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The Asian Eye Genetics Consortium (AGEC) established in 2014 brought collective thinking and ideas of the Asian and non-Asian researchers who have an interest in genetic eye research. As the consortium grew, requests to join the consortium from outside of Asia were increasing. During the AGEC meeting at ARVO 2018 in Honolulu, USA, the members unanimously voted to expand the consortium activities beyond Asia and explore unique phenotype and genotype populations in the rest of the world, particularly in Africa and South America. The consortium was renamed the Global Eye Genetics Consortium (GEGC, https://gegc.org) by the general membership. The consortium aims were adjusted and the new GEGC phenotype-genotype database GenEye (https://geneye.kankakuki.jp) was constructed to collect and catalog genetic eye diseases at global scale. GEGC membership has grown to over 200 from five continents, performing GEGC meetings and sessions during ARVO, AIOS, APAO, WOC, and ISER meetings. A number of scientific collaboration and young investigator visiting programs have been successfully launched over the past 6 years.

Retina is a multilayered structure containing several different cell types crucial for visual functions. Light signals are converted into electrochemical signals on the retina and transferred to the brain through the optic nerve. A dysfunctional retina leads to various retinal diseases that can result in vision impairment and even irreversible blindness. Genetic factors play important roles in retina structure and functions. In recent decades, there are significant advancements in mapping retina genes associated with retinal diseases, some are monogenic and some multifactorial in etiology. Some retinal diseases overlap in clinical courses and even genetic constitutions, with both similarities and differences in presentations among ethnic populations. We have investigated CFH, HTRA1, BEST1, CETP, ABCA4, RHO, RP1, CYP4V2, and other genes in Chinese patients with retinal diseases including age-related macular degeneration, polypoidal choroidal vasculopathy diabetic retinopathy, retinitis pigmentosa, Best vitelliform macular dystrophy, and Stargardt disease.

Glaucoma is a leading cause of irreversible blindness worldwide. Genetic studies in glaucoma provide evidences of genes and loci related to the disease development and insights of the pathogenesis in glaucoma. Gene mutations with strong associations to the disease were found in family linkage studies in which the glaucoma patients usually had early-onset and severe disease features. From these studies, several genes, such as MYOC, OPTN, TBK1, and TIE2, have been found to be related to glaucoma. On the other hand, sequence variants linked to common and late-onset forms of glaucoma were mainly discovered from genome-wide association studies (GWAS). Up to date, 15 GWAS have identified common variants for the risk of different types of glaucoma including primary open-angle glaucoma (POAG), primary angle-closure glaucoma (PACG), and exfoliation glaucoma (XFG). While many GWAS utilized East Asian cohorts as primary cohorts, the effects of the variants contributing to glaucoma susceptibility vary across ethnic groups due to differential genetic background. In this chapter, we focus on the genetics of different glaucoma forms in East Asian populations.

Retinoblastoma is the commonest pediatric intraocular malignancy across most ethnic populations. Its genetic basis follows a two-hit model, in which two events are needed to inactivate both alleles of the disease-causative gene, RB1. Loss of heterozygosity (LOH) is a major driving force to inactivate the whole RB1 gene. Epigenetic modifications such as DNA methylation involving different genes and microRNA (miRNA) expressions also play important roles in retinoblastoma tumorigenesis. Functionally, as RB1 is important in maintaining chromosomal stability and cell cycle progression, loss of its function would underlie aberrations in other chromosomal regions. In addition, genes other than RB1 have been identified as direct or indirect causes of retinoblastoma tumorigenesis. In this chapter, we review the major genetic studies of retinoblastoma that have been conducted in Chinese. Contrasts with other ethnic groups will be made. These studies help us to understand the mechanisms of inactivating RB1, its functional consequences, and maintaining genome stability. Evidences have also been obtained on epigenetic contribution to retinoblastoma, especially by DNA repair genes. On the basis of the genetic and epigenetic findings, development of potential alternative therapy for retinoblastoma will be discussed, together with key issues in attempts of awareness campaign for early detection and genetic counselling.

Myopia is the most common ocular disorder causing visual impairment worldwide. It is a public health issue in many parts of the world. Compared with Caucasian or other ethnicities, its prevalence in Asians, especially Japanese, Koreans, and Chinese, is much higher. Environmental and genetic factors play important roles in myopia development. Myopia is a multifactorial disease. Time spent outdoors, amount of near work, and educational level influence myopia onset and progression. Recent advances in modern technology and molecular biology including linkage analyses, candidate gene analysis, genome-wide association studies (GWAS), whole-exome sequencing (WES), and next-generation sequencing (NGS) have led to mapping and identifying many myopia-associated gene loci and variants. Understanding the genetic basis may help in myopia prediction and prevention. This review is to summarize recent major findings in myopia genetics with a focus in Asian populations.

Keratoconus is a corneal disease characterized by conical protrusion and progressive thinning of the cornea, resulting in various degrees of visual impairment. Keratoconus affects all ethnic groups, but the prevalence is higher among the Asian populations. The onset of keratoconus is insidious and often occurs during late childhood. Early diagnosis is difficult. If untreated, the disease often progresses irreversibly and can lead to blindness. Nowadays, corneal collagen cross-linking has shown some promising results in retarding or halting keratoconus progression, but currently there is no complete cure. Keratoconus is a multifactorial disease resulting from the interaction of environmental, behavioral, and genetic factors. Its progression has been associated with structural, biochemical, cellular, and molecular alternations in corneal collagen lamellae, higher systemic oxidative stress, and modifications in corneal proteins. However, the etiology of keratoconus remains unclear and the exact regulatory mechanism still elusive. There is evidence of familial aggregation, monozygotic twin concordance, association with other genetic diseases, and the ethnic difference in prevalence and incidences. This chapter attempts to summarize the current knowledge and research of keratoconus epidemiology, pathology, and genetics, with a particular focus for studies in the Chinese population.

Glaucoma is a multi-factorial blinding disease in which genetic factors play an important role. Elevated intraocular pressure is a highly heritable risk factor for primary open angle glaucoma and currently the only target for glaucoma therapy. Our study helps to better understand underlying genetic and molecular mechanisms that regulate intraocular pressure, and identifies a new candidate gene, Cacna2d1, that modulates intraocular pressure and a promising therapeutic, pregabalin, which binds to CACNA2D1 protein and lowers intraocular pressure significantly. Because our study utilizes a genetically diverse population of mice with known sequence variants, we are able to determine that the intraocular pressure-lowering effect of pregabalin is dependent on the Cacna2d1 haplotype. Using human genome-wide association study (GWAS) data, evidence for association of a CACNA2D1 single-nucleotide polymorphism and primary open angle glaucoma is found. Importantly, these results demonstrate that our systems genetics approach represents an efficient method to identify genetic variation that can guide the selection of therapeutic targets., Elevated intraocular pressure (IOP) is a heritable risk factor for primary open angle glaucoma. Using forward mouse genetics, cell biology, pharmacology and human genetic data, the authors identify CACNA2D1 as an IOP risk gene that can be therapeutically targeted by the drug pregabalin in animal models.

Retinoblastoma (RB) is the most common intraocular cancer in children affecting all populations. Prognosis is highly dependent on the timing of diagnosis. Late presentation with extraocular spread is often fatal. In contrast, early-staged diseases are mostly curable using systemic plus focal therapy. Therefore, early presymptomatic diagnosis and even prenatal diagnosis are crucial to improve the clinical outcome. In recent years extensive studies on the RB1 gene and other RB-related genes have contributed to the better understanding of the disease mechanism. Inactivation of both copies of the RB1 gene on chromosome 13q14, due to loss-of-function mutations, is a prerequisite for tumorigenesis in RB. Secondary genetic alterations, such as lesions in another gene, are necessary to precipitate tumour development. We have found in Hong Kong Chinese about 19% of RB patients carry a germ-line RB1 mutation with no methylation at the RB1 promoter. We detected inactivation of the RB1 gene by loss-of-function mutations and loss of heterozygosity (LOH), but rarely by promoter hypermethylation, in Chinese sporadic RB. Promoter hypermethylation that silences gene expressions in the tumour suppressor gene RASSF1A and the DNA repair genes MGMT and MLH1 is a causative factor of retinoblastoma. We have also revealed the presence of microsatellite instability and recurrent loss of heterozygosity at multiple chromosomal regions in the retinoblastoma genome, showing genes other than RB1 as primary or secondary cause of retinoblastoma. Recently, we are working on extraocular regulation of RB development. Our studies on Chinese RB samples have led to useful information in the RB genome and cell biology for novel design of therapeutic modalities for RB.

PURPOSE: To identify genetic risk factors contributing to central corneal thickness (CCT) in individuals from South India, a population with a high prevalence of ocular disorders. METHODS: One hundred ninety-five individuals from 15 large South Indian pedigrees were genotyped using the Omni2.5 bead array. Family-based association for CCT was conducted using the score test in MERLIN. RESULTS: Genome-wide association study (GWAS) identified strongest association for single nucleotide polymorphisms (SNPs) in the first intron of WNT7B and CCT (top SNP rs9330813; β = −0.57, 95% confidence interval CI: −0.78 to −0.36; P = 1.7 × 10−7). We further investigated rs9330813 in a Latino cohort and four independent European cohorts. A meta-analysis of these data sets demonstrated statistically significant association between rs9330813 and CCT (β = −3.94, 95% CI: −5.23 to −2.66; P = 1.7 × 10−9). WNT7B SNPs located in the same genomic region that includes rs9330813 have previously been associated with CCT in Latinos but with other ocular quantitative traits related to myopia (corneal curvature and axial length) in a Japanese population (rs10453441 and rs200329677). To evaluate the specificity of the observed WNT7B association with CCT in the South Indian families, we completed an ocular phenome-wide association study (PheWAS) for the top WNT7B SNPs using 45 ocular traits measured in these same families including corneal curvature and axial length. The ocular PheWAS results indicate that in the South Indian families WNT7B SNPs are primarily associated with CCT. CONCLUSIONS: The results indicate robust evidence for association between WNT7B SNPs and CCT in South Indian pedigrees, and suggest that WNT7B SNPs can have population-specific effects on ocular quantitative traits.

Background: The trabecular meshwork (TM) is a specialized tissue which is crucial to maintain ocular health (e.g. intraocular pressure) and to sustain optical clarity. Since collagen and elastic fibers are the primary structural components of the tissue, the characterization of these fibers in the fetal eye would advance our understanding of the basic morphology and further congenital studies related to the TM. Aims: To reveal the early development of the human fetal TM. Results: The results showed the presence of circular (radial) and longitudinal collagen fibers as well as trabecular cells in the TM by 12 weeks of gestation. By 26 weeks, the venous system connected with Schlemm’s canal and thin elastic fibers began to form. At birth, longitudinal collagen fibers linked with each other to form long strands. There was also evidence of an increase in circular (or radial) collagen fibers in the TM. Conclusion: The present study characterized the developmental and morphological changes in the genesis of the fetal TM in terms of growth in collagen and elastic fibers. The elastic fibers were found to exist in small quantity at birth, and, thus, any increase in these fibers to maturity is likely to occur after birth.

Objective To evaluate the relative contribution of cord occlusion length intervals between occlusions and experimental duration on oxidative stress in the fetal lamb brain. Design Acute, partially exteriorised fetal lambs with intermittent total cord occlusion. Setting The Vivarium of Westmead Hospital, University of Sydney, Australia and The Chinese University of Hong Kong. Main outcome measures Arterio-venous differences in the concentration of organic hydroperoxides, measured in paired samples of carotid arterial and jugular venous blood, as an index of oxidative stress in the brain. Methods Thirty-two fetal lambs were exposed to graded hypoxia, induced by intermittent total umbilical cord compression of 30 seconds, 60 seconds and 90 seconds duration, occurring every minute for a total of 27 occlusions over 81 minutes. Three sham experiments were also performed. In addition to organic hydroperoxides, carotid arterial blood samples were also assayed in 15 animals (two sham) for oxygen saturation, pH, hypoxanthine, xanthine and urate concentrations. A causal model for oxidative stress was defined: occlusions leading to hypoxia with a rise in hypoxanthine; reperfusion during intervals between occlusions leading to the accelerated production of xanthine and uric acid and the generation of oxygen free radicals, which in turn, are responsible for the rise in lipid peroxidation. Path analysis was performed to assess the strength of the relationships between these variables and the cord occlusion length, the interval between occlusions and the duration of the experiment. Results Sham experiments showed no change in organic hydroperoxide production. Following 30-second umbilical cord occlusions a sixfold drop in mean organic hydroperoxides was observed between carotid arterial and jugular venous levels. In contrast, following occlusions of 60 seconds duration (or longer) a median 20-fold increase in organic hydroperoxide production was observed. Path analysis revealed a strong indirect pathway from occlusion length hypoxanthine urate and weak positive pathways from oxygen saturation urate and from interval between occlusions urate. After accounting for these pathways reflecting oxidative stress, a strong direct path remained from time from first occlusion organic hydroperoxide production. Conclusions Peroxidation of lipids in the brain occurs under conditions of severe hypoxia and reperfusion associated with intermittent umbilical cord occlusions of 60 seconds or longer. The path analysis supported the causal model as originally defined, with the exception that the indirect pathway via pH was found to be trivial.

Background: Previous studies have indicated that microchimerism is present in body tissues, peripheral blood, and plasma of recipients after organ transplantation. We hypothesize that donor-derived DNA may also be present in cell-free urine of renal transplant recipients and that the concentrations of urine DNA may be correlated with graft rejection. Methods: Thirty-one female patients who had renal transplantation were enrolled in the study. In women with male organ donors, the SRY gene on the Y chromosome was used as a marker for donor-derived DNA. Real-time quantitative PCR for the SRY and β-globin genes was carried out on cell-free urinary DNA from these patients. Serial urine samples from a female renal transplant recipient undergoing an acute rejection episode were also collected and analyzed with the β-globin quantitative PCR system. Results: SRY sequences were detected in the urine of 14 of 17 female patients with male organ donors. None of the 14 patients with female organ donors had detectable SRY sequences in urinary DNA. The median fractional concentration of donor-derived DNA was 8.7% (interquartile range, 1.9–26.4%). During the acute rejection episode, urinary concentrations of the β-globin gene were markedly increased, with the concentrations returning rapidly to normal following antirejection treatment. Conclusions: Our results demonstrate that urinary DNA chimerism is present following renal transplantation. The measurement of urinary DNA using quantitative PCR may be useful for the diagnosis and monitoring of graft rejection.

Fragile X syndrome is recognized as the most common inherited cause of mental retardation in western countries. The prevalence of the fragile X syndrome in Asian populations is uncertain. We report a multi-institutional collaborative study of molecular screening for the fragile X syndrome from 1,127 Chinese mentally retarded (MR) individuals. We found that 2.8% of the Chinese MR population screened by DNA analysis had the fragile X full mutation. Our screening indicated that the fragile X syndrome prevalence was very close to that of Caucasian subjects. In addition, we found that 62.5% of fragile X chromosomes had a single haplotype for DXS548-FRAXAC1 (21-18 repeats) which was present in only 9.7% of controls. This unique distribution of microsatellite markers flanking the FMR1 CGG repeats suggests that the fragile X syndrome in Chinese populations, as in the Caucasian, may also be derived from founder chromosomes.

To assess fetal cellular injury arising from oxygen free radical activity in relation to the duration of the second stage of labor.Cord arterial pH, malondialdehyde and organic hydroperoxides levels were determined following vaginal delivery of 326 term singleton pregnancies. Of these, 35 (11%) received epidural analgesia. The length of the second stage was recorded from the time of full dilatation to delivery.Arterial cord pH, malondialdehyde and organic hydroperoxides were significantly correlated with duration of second stage of labor (r=-0.4492; r=0.2542; r=0.2244; respectively, p0.001). The association of lipid peroxidation products with second stage duration was independent of cord pH. This correlation was unchanged when cases of operative delivery were excluded. However, the relationship lost statistical significance amongst cases who received epidurals.The duration of the second stage is correlated with raised reactive oxygen species-derived lipid peroxidation products. Caution should be exercised in the management of prolonged second stage of labor.

To examine the additive effect of the z-4 microsatellite polymorphism of aldose reductase gene (ALR2) and glycaemic control on risk of cataract in a prospective cohort of Chinese type 2 diabetic patients.The (CA)n microsatellite polymorphism of ALR2 was determined using PCR followed by capillary gel electrophoresis. Cataract was defined by presence of lens opacity on direct ophthalmoscopy or history of cataract surgery. A non-linear curve approach was used to identify the threshold of glycated hemoglobin (HbA1c) at which the odds ratio (OR) for cataract started to increase. The association of z-4 allele with cataract, above and below this threshold, was assessed using multiple logistic regression analysis.Of the 5823 patients analyzed, 28.1% had cataracts. After adjusting for conventional risk factors and using non-z-4 carriers with HbA1c8.0% as referent group (n = 3173), the OR (95% confidence intervals) for cataract was highest in z-4 carriers with HbA1c ≥ 8.0% [1.43 (1.05-1.96), n = 244], compared to non-z-4 carriers with HbA1c ≥ 8.0 [1.27 (1.10-1.47), n = 1836] and z-4 carriers with HbA1c8.0%[1.01 (0.77-1.29), n = 420, P(trend)0.001]. This additive association remained significant after additional adjustments for drug use (P(trend) = 0.002) and renal function (P(trend) = 0.01).In type 2 diabetic patients with suboptimal glycaemic control, the z-4 allele of ALR2 (CA)n polymorphism was independently associated with increased susceptibility to cataracts.

FRAXE is a fragile site located at Xq27-8, which contains polymorphic triplet GCC repeats associated with a CpG island. Similar to FRAXA, expansion of the GCC repeats results in an abnormal methylation of the CpG island and is associated with a mild mental retardation syndrome (FRAXE-MR). We surveyed the GCC repeat alleles of FRAXE from 3 populations. A total of 665 X chromosomes including 416 from a New York Euro-American sample (259 normal and 157 with FRAXA mutations), 157 from a Chinese sample (144 normal and 13 FRAXA), and 92 from a Finnish sample (56 normal and 36 FRAXA) were analyzed by polymerase chain reaction. Twenty-seven alleles, ranging from 4 to 39 GCC repeats, were observed. The modal repeat number was 16 in the New York and Finnish samples and accounted for 24% of all the chromosomes tested (162/665). The modal repeat number in the Chinese sample was 18. A founder effect for FRAXA was suggested among the Finnish FRAXA samples in that 75% had the FRAXE 16 repeat allele versus only 30% of controls. Sequencing of the FRAXE region showed no imperfections within the GCC repeat region, such as those commonly seen in FRAXA. The smaller size and limited range of repeats and the lack of imperfections suggests the molecular mechanisms underlying FRAXE triplet mutations may be different from those underlying FRAXA.

To evaluate the intraocular penetration of lidocaine 2% gel after different duration of application and to assess their effects on intraoperative pain.Samples of aqueous humor were obtained in 41 eyes that had phacoemulsification under topical anesthesia with 2% lidocaine gel. The duration between lidocaine gel application and paracentesis was recorded. The aqueous concentration of lidocaine was measured using high performance liquid chromatography (HPLC). Patients were also asked to report the severity of intraoperative pain using a verbal analogue scale. Correlation analysis was performed to analyze the relationship between duration of lidocaine gel application, aqueous lidocaine concentration and intraoperative pain score.The mean duration of lidocaine gel application was 20.3+/-6.1 min and the mean aqueous lidocaine level was 14.2+/-8.5 micro g/ml. Longer duration of lidocaine gel application was significantly associated with higher aqueous concentration of lidocaine (Spearman's rho=0.58, P0.001). Eyes in which lidocaine gel was applied for 20 minutes or more had significantly higher aqueous lidocaine level (two-tailed t-test, P=0.001) However, the duration of lidocaine gel application and the aqueous concentration of lidocaine showed no correlation with the patent's perceived pain score (P=0.20 and P=0.79, respectively).Increase in duration of lidocaine gel application resulted in higher aqueous concentration of lidocaine. Patients' level of perceived pain during phacoemulsification under lidocaine gel anesthesia was not related to the intraocular lidocaine absorption level after 10 min of gel application.

The article is about the Asia Pacific society of eye genetics.

Purpose To evaluate the relationships between optic disc measurements, obtained by an optical coherence tomograph and a confocal scanning laser ophthalmoscope, and myopia. Methods One hundred thirty-three eyes from 133 healthy subjects with mean spherical equivalent -6.0 +/- 4.2 D (range, -13.13 to +3.25 D) were analyzed. Optic disc measurements including disc area, rim area, cup area, cup-to-disc area, and vertical and horizontal ratios were obtained with an optical coherence tomograph (StratusOCT; Carl Zeiss Meditec Inc., Dublin, CA) and a confocal scanning laser ophthalmoscope (Heidelberg Retina Tomograph, HRT 3; Heidelberg Engineering, GmbH, Dossenheim, Germany). The modified axial length method derived from prior published work was used to correct the OCT measurements for ocular magnification. Bland-Altman plots were used to evaluate the agreement for each optic disc parameter. Associations between optic disc area and axial length/spherical equivalent were evaluated by linear regression analysis. Results Disc area increased with the axial length/negative spherical equivalent in the HRT and the corrected OCT measurements although opposite directions of associations were found when the OCT measurements were not corrected for magnification. The difference of the corrected OCT and HRT disc area (corrected OCT disc area minus HRT disc area) was correlated with the axial length (r = 0.195, P = 0.025). When the ametropia was limited to -8.0 to +4.0 D, the correlations became insignificant in the HRT. Using the corrected OCT measurements, disc area, rim area, and cup area, cup-to-disc area, and cup-to-disc horizontal and vertical ratios were significantly larger than those measured by the HRT, with a span of 95% limits of agreement at 1.99, 1.33, and 1.86 mm(2) for the areas, 0.34, 0.53, and 0.58 for the ratios, respectively. Conclusions While optic disc area generally increased with the axial length and myopic refraction, the HRT measurements demonstrated that optic disc size was largely independent of axial length and refractive error between -8 and +4 D. OCT may overestimate optic disc size in myopic eyes and results in poor agreement between the two instruments.