefficient of 0.14, 0.15, and 0.20, respectively) and AL elongation (coefficient of -0.10, -0.11, and -0.12, respectively) over 2 years; the younger the age, the poorer the response. At each year of age from 4 to 12 years across the treatment groups, higher-concentration atropine showed a better treatment response, following a concentration-dependent effect (Ptrend <0.05 for each age group). In addition, the mean SE progression in 6-year-old children receiving 0.05% atropine (-0.90 diopter [D]; 95% CI, -0.99 to -0.82) was similar to that of 8-year-old children receiving 0.025% atropine (-0.89 D; 95% CI, -0.94 to -0.83) and 10-year-old children receiving 0.01% atropine (-0.92 D; 95% CI, -0.99 to -0.85). All concentrations were well tolerated in all age groups. CONCLUSIONS: Younger age is associated with poor treatment response to low-concentration atropine at 0.05%, 0.025%, and 0.01%. Among concentrations studied, younger children required the highest 0.05% concentration to achieve similar reduction in myopic progression as older children receiving lower concentrations.

Differential Effects on Ocular Biometrics by 0.05%, 0.025%, and 0.01% Atropine: Low-Concentration Atropine for Myopia Progression Study.

PURPOSE: To evaluate changes in ocular biometrics in groups receiving 0.05%, 0.025%, and 0.01% atropine compared with placebo over 1 year based on the Low-Concentration Atropine for Myopia Progression (LAMP) study. DESIGN: Double-blinded, randomized, placebo-controlled trial. PARTICIPANTS: Three hundred eighty-three children aged 4 to 12 years who were assigned randomly to receive 0.05%, 0.025%, 0.01% atropine, or placebo once daily in both eyes and completed the first year of the LAMP study. METHODS: Cycloplegic spherical equivalent (SE), axial length (AL), corneal curvature (K), and anterior chamber depth (ACD) were measured by IOLMaster. Corneal astigmatism and lens power were calculated. The ocular biometric parameter changes were compared among groups. Contributions to SE progression from ocular parameters were determined and compared among groups. MAIN OUTCOME MEASURES: Changes in ocular biometrics and their associations with the changes in SE. RESULTS: Over 1 year, changes in AL were 0.20 ± 0.25 mm, 0.29 ± 0.20 mm, 0.36 ± 0.29 mm, and 0.41 ± 0.22 mm in the 0.05% atropine, 0.025% atropine, 0.01% atropine, and placebo groups, respectively (P < 0.001), with a concentration-dependent response. Corneal power remained stable, and its changes were similar across all atropine concentrations: -0.02 ± 0.14 diopter (D), -0.01 ± 0.14 D, -0.01 ± 0.12 D, and 0.01 ± 0.14 D in the 0.05% atropine, 0.025% atropine, 0.01% atropine, and placebo groups, respectively (P = 0.10). Lens power decreased over time in each concentration, but its changes also were similar across all concentrations: -0.31 ± 0.43 D, -0.38 ± 0.47 D, -0.40 ± 0.43 D, and -0.41 ± 0.43 D in the 0.05% atropine, 0.025% atropine, 0.01% atropine, and placebo groups, respectively (P = 0.24). Changes in ACD remained similar across all concentrations (P = 0.41). The contributions to SE progression from the ocular biometric changes after adjusting for age and gender in each concentration were similar across all groups (P > 0.05). CONCLUSIONS: Low-concentrations of atropine (0.05%, 0.025%, and 0.01%) have no clinical effect on corneal or lens power. Antimyopic effects of low-concentration atropine act mainly on reducing AL elongation, and therefore could reduce the risk of subsequent myopia complications.

Two-Year Clinical Trial of the Low-Concentration Atropine for Myopia Progression (LAMP) Study: Phase 2 Report.

PURPOSE: To evaluate the efficacy and safety of 0.05%, 0.025%, and 0.01% atropine eye drops over 2 years to determine which is the optimal concentration for longer-term myopia control. DESIGN: Randomized, double-masked trial extended from the Low-Concentration Atropine for Myopia Progression (LAMP) Study. PARTICIPANTS: Three hundred eighty-three of 438 children (87%) aged 4 to 12 years with myopia of at least -1.0 diopter (D) originally randomized to receive atropine 0.05%, 0.025%, 0.01%, or placebo once daily in both eyes in the LAMP phase 1 study were continued in this extended trial (phase 2). METHODS: Children in the placebo group (phase 1) were switched to receive 0.05% atropine from the beginning of the second-year follow-up, whereas those in the 0.05%, 0.025%, and 0.01% atropine groups continued with the same regimen. Cycloplegic refraction, axial length (AL), accommodation amplitude, photopic and mesopic pupil diameter, and best-corrected visual acuity were measured at 4-month intervals. MAIN OUTCOME MEASURES: Changes in spherical equivalent (SE) and AL and their differences between groups. RESULTS: Over the 2-year period, the mean SE progression was 0.55±0.86 D, 0.85±0.73 D, and 1.12±0.85 D in the 0.05%, 0.025%, and 0.01% atropine groups, respectively (P = 0.015, P < 0.001, and P = 0.02, respectively, for pairwise comparisons), with mean AL changes over 2 years of 0.39±0.35 mm, 0.50±0.33 mm, and 0.59±0.38 mm (P = 0.04, P < 0.001, and P = 0.10, respectively). Compared with the first year, the second-year efficacy of 0.05% and 0.025% atropine remained similar (P >0.1), but improved mildly in the 0.01% atropine group (P = 0.04). For the phase 1 placebo group, the myopia progression was reduced significantly after switching to 0.05% atropine (SE change, 0.18 D in second year vs. 0.82 D in first year [P < 0.001]; AL elongated 0.15 mm in second year vs. 0.43 mm in first year [P < 0.001]). Accommodation loss and change in pupil size in all concentrations remained similar to the first-year results and were well tolerated. Visual acuity and vision-related quality of life remained unaffected. CONCLUSIONS: Over 2 years, the efficacy of 0.05% atropine observed was double that observed with 0.01% atropine, and it remained the optimal concentration among the studied atropine concentrations in slowing myopia progression.

Low-Concentration Atropine for Myopia Progression (LAMP) Study: A Randomized, Double-Blinded, Placebo-Controlled Trial of 0.05%, 0.025%, and 0.01% Atropine Eye Drops in Myopia Control.

PURPOSE: Low-concentration atropine is an emerging therapy for myopia progression, but its efficacy and optimal concentration remain uncertain. Our study aimed to evaluate the efficacy and safety of low-concentration atropine eye drops at 0.05%, 0.025%, and 0.01% compared with placebo over a 1-year period. DESIGN: Randomized, placebo-controlled, double-masked trial. PARTICIPANTS: A total of 438 children aged 4 to 12 years with myopia of at least -1.0 diopter (D) and astigmatism of -2.5 D or less. METHODS: Participants were randomly assigned in a 1:1:1:1 ratio to receive 0.05%, 0.025%, and 0.01% atropine eye drops, or placebo eye drop, respectively, once nightly to both eyes for 1 year. Cycloplegic refraction, axial length (AL), accommodation amplitude, pupil diameter, and best-corrected visual acuity were measured at baseline, 2 weeks, 4 months, 8 months, and 12 months. Visual Function Questionnaire was administered at the 1-year visit. MAIN OUTCOME MEASURES: Changes in spherical equivalent (SE) and AL were measured, and their differences among groups were compared using generalized estimating equation. RESULTS: After 1 year, the mean SE change was -0.27±0.61 D, -0.46±0.45 D, -0.59±0.61 D, and -0.81±0.53 D in the 0.05%, 0.025%, and 0.01% atropine groups, and placebo groups, respectively (P < 0.001), with a respective mean increase in AL of 0.20±0.25 mm, 0.29±0.20 mm, 0.36±0.29 mm, and 0.41±0.22 mm (P < 0.001). The accommodation amplitude was reduced by 1.98±2.82 D, 1.61±2.61 D, 0.26±3.04 D, and 0.32±2.91 D, respectively (P < 0.001). The pupil sizes under photopic and mesopic conditions were increased respectively by 1.03±1.02 mm and 0.58±0.63 mm in the 0.05% atropine group, 0.76±0.90 mm and 0.43±0.61 mm in the 0.025% atropine group, 0.49±0.80 mm and 0.23±0.46 mm in the 0.01% atropine group, and 0.13±1.07 mm and 0.02±0.55 mm in the placebo group (P < 0.001). Visual acuity and vision-related quality of life were not affected in each group. CONCLUSIONS: The 0.05%, 0.025%, and 0.01% atropine eye drops reduced myopia progression along a concentration-dependent response. All concentrations were well tolerated without an adverse effect on vision-related quality of life. Of the 3 concentrations used, 0.05% atropine was most effective in controlling SE progression and AL elongation over a period of 1 year.

Genetic Associations of Primary Angle-Closure Disease: A Systematic Review and Meta-analysis.

TOPIC: Systematic review and meta-analysis of the genetic associations of primary angle-closure disease (PACD). CLINICAL RELEVANCE: To confirm the genetic biomarkers for PACD, including primary angle-closure glaucoma (PACG) and related phenotypes. METHODS: We searched in the MEDLINE and EMBASE databases for genetic studies of PACG or other PACD published from the start dates of the databases to May 11, 2015. We estimated the summary odds ratios (ORs) and 95% confidence intervals (CIs) for each polymorphism in PACG, primary angle-closure suspect (PACS), and primary angle-closure (PAC) using fixed- or random-effect models. We also performed sensitivity analysis to test the robustness of the results. RESULTS: Our literature search yielded 6463 reports. Among them, we identified 24 studies that fulfilled the eligibility criteria for meta-analysis, involving 28 polymorphisms in 11 genes/loci. We affirmed the association of PACG and combined PACS/PAC/PACG with 10 polymorphisms in 8 genes/loci, including COL11A1 (rs3753841-G, OR, 1.22; P = 0.00046), HGF (rs17427817-C, OR, 2.02; P = 6.9E-07; rs5745718-A, OR, 2.11; P = 9.9E-07), HSP70 (rs1043618, GG+GC, OR, 0.52; P = 0.0010), MFRP (rs2510143-C, OR, 0.66; P = 0.012; rs3814762-G, OR, 1.40; P = 0.0090), MMP9 (rs3918249-C, OR, 1.35; P = 0.034), NOS3 (rs7830-A, OR, 0.80; P = 0.036), PLEKHA7 (rs11024102-G, OR, 1.24; P = 8.3E-05), and PCMTD1-ST18 (rs1015213-A, OR, 1.59; P = 0.00013). Sensitivity analysis indicated that the results were robust. CONCLUSIONS: In this study, we confirmed multiple polymorphisms in 8 genes/loci as genetic biomarkers for PACD, among which 3 were identified in a genome-wide association study (COL11A1, PLEKHA7, and PCMTD1-ST18), and 5 were identified in candidate gene studies (HGF, HSP70, MFRP, MMP9, and NOS3).

PAX6 gene associated with high myopia: a meta-analysis.

PURPOSE: The PAX6 gene is among the most studied genes in high myopia, but reported findings of association studies on PAX6 and high myopia are inconsistent. We conducted a systematic review and meta-analysis to evaluate the association of PAX6 polymorphisms and high myopia. METHODS: All case-control association studies on PAX6 and high myopia reported in EMBASE and MEDLINE were retrieved. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for single-nucleotide polymorphisms (SNPs) that have been involved in at least two studies. Heterogeneity and publication bias analyses were also conducted. RESULTS: There were totally 63 publications on PAX6 and myopia. Among them, six articles met all the inclusion criteria, involving 3626 patients and 3262 controls of Asian ancestry. Five PAX6 SNPs, rs3026354, rs667773, rs2071754, rs644242, and rs3026393, were meta-analyzed in high myopia and two, rs667773 and rs644242, in extreme myopia. Single-nucleotide polymorphism rs644242 was associated with high myopia in the dominant model (OR = 0.87; 95% CI, 0.76 to 0.99; p = 0.035) and heterozygous model (OR = 0.85; 95% CI, 0.74 to 0.97; p = 0.019) and with extreme myopia in the dominant model (OR = 0.79; 95% CI, 0.65 to 0.95; p = 0.015), allelic model (OR = 0.81; 95% CI, 0.68 to 0.96; p = 0.014), and heterozygous model (OR = 0.80; 95% CI, 0.65 to 0.97; p = 0.024). However, the associations cannot withstand Bonferroni correction (p > 0.005). The other four SNPs did not show significant association with high myopia. CONCLUSIONS: Meta-analysis of existing data revealed a suggestive association of PAX6 rs644242 with extreme and high myopia, which awaits validation in further studies. Nevertheless, PAX6 may only confer a small effect to myopia development.

Trehalose promotes functional recovery of keratinocytes under oxidative stress and wound healing via ATG5/ATG7.

Wounds are in a stressed state, which precludes healing. Trehalose is a stress metabolite that protects cells under stress. Here, we explored whether trehalose reduces stress-induced wound tissue damage. A stress model was prepared by exposing human keratinocytes to hydrogen peroxide (H2O2), followed by trehalose treatment. Trehalose effects on expression of the autophagy-related proteins ATG5 and ATG7 and cell proliferation and migration were evaluated. For in vivo verification, a wound model was established in Sprague-Dawley rats, to measure the effects of trehalose wound-healing rate and reactive oxygen species (ROS) content. Histological changes during wound healing and trehalose's effects on ATG5 and ATG7 expression, necrosis, and apoptosis were examined·H2O2 stress increased ATG5 and ATG7 expression in vitro, but this was insufficient to prevent stress-induced damage. Trehalose further increased ATG5/ATG7 levels, which restored proliferation and increased migration by depolymerizing the cytoskeleton. However, trehalose did not exert these effects after ATG5 and ATG7 knockout. In vivo, the ROS content was higher in the wound tissue than in normal skin. Trehalose increased ATG5/ATG7 expression in wound tissue keratinocytes, reduced necrosis, depolymerized the cytoskeleton, and promoted cell migration, thereby promoting wound healing.

Effect of Myopic Undercorrection on Habitual Reading Distance in Schoolchildren: The Hong Kong Children Eye Study.

INTRODUCTION: This study aimed to evaluate the habitual reading distance among non-myopic children and also myopic children with undercorrection and with full correction. METHODS: This was a population-based cross-sectional study with a total of 2363 children aged 6-8 years who were recruited from the Hong Kong Children Eye Study. Cycloplegic autorefraction, subjective refraction, habitual visual acuity, and best corrected visual acuity were measured. The entire reading process (9 min) was recorded using a hidden video camera placed 5 m away from the reading desk. Reading distances were taken at 6, 7, 8, and 9 min after the child began reading and were measured using a customized computer program developed in MATLAB. The main outcome was the association of habitual reading distances with refraction status. Habitual reading distances of children were documented via video camera footage. RESULTS: The habitual reading distances of undercorrected myopic children (23.37 ± 4.31 cm) were the shortest when compared to non-myopic children (24.20 ± 4.73 cm, P = 0.002) and fully corrected myopic children (24.81 ± 5.21 cm, P < 0.001), while there was no significant difference between the last two children groups (P = 0.17). A shorter reading distance was associated with myopia (OR 1.67; 95% CI 1.11-2.51; P = 0.013) after adjusting for age, sex, height, near work time, outdoor time, and parental myopia. The association of reading distance with myopia did not hold after undercorrected myopic children were excluded (OR 0.97, 95% CI 0.55-1.73; P = 0.92). A shorter reading distance correlated with poorer vision under habitual correction (ß = - 0.003, P < 0.001). CONCLUSION: A shorter reading distance was present among undercorrected myopic children. Myopia undercorrection is not recommended as a strategy for slowing myopic progression.

Increase in Bruch's membrane opening minimum rim width with age in healthy children: the Hong Kong Children Eye Study.

BACKGROUND/AIMS: To identify normative values and determinants for Bruch's membrane opening (BMO) and the minimum rim width of BMO (BMO-MRW) among healthy children. METHODS: A population-based cross-sectional study from the Hong Kong Children Eye Study, recruiting 1, 226 children aged 6-8 years. Spherical refractive error, axial length (AL), body mass index and intraocular pressure (IOP) were measured. The optic nerve head and the peripapillary retinal nerve fibre layer (p-RNFL) were imaged through spectral domain-optical coherence tomography, using 24 equally spaced radial B-scans. Global and sectoral BMO-MRW values, BMO area and fovea-to-BMO (FoBMO) angle were calculated. Multiple regression analysis was performed to define the determinants of BMO area and BMO-MRW in relation to demographic and ocular parameters. RESULTS: The mean values for global BMO-MRW, BMO area and FoBMO angle among children were 345.76±54.08 µm, 2.34±0.49 mm2 and -5.45±4.36°, respectively. Global and sectoral values for BMO-MRW correlated with p-RNFL thickness (r=0.11-0.35, p<0.001). After adjusting for demographic and ocular parameters, global BMO-MRW increased with age (ß=6.4, p<0.001) and greater global p-RNFL thickness (ß=1.41, p<0.001), but decreased with larger BMO area (ß=-47.46, p<0.001) and higher IOP (ß=-1.73, p<0.001). Global BMO-MRW did not associate with AL, whereas both BMO area and FoBMO angle associated with AL (ß=0.04, p=0.02 and ß=0.31, p=0.03, respectively), but not with age. CONCLUSION: We observed that BMO-MRW increases with age among children. Our results provide normative values and the determinants of BMO parameters among Chinese children.

Association of Corneal Biomechanics Properties with Myopia in a Child and a Parent Cohort: Hong Kong Children Eye Study.

Associations between corneal biomechanics, axial elongation and myopia are important but previous results are conflicting. Our population-based study aimed to investigate factors associated with corneal biomechanics, and their relationships with myopia in children and adults. Data from 3643 children and 1994 parents showed that children had smaller deformation amplitudes (DA) than parents (p < 0.001). A larger DA was significantly associated with elongated axial length (AL; children: ß = 0.011; adults: ß = 0.0013), higher corneal curvature (children: ß = 0.0086; adults: ß = 0.0096), older age (children: ß = 0.010; adults: ß = 0.0013), and lower intraocular pressure (IOP; children: ß = -0.029; adults: ß = -0.031) in both cohorts. The coefficient of age for DA in children was larger than in adults (p < 0.001), indicating that the DA change with age in children is faster than in adults. DA was significantly associated with spherical equivalent (p < 0.001) resulting from its correlation with AL and corneal curvature. In conclusion, the cornea is more deformable in adults than in children, whereas corneal deformation amplitude increases faster with age in children than that in adults, along with AL elongation. Longer AL, steeper corneal curvature, older age and smaller IOP correspond to a more deformable cornea. The association between corneal deformation amplitude and refraction was mediated via AL and corneal curvature.

Association of polymorphisms in ZFHX1B, KCNQ5 and GJD2 with myopia progression and polygenic risk prediction in children.

AIMS: To assess the association of single-nucleotide polymorphisms (SNPs) with myopia progression for polygenic risk prediction in children. METHODS: Six SNPs (ZC3H11B rs4373767, ZFHX1B rs13382811, KCNQ5 rs7744813, MET rs2073560, SNTB1 rs7839488 and GJD2 rs524952) were analysed in 1043 school children, who completed 3-year follow-up, using TaqMan genotyping assays. SNP associations with progression in spherical equivalent (SE) were analysed by logistic regression. Polygenic risk scores (PRS) were applied for computing the sum of the risk alleles of multiple SNPs corresponding to myopia progression, weighted by the effect sizes of corresponding SNPs. RESULTS: GJD2 rs524952 showed significant association with fast progression (OR=1.32, 95% CI 1.10 to 1.59; p=0.003) and KCNQ5 rs7744813 had nominal association (OR=1.32, 95% CI 1.04 to 1.67; p=0.02). In quantitative traits locus analysis, GJD2 rs524952 and KCNQ5 rs7744813 were associated with progression in SE (ß=-0.038 D/year, p=0.008 and ß=-0.042 D/year, p=0.02) and axial elongation (ß=0.016 mm/year, p=0.01 and ß=0.017 mm/year, p=0.027). ZFHX1B rs13382811 also showed nominal association with faster progression in SE (ß=-0.041 D/year, p=0.02). PRS analysis showed that children with the highest PRS defined by rs13382811, rs7744813 and rs524952 had a 2.26-fold of increased risk of fast myopia progression (p=4.61×10-5). PRS was also significantly associated with SE progression (R2=1.6%, p=3.15×10-5) and axial elongation (R2=1.2%, p=2.6×10-4). CONCLUSIONS: In this study, multi-tiered evidence suggested SNPs in ZFHX1B, KCNQ5 and GJD2 as risk factors for myopia progression in children. Additional attention and appropriate interventions should be given for myopic children with high-risk PRS as defined by GJD2 rs524952, KCNQ5 rs7744813 and ZFHX1B rs13382811.

Genetic associations of myopia severities and endophenotypes in children.

OBJECTIVE: To investigate the associations of multiple single-nucleotide polymorphisms (SNPs) with the severities and endophenotypes of myopia in children. METHODS: A total of 3300 children aged 5-10 years were recruited: 137 moderate and high myopia (SE≤-3.0D), 670 mild myopia (-3.0D-0.5D). 13 SNPs in 13 genes/loci were selected for genotyping in all subjects using TaqMan assays. Associations between each SNP with myopia severities and ocular traits (spherical equivalent (SE), axial length (AL) and corneal radius (CR)) were analysed. RESULTS: When compared with controls, SNPs ZC3H11B rs4373767 (OR=1.15, p=0.038), BICC1 rs7084402 (OR=1.18, p=0.005) and GJD2 rs524952 (OR=1.14, p=0.025) showed nominal associations with overall myopia. ZC3H11B rs4373767 and BICC1 rs7084402 showed stronger associations with moderate and high myopia (rs4373767: OR=1.42, p=0.018; rs7084402: OR=1.33, p=0.025), while GJD2 rs524952 had a stronger association with mild myopia (OR=1.14, p=0.025). GJD2 rs524952 also showed a difference between emmetropia and hyperopia (p=0.018). In quantitative trait locus analysis, ZC3H11B rs4373767, KCNQ5 rs7744813 and GJD2 rs524952 were correlated with both myopic SE (ß=-0.09, p=0.03; ß=-0.12, p=0.007; ß=-0.13, p=0.0006, respectively) and AL (ß=0.07, p=0.002; ß=0.09, p=0.0008; ß=0.07, p=0.0003, respectively). SNTB1 rs7839488 was correlated with both AL (ß=0.07, p=0.005) and CR (ß=0.02, p=0.006). Moreover, ZC3H11B rs4373767-T (ß=0.006; p=0.018), KCNQ5 rs7744813-A (ß=0.007; p=0.015) and GJD2 rs524952-T (ß=0.009; p=0.0006) were correlated with AL-CR ratio. CONCLUSIONS AND RELEVANCE: ZC3H11B and BICC1 are genetic risk factors for moderate and high myopia, while ZC3H11B, KCNQ5, SNTB1 and GJD2 confer risk to excessive AL in children.

Association of the ZC3H11B, ZFHX1B and SNTB1 genes with myopia of different severities.

OBJECTIVE: To investigate the associations of single-nucleotide polymorphisms (SNPs) in the ZC3H11B, ZFHX1B, VIPR2, SNTB1 and MIPEP genes with severities of myopia in Chinese populations. METHODS: Based on previous myopia genome-wide association studies, five SNPs (ZC3H11B rs4373767, ZFHX1B rs13382811, VIPR2 rs2730260, SNTB1 rs7839488 and MIPEP rs9318086) were selected for genotyping in a Chinese cohort of 2079 subjects: 252 extreme myopia, 277 high myopia, 393 moderate myopia, 366 mild myopia and 791 non-myopic controls. Genotyping was performed by TaqMan assays. Allelic frequencies of the SNPs were compared with myopia severities and ophthalmic biometric measurements. RESULTS: The risk allele T of ZC3H11B SNP rs4373767 was significantly associated with high myopia (OR=1.39, p=0.007) and extreme myopia (OR=1.34, p=0.013) when compared with controls, whereas ZFHX1B rs13382811 (allele T, OR=1.33, p=0.018) and SNTB1 rs7839488 (allele G, OR=1.71, p=8.44E-05) were significantly associated with extreme myopia only. In contrast, there was no significant association of these SNPs with moderate or mild myopia. When compared with mild myopia, subjects carrying T allele of rs4373767 had a risk of progressing to high myopia (spherical equivalent ≤-6 dioptres) (OR=1.29, p=0.017). Similarly, the T allele of rs13382811 also imposed a significant risk to high myopia (OR=1.36, p=0.007). In quantitative traits analysis, SNPs rs4373767, rs13382811 and rs7839488 were correlated with axial length and refractive errors. CONCLUSIONS: We confirmed ZC3H11B as a susceptibility gene for high and extreme myopia, and ZFHX1B and SNTB for extreme myopia in Chinese populations. Instead of myopia onset, these three genes were more likely to impose risks of progressing to high and extreme myopia.

Independent Influence of Parental Myopia on Childhood Myopia in a Dose-Related Manner in 2,055 Trios: The Hong Kong Children Eye Study.

PURPOSE: To determine the effects on childhood myopia of parental myopia, parental education, children's outdoor time, and children's near work. DESIGN: Population-based cross-sectional study. METHODS: A total of 6,155 subjects in 2,055 family trios (1 child and both parents). Cycloplegic autorefraction was measured for children and noncycloplegic autorefraction for parents. Parental education, children's outdoor time, and near work were collected by questionnaires. Children were categorized into 10 groups based on parental myopia levels. Associations of the above factors with myopia were evaluated by regression analyses. The areas under the receiver operating characteristic curve (AUROCs) for myopia were evaluated. RESULTS: Mild parental myopia did not increase childhood myopia's risk, but the risk was 11.22-folds when both parents were highly myopic. Higher parental education (Father: OR 1.08, P = .046; Mother: OR 1.11, P = .001) and more reading time of children were risk factors (OR 1.21, P = .044). Reduced odds of myopia were associated with more time spent on outdoor activities (OR 0.78, P = .017). Notably, all these factors became insignificant after adjustment, except for parental myopia. Children with more severe parental myopia spent more time on reading, but less on electronic devices. Parental myopic status alone accounted for 11.82% of myopia variation in children. With age and parental myopia, the AUROC for myopia was 0.731. CONCLUSIONS: Among parental and environmental factors, parental myopia confers, in a dose-related manner, the strongest independent effect on childhood myopia. Therefore children with high risk of myopia can be identified for early prevention, based on parental myopia data.

Association of WNT7B and RSPO1 with Axial Length in School Children.

Purpose: To evaluate the association between single-nucleotide polymorphisms (SNPs) in the ZC3H11B, RSPO1, C3orf26, GJD2, ZNRF3, and WNT7B genes and myopia endophenotypes in children. Methods: Seven SNPs identified in previous genome-wide association studies of axial length (AL) were genotyped in 2883 Southern Han Chinese children. Multiple linear regression analyses were conducted to evaluate the genotype association with AL, spherical equivalent (SE), corneal curvature (CC), and central corneal thickness (CCT). Results: Two SNPs-namely, rs12144790 in RSPO1 (allele T, P = 0.0066, ß = 0.062) and rs10453441 in WNT7B (allele A, P = 8.03 × 10-6, ß = 0.103)-were significantly associated with AL. The association of rs4373767 in ZC3H11B (allele C, P = 0.030, ß = -0.053) could not withstand the correction for multiple testing. WNT7B rs10453441 showed a strong association with CC (P = 1.17 × 10-14, ß = 0.053) and with CCT (P = 0.0026, ß = 2.65). None of the tested SNPs was significantly associated with SE. The C allele of SNP rs12321 in ZNRF3 was associated with CC (P = 0.0060, ß = -0.018). Conclusions: This study revealed that the RSPO1 SNP rs12144790 was associated with AL, whereas WNT7B rs10453441 was associated with AL, CC, and CCT in children. A novel association between ZNRF3 rs12321 and CC was discovered. Our data suggest that the RSPO1 and WNT7B genes might exert their effects on multiple aspects of eye growth during childhood. Potential differences in the genetic profiles of AL between children and adults should be explored in larger cohorts.

High prevalence of myopia in children and their parents in Hong Kong Chinese Population: the Hong Kong Children Eye Study.

PURPOSE: To determine the myopia prevalence in Hong Kong Chinese children and their parents. METHODS: It was a population-based cross-sectional study. A total of 4257 children aged 6-8 years, and 5880 parents were recruited in the Hong Kong Children Eye Study. Cycloplegic autorefraction was measured for children; and non-cycloplegic autorefraction for parents. Parental educational level, children's outdoor time, and near work were collected by validated questionnaires. RESULTS: In children aged 6-8 years, 25.0% were myopic, and among them, 12.7% for the 6-year-olds, 24.4% for the 7-year-olds and 36.1% for the 8-year-old. About 0.7% of children aged 8 years were high myopia. In all age groups, boys (their myopia rate: 13.9% at 6 years, 26.7% at 7 years, and 38.3% at 8 years) were more myopic than girls (11.3% at 6 years, 22.0% at 7 years, 33.4% at 8 years). Among parents, 72.2% were myopic (mother, 73.2%; father, 70.7%) and 13.5% high myopia (mother, 12.8%; father, 14.5%). It was observed that prevalence decreased with ages and increased with education level. CONCLUSION: There is a strikingly high prevalence of myopia in Hong Kong children aged 6-8, much higher than that of other regions of China. Of note, the prevalence of children was similar to that in 15 years ago. Furthermore, the myopia prevalence of parents is high, and it had already increased in this cohort. Prevention of childhood myopia is important, likewise for visual complications from high myopia in adults.

Effects of etanercept on the apoptosis of ganglion cells and expression of Fas, TNF-α, caspase-8 in the retina of diabetic rats.

AIM: To evaluate the effects of etanercept on the expression of Fas, tumor necrosis factor-alpha (TNF-α) and caspase-8 in the early stage of the apoptotic pathway in diabetic rats, and to explore the therapeutic effect of etanercept on diabetic retinopathy. METHODS: A total of 60 Sprague-Dawley (SD) rats were randomly and evenly divided into 3 groups with 20 rats each, including control group, and diabetic groups with or without treatment. Streptozotocin (STZ)-induced diabetic rats were established for diabetic groups. Blood glucose and body weight were measured weekly. All the rats were sacrificed at the 12wk after treatment. The expressions of Fas, TNF-α and caspase-8 in rat retina were quantitatively detected by PCR and Western blot. The leakage of Evan blue was adopted to measure the retinal vascular leakage quantitatively, and to compare it among different groups. TUNEL method was used to compare the amount of apoptotic bodies quantitatively in rat retina ganglion cells under electron microscope. RESULTS: The expressions of Fas, TNF-α and caspase-8 in each group were compared via PCR and Western blot, in which the diabetic group with treatment was lower than those without treatment (P<0.01), but all the diabetic groups were higher than the control group (P<0.01). Evans blue leakage in the diabetic treatment group was lower than those without treatment (P<0.01), but those in the control group was the lowest compared with the other two groups (P<0.01). TUNEL method showed that the apoptotic bodies of retina in the diabetic treatment group was lower than those without treatment (P<0.01), while those in the control group was the lowest compared with the other two groups (P<0.01). CONCLUSION: Etanercept can effectively reduce the expression of Fas, TNF-α and caspase-8, as well as the retinal leakage and retinal cell apoptosis in diabetic rats.

Vitamin D and its pathway genes in myopia: systematic review and meta-analysis.

OBJECTIVE: To conduct a systematic review and meta-analysis of the association of blood vitamin D (25-hydroxyvitamin D, 25(OH)D) concentration and vitamin D pathway genes with myopia. METHODS: We searched the MEDLINE and EMBASE databases for studies published up to 29 January 2018. Cross-sectional or cohort studies which evaluated the blood 25(OH)D concentration, blood 25(OH)D3 concentration or vitamin D pathway genes, in relation to risk of myopia or refractive errors were included. Standard mean difference (SMD) of blood 25(OH)D concentrations between the myopia and non-myopia groups was calculated. The associations of blood 25(OH)D concentrations and polymorphisms in vitamin D pathway genes with myopia using summary ORs were evaluated. RESULTS: We summarised seven studies involving 25 008 individuals in the meta-analysis. The myopia group had lower 25(OH)D concentration than the non-myopia group (SMD=-0.27 nmol/L, p=0.001). In the full analysis, the risk of myopia was inversely associated with blood 25(OH)D concentration after adjusting for sunlight exposure or time spent outdoors (adjusted odds ratio (AOR)=0.92 per 10 nmol/L, p<0.0001). However, the association was not statistically significant for the <18 years subgroup (AOR=0.91 per 10 nmol/L, p=0.13) and was significant only for 25(OH)D3 (likely to be mainly sunlight derived), but not total 25(OH)D (AOR=0.93 per 10 nmol/L, p=0.00007; AOR=0.91 per 10 nmol/L, p=0.15). We analysed four single nucleotide polymorphisms in the VDR gene from two studies; there was no significant association with myopia. CONCLUSIONS: Lower 25(OH)D is associated with increased risk of myopia; the lack of a genetic association suggests that 25(OH)D level may be acting as a proxy for time outdoors.

Association of the PAX6 gene with extreme myopia rather than lower grade myopias.

AIMS: To investigate the association of the paired box gene 6 (PAX6) with different severities of myopia. METHODS: A total of four haplotype-tagging single-nucleotide polymorphisms (SNPs; rs2071754, rs3026354, rs3026390 and rs628224) and two previously reported SNPs (rs644242 and rs662702) in the PAX6 gene were analysed in a Hong Kong Chinese cohort of 1288 myopia subjects (including 252 extreme myopia, 277 high myopia, 393 moderate myopia and 366 mild myopia) and 791 no myopia controls. Allelic association analyses were performed for individual SNPs in different subgroups of myopia and in combined myopia, followed by a meta-analysis of our current data with reported data on PAX6 in myopia. RESULTS: The association of tagging SNPs rs2071754 and rs644242 with extreme myopia could not withstand multiple correction (rs2071754: OR=1.25, P value=0.031; rs644242: OR=1.33, P value=0.032). In the meta-analysis, rs644242 showed an enhanced, significant association with extreme myopia (OR=1.27, 95% CI 1.10 to 1.46, P value=0.001; I2=0%). In contrast, there was no significant association between the PAX6SNPs and high, moderate or mild myopia. No linear correlation was found between the PAX6SNPs and axial length. CONCLUSION: This study provides additional evidence suggesting that the PAX6 SNP rs644242 is associated with extreme myopia but not lower grade myopia. Thus, PAX6 may be implicated in the development or progression into severe myopia. Further longitudinal studies are warranted.