Correlation between tear levels of vascular endothelial growth factor and vitamin D at retinopathy of prematurity stages in preterm infants.

Deregulation of vascular endothelial growth factor (VEGF) levels leads to retinopathy of prematurity (ROP). Vitamin D (VIT-D) is known to regulate VEGF in an oxygen dependent manner. The purpose of this study was to correlate tear levels of VEGF and VIT-D with different ROP stages in preterm infants. In this prospective cross-sectional study, we enrolled 104 pre-term infants. They were grouped into: Group-1 (Classical ROP) and Group-2 (Aggressive ROP), which were further subdivided into Group-1A (progressing), Group-1B (regressing), Group-2A (pre-treatment), and Group-2B (post-treatment). Tear VEGF and VIT-D levels and their association with different ROP stages were assessed. Stage 1 and stage 2 had higher whereas stage 3 had lower VEGF levels in Group-1B compared to Group-1A. Stage 1 and stage 3 showed higher levels of VIT-D with no difference in stage 2 in Group-1B compared to Group-1A., Group-2B showed higher VEGF and lower VIT-D levels compared to Group-2A. Presence of a positive correlation at an early stage (stage 1) of ROP and a negative correlation at a more advanced stage (stage 3) of ROP with VIT-D and VEGF implies stage-specific distinct signaling crosstalk. These findings suggest that VIT-D supplementation may have the potential to modify the course and outcome of ROP.

Inherited retinal disorders: a genotype-phenotype correlation in an Indian cohort and the importance of genetic testing and genetic counselling.

PURPOSE: Recent advances in sequencing technologies have enabled radical and rapid progress in the genetic diagnosis of inherited retinal disorders (IRDs). Although the list of gene variations continues to grow, it lacks the genetic etiology of ethnic groups like South Asians. Differences in racial backgrounds and consanguinity add to genetic heterogeneity and phenotypic overlaps. METHODS: This retrospective study includes documented data from the Gen-Eye clinic from years 2014 to 2019. Medical records and pedigrees of 591 IRD patients of Indian origin and genetic reports of 117 probands were reviewed. Genotype-phenotype correlations were performed to classify as correlating, non-correlating and unsolved cases. RESULTS: Among the 591 patients, we observed a higher prevalence of clinically diagnosed retinitis pigmentosa (38.9%) followed by unspecified diagnoses (28.5%). Consanguinity was reported to be high (55.6%) in this cohort. Among the variants identified in 117 probands, 36.4% of variants were pathogenic, 19.2% were likely pathogenic, and 44.4% were of uncertain significance. Among the pathogenic and likely pathogenic variants, autosomal recessive inheritance showed higher prevalence. About 35% (41/117) of cases showed genotype-phenotype correlation. Within the correlating cases, retinitis pigmentosa and Stargardt disease were predominant. Novel variants identified in RP, Stargardt, and LCA are reported here. CONCLUSION: This first-of-a-kind report on an Indian cohort contributes to existing knowledge and expansion of variant databases, presenting relevant and plausible novel variants. Phenotypic overlap and variability lead to a differential diagnosis and hence a clear genotype-phenotype correlation helps in precise clinical confirmation. The study also emphasizes the importance of genetic counselling and testing for personalized vision care in a tertiary eye hospital.

Ophthalmic genetic counselling: emerging trends in practice perspectives in Asia.

Genetic counselling (GC) provides information to the patient and the family to make informed choices. Among the advanced Western countries and a few Asian countries, there are certified or trained professionals who perform GC. The Human Genome Project and next-generation sequencing diagnostics have provided an opportunity for increased genetic testing in the field of ophthalmology. The recent interventional therapeutic research strategies have also generated additional interest to seek GC globally, including in Asia. However, GC has several barriers to practise in the developing countries in Asia, namely, (a) shortage of qualified or trained genetic counsellors, (b) poor knowledge and reluctance in clinical adoption of genomics among the physicians in clinical practice, (c) overstretched public health services, and (d) negligible ophthalmic GC-related research and publications. The GC inadequacy in Asia is glaring in the most populous countries like China and India. Cultural differences, religious beliefs, misogyny, genetic discrimination, and a multitude of languages in Asia create unique challenges that counsellors in the West may only encounter with the immigrant minorities. Since there are currently 500 or more specific Mendelian genetic eye disorders, it is important for genetic counsellors to translate the genetic results at a level that the patient and family understand. There is therefore a need for governmental and healthcare organisations to train genetic counsellors in Asia and especially this practice must be included in the routine comprehensive ophthalmic care practice.

Impact of Literacy on Hypertension Knowledge and Control of Blood Pressure in a Southern Indian Tertiary Hospital.

BACKGROUND: Hypertension is a global public health concern. Awareness and knowledge about the disease in a community collectively would allow adequate prevention, promote self-care practices, adherence to medication and ultimately effective management of hypertension. AIMS: To ascertain the level of education associated with the knowledge of hypertension and control of blood pressure. METHODS: A cross-sectional questionnaire survey consisting of item questions about awareness and knowledge of hypertension. Hypertensive patients (n = 424) of both genders and more than 20 years of age were included in the study. Hypertensive patients were divided into two groups (school group and school pass-out group) to assess the level of knowledge. Chi-square test was performed to determine the assessment, and p-value < 0.05 was considered significant. RESULTS: Out of 424 participants, 71.2% were school group and 28.7% school pass-out group. School pass-out group had significant knowledge about dangerous natural course of hypertension (p = 0.00069), hypertension can lead to death if untreated (p = 0.015), benefits of cessation of smoking (p = 0.03), advantage of limiting alcohol (p = 0.019) and performing regular exercise (p = 0.013) reduces blood pressure. School pass-out group had significant (p = 0.04) hypertension control compared to the school group. CONCLUSION: Educational status plays a vital role in increasing knowledge and improving the management of hypertension through better self-care practices and strict adherence to medication. Community- based health education interventional programs targeting the lower socioeconomic group of a population would help to reduce the gap in awareness and effective control of hypertension.

Current concepts and molecular mechanisms in pharmacogenetics of essential hypertension.

Hypertension is a leading age-related disease in our society and if left untreated, leads to fatal cardiovascular complications. The prevalence of hypertension has increased and becomes a significant global health economic burden, particularly in lower-income societies. Many loci associated with blood pressure and hypertension have been reported by genome-wide association studies that provided potential targets for pharmacotherapy. Pharmacogenetic research had shown interindividual variations in drug efficacy, safety, and tolerability. This could be due to genetic polymorphisms in the pharmacokinetics (genes involved in a transporter, plasma protein binding, and metabolism) or pharmacodynamic pathway (receptors, ion channels, enzymes). Pharmacogenetics promises great hope toward targeted therapy, but challenges remain in implementing pharmacogenetic aided antihypertensive therapy in clinical practice. Using various databases, we analyzed the underlying mechanisms between the candidate gene polymorphisms and antihypertensive drug interactions and the challenges of implementing precision medicine. We review the emergence of pharmacogenetics and its relevance to clinical pharmacological practice.

Retinoblastoma genetics screening and clinical management.

BACKGROUND: India accounts for 20% of the global retinoblastoma (RB) burden. However, the existing data on RB1 gene germline mutations and its influence on clinical decisions is minimally explored. METHODS: Fifty children with RB underwent complete clinical examination and appropriate multidisciplinary management. Screening of germline RB1 gene mutations was performed through next-generation sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA) analysis. The mutation and non-mutation groups were compared for clinical parameters especially severity, progression and recurrence. RESULTS: Twenty-nine patients had bilateral RB (BLRB) and 21 had unilateral RB (ULRB). The genetic analysis revealed 20 RB1 variations in 29 probands, inclusive of 3 novel mutations, known 16 mutations and heterozygous whole gene deletions. The mutation detection rate (MDR) was 86.2% in BLRB and 19% in ULRB. Associations of disease recurrence (p = 0.021), progression (p = 0.000) and higher percentage of optic nerve invasion, subretinal seeds and high-risk pathological factors were observed in the mutation group. Clinical management was influenced by the presence of germline mutations, particularly while deciding on enucleation, frequency of periodic follow up and radiotherapy. CONCLUSIONS: We identified novel RB1 mutations, and our mutation detection rate was on par with the previous global studies. In our study, genetic results influenced clinical management and we suggest that it should be an essential and integral component of RB-care in India and elsewhere.

Ophthatome™: an integrated knowledgebase of ophthalmic diseases for translating vision research into the clinic.

BACKGROUND: Medical big data analytics has revolutionized the human healthcare system by introducing processes that facilitate rationale clinical decision making, predictive or prognostic modelling of the disease progression and management, disease surveillance, overall impact on public health and research. Although, the electronic medical records (EMR) system is the digital storehouse of rich medical data of a large patient cohort collected over many years, the data lack sufficient structure to be of clinical value for applying deep learning methods and advanced analytics to improve disease management at an individual patient level or for the discipline in general. Ophthatome™ captures data contained in retrospective electronic medical records between September 2012 and January 2018 to facilitate translational vision research through a knowledgebase of ophthalmic diseases. METHODS: The electronic medical records data from Narayana Nethralaya ophthalmic hospital recorded in the MS-SQL database was mapped and programmatically transferred to MySQL. The captured data was manually curated to preserve data integrity and accuracy. The data was stored in MySQL database management system for ease of visualization, advanced search functions and other knowledgebase applications. RESULTS: Ophthatome™ is a comprehensive and accurate knowledgebase of ophthalmic diseases containing curated clinical, treatment and imaging data of 581,466 ophthalmic subjects from the Indian population, recorded between September 2012 and January 2018. Ophthatome™ provides filters and Boolean searches with operators and modifiers that allow selection of specific cohorts covering 524 distinct ophthalmic disease types and 1800 disease sub-types across 35 different anatomical regions of the eye. The availability of longitudinal data for about 300,000 subjects provides additional opportunity to perform clinical research on disease progression and management including drug responses and management outcomes. The knowledgebase captures ophthalmic diseases in a genetically diverse population providing opportunity to study genetic and environmental factors contributing to or influencing ophthalmic diseases. CONCLUSION: Ophthatome™ will accelerate clinical, genomic, pharmacogenomic and advanced translational research in ophthalmology and vision sciences.

Ex vivo model for studying endothelial tip cells: Revisiting the classical aortic-ring assay.

A drug undergoes several in silico, in vitro, ex vivo and in vivo assays before entering into the clinical trials. In 2014, it was reported that only 32% of drugs are likely to make it to Phase-3 trials, and overall, only one in 10 drugs makes it to the market. Therefore, enhancing the precision of pre-clinical trial models could reduce the number of failed clinical trials and eventually time and financial burden in health sciences. In order to attempt the above, in the present study, we have shown that aortic ex-plants isolated from different stages of chick embryo and different regions of the aorta (pulmonary and systemic) have differential sprouting potential and response to angiogenesis modulatory drugs. Aorta isolated from HH37 staged chick embryo showed 16% (p < 0.001) and 11% (p < 0.001) increase in the number of tip cells at 72 h of culture compared to that of HH35 and HH29 respectively. The ascending order of the number of tip cells was found as central (Gen II), proximal (Gen I) and distal (Gen III) in a virtual zonal segmentation of endothelial sprouting. The HH37 staged aortas displayed differential responses to pro- and anti-angiogenic drugs like Vascular endothelial growth factor (VEGF), nitric oxide donor (spNO), and bevacizumab (avastin), thalidomide respectively. The human placenta tissue-culture however evinced endothelial sprouting only on day 12, with a gradual decrease in the number of tip cells until 21 days. In summary, this study provides an avant-garde angiogenic model emphasized on tip cells that would enhance the precision to test next-generation angiogenic drugs.

Consanguinity and its association with visual impairment in southern India: the Pavagada Pediatric Eye Disease Study 2.

To determine the association of consanguinity with the occurrence of genetically transmitted eye diseases in rural and urban populations in Pavagada and Madhugiri taluks, Karnataka state, south India. This study was part of a population based cross-sectional prevalence survey, "The Pavagada pediatric eye disease study 2." As a part of the demographic data, trained investigators collected information on consanguinity from the parents of children identified for the study. The children underwent visual acuity measurements and were examined by an ophthalmologist. Children with minor eye diseases were treated and those with major eye diseases were seen by a pediatric ophthalmologist. Eight thousand five hundred and fifty-three children were examined. The prevalence of ocular morbidity was 6.54% and blindness was 0.09%. The percentage of consanguineously married couples in the screened population was 34.33%. Among the blind children, 75% were blind with a disease with potential genetic etiology. Out of that, 66.67% were born out of consanguineous marriage (uncle-niece). Among children with diseases with a potential genetic etiology 54.29% of the children were born out of consanguineous union. Most of these children (71.43%) were born out of uncle-niece marriages. Further analysis showed that consanguineous parents were more likely to have children with disease with a potential genetic etiology as compared to nonconsanguineous parents (odds ratio: 2.551, p = 0.012). It is evident that consanguineous marriages, especially uncle-niece unions are common in the study area. Consanguinity is more likely to result in children with eye diseases with potential genetic etiology.

Correction: A 32 kb Critical Region Excluding Y402H in CFH Mediates Risk for Age-Related Macular Degeneration.

[This corrects the article DOI: 10.1371/journal.pone.0025598.].

Emerging trends in childhood blindness and ocular morbidity in India: the Pavagada Pediatric Eye Disease Study 2.

AIM: To discuss the aims, methods, and results of a population-based cross-sectional prevalence survey of children ≤15 years, in South India and compare it with a study conducted earlier, in the same area. We also discuss the changing trends in the domain of childhood blindness in India. METHODS: A population-based cross-sectional prevalence survey of children ≤15 years, in Pavagada and Madhugiri taluks of Tumkur district in Karnataka state in south India, was conducted in 2 phases. One trained medical-social-worker and one field-investigator identified eligible children and brought them to a makeshift clinic in the village school, where they were examined by an ophthalmologist. Children with minor problems were treated on the field and those with major conditions were referred to the pediatric ophthalmologist in the tertiary hospital. The prevalence of specific diseases were calculated in percentages. RESULTS: The prevalence of childhood ocular morbidity (COM) was 6.54%. Refractive errors (2.77%) constituted the major cause of COM. The prevalence of blindness (best corrected visual acuity of <3/60 in the better eye) was 0.09%. Whole-globe anomalies (25%) and uveal coloboma (25%) constituted the main cause of blindness. CONCLUSION: A major proportion of the blindness was due to unavoidable causes. Unlike several earlier studies, corneal blindness is no longer the main cause of blindness. This shows that there is a changing trend in the pattern of childhood blindness in India. The current data demonstrate the need for low vision rehabilitative services and a review of public health strategy in India.

Acute Myeloid Leukemia: Diagnosis and Management Based on Current Molecular Genetics Approach.

BACKGROUND & OBJECTIVE: Acute Myeloid Leukemia (AML) is characterized by the accumulation of ≥20% myeloid premature blast cells in the bone marrow and they are most often found in the peripheral blood. AML is generally classified based on either French-American-British (FAB) or World Health Organization (WHO) systems. For better clinical management, cytogenetic finding in AML is necessary and in patients with normal karyotypes - molecular, epigenetic and proteomic biomarkers are very important in choosing which drugs to prescribe. Mutations of certain genes like NPM1, FLT3, CEBPA, RUNX1 and MLL play a crucial role in the risk management and clinical stratification of AML patients. We reviewed the literature for the current trends of clinical practice based on laboratory based diagnostic tests in AML. Outcome and Result: We listed in AML chromosomal aberrations (translocations, fusions or RUNX1, CBFB, MYHI1, MLL, EVI1, PML-RARA), genes and mutations (NPM1, FLT3, CEPBA, MLL) epigenetic factors (DNMT34, TET2) and proteomic biomarkers (PTP, PTK, PIP) and analysed how on the basis of these factors medical risk was stratified and accordingly managed. CONCLUSION: AML is genetically and functionally a heterogenous malignant disease. In the western world, leukemia is one of the most common among all cancers. India is ranked 3rd in cancer disease after United States of America and China. Cytogenetic analysis, molecular/proteomic biomarkers and epigenetic factors assist in determining the management strategies and prognosis of the disease. A number of targeted drugs in pre-clinical and clinical trials based on molecular factors and epigenetic mechanisms have been reported to have promising results in AML patients.

Prevalence of Diabetic Retinopathy in Urban Slums: The Aditya Jyot Diabetic Retinopathy in Urban Mumbai Slums Study-Report 2.

OBJECTIVES: The aims of the study were to estimate the prevalence of diabetic retinopathy (DR) and enumerate history-based risk factors in the urban slums of Western India. METHODS: The population-based study was conducted in seven wards of Mumbai urban slums, where we screened 6569 subjects of ≥ 40 years age, with a response rate of 98.4%, for type 2 diabetes mellitus (T2DM) based on American Diabetes Association criteria. All subjects with T2DM underwent dilated 30° seven-field stereo-fundus-photography for DR severity grading based on modified Airlie House classification. A multivariate logistic regression model was used to assess the correlation of DR with the history-based risk factors. RESULTS: The prevalence of DR in the general population of Mumbai urban slums was 1.41% (95% CI 0.59-2.23) and in the T2DM population it was 15.37% (95% CI 8.87-21.87). The positive associations with DR were the longer duration of DM (≥ 11 years: OR, 12.77; 95% CI 2.93-55.61) and male gender (OR, 2.05; 95% CI 1.08-3.89); increasing severity of retinopathy was also significantly associated with longer duration of DM (p < 0.001). However, history of hypertension, family history of DM, consanguineous marriage and migration status were not associated with DR in the study population. CONCLUSIONS: The prevalence of DR in the general population and T2DM subjects were 1.41% and 15.37% respectively in Mumbai urban slums. Duration of DM and male gender were significantly associated with DR. The slums in Western India show the trends of urban lifestyle influences similar to the rest of urban India.

Age-Related Macular Degeneration: Genetics and Biology.

Age-related macular degeneration (AMD), widely prevalent across the globe, is a major stakeholder among adult visual morbidity and blindness, not only in the Western world but also in Asia. Several risk factors have been identified, including critical genetic factors, which were never imagined 2 decades ago. The etiopathogenesis is emerging to demonstrate that immune and complement-related inflammation pathway members chronically exposed to environmental insults could justifiably influence disease morbidity and treatment outcomes. Approximately half a dozen physiological and biochemical cascades are disrupted in the AMD disease genesis, eventually leading to the distortion and disruption of the subretinal space, subretinal pigment epithelium, and Bruch membrane, thus setting off chaos and disorder for signs and symptoms to manifest. Approximately 3 dozen genetic factors have so far been identified, including the recent ones, through powerful genomic technologies and large robust sample sizes. The noteworthy genetic variants (common and rare) are complement factor H, complement factor H-related genes 1 to 5, C3, C9, ARMS2/HTRA1, vascular endothelial growth factor A, vascular endothelial growth factor receptor 2/KDR, and rare variants (show causal link) such as TIMP3, fibrillin, COL4A3, MMP19, and MMP9. Despite the enormous amount of scientific information generated over the years, diagnostic genetic or biomarker tests are still not available for clinicians to understand the natural course of the disease and its management in a patient. However, further research in the field should reduce this gap not only by aiding the clinician but also through the possibilities of clinical intervention with complement pathway-related inhibitors entering preclinical and clinical trials in the near future.

Association of Genetic Variants with Polypoidal Choroidal Vasculopathy: A Systematic Review and Updated Meta-analysis.

TOPIC: A systematic review and meta-analysis of the genetic association with polypoidal choroidal vasculopathy (PCV) and the genetic difference between PCV and neovascular age-related macular degeneration (nAMD). CLINICAL RELEVANCE: To identify genetic biomarkers that are potentially useful for genetic diagnosis of PCV and for differentiating PCV from nAMD. METHODS: We performed a literature search in EMBASE, PubMed, Web of Science, and the Chinese Biomedical Database for PCV genetic studies published before February 6, 2015. We then conducted a meta-analysis of all polymorphisms that had sufficient genotype/allele data reported in ≥2 studies and estimated the summary odds ratio (OR) and 95% confidence intervals (CIs) for PCV. We also compared the association profiles between PCV and nAMD, and performed a sensitivity analysis. RESULTS: A total of 66 studies were included in the meta-analysis, involving 56 polymorphisms in 19 genes/loci. In total, 31 polymorphisms in 10 genes/loci (age-related maculopathy susceptibility 2 [ARMS2], high-temperature requirement factor A1 [HTRA1], complement factor H [CFH], complement component 2 [C2], CFB, RDBP, SKIV2L, CETP, 8p21, and 4q12) were significantly associated with PCV. Another 25 polymorphisms in 13 genes (ARMS2, HTRA1, C2, CFB, ELN, LIPC, LPL, ABCA1, VEGF-A, TLR3, LOXL1, SERPING1, and PEDF) had no significant association. Twelve polymorphisms at the ARMS2-HTRA1 locus showed significant differences between PCV and nAMD. The sensitivity analysis validated the significance of our analysis. CONCLUSIONS: This study revealed 31 polymorphisms in 10 genes/loci that contribute to PCV susceptibility. Among them, ARMS2-HTRA1 also showed allelic diversity between PCV and nAMD. Our results confirm the gene variants that could affect the phenotypic expressions of PCV and nAMD.

Two novel missense substitutions in the VSX1 gene: clinical and genetic analysis of families with Keratoconus from India.

BACKGROUND: Visual system homeobox gene (VSX1) plays a major role in the early development of craniofacial and ocular tissues including cone opsin gene in the human retina. To date, few disease-causing mutations of VSX1 have been linked to familial and sporadic keratoconus (KC) in humans. In this study, we describe the clinical features and screening for VSX1 gene in families with KC from India. METHODS: Clinical data and genomic DNA were collected from patients with clinically diagnosed KC and their family members. The study was conducted on 20 subjects of eight families from India. The coding exons of VSX1 gene were amplified using PCR and amplicons were analyzed by direct sequencing. Predictive effect of the mutations was performed using Polyphen-2, SIFT and mutation assessor algorithms. Additionally, haplotypes of VSX1 gene were constructed for affected and unaffected individuals using SNPs. RESULTS: In the coding region of VSX1, one novel missense heterozygous change (p.Leu268His) was identified in five KC patients from two unrelated families. Another family of three members had a novel heterozygous change (p.Ser251Thr). These variants co-segregated with the disease phenotype in all affected individuals but not in the unaffected family members and 105 normal controls. In silico analysis suggested that p.Leu268His could have a deleterious effect on the protein coded by VSX1, while p.Ser251Thr has a neutral effect on the functional properties of VSX1. Haplotype examination revealed common SNPs around the missense change (p.Leu268His) in two unrelated KC families. CONCLUSIONS: In this study, we add p.Leu268His, a novel missense variation in the coding region of VSX1 to the existing repertoire of VSX1 coding variations observed in Indian patients with the characteristic phenotype of KC. The variant p.Ser251Thr might be a benign polymorphism, but further biophysical studies are necessary to evaluate its molecular mechanism. The shared haplotype by two families with the same variant suggests the possibility of a founder effect, which requires further elucidation. We suggest that p.Leu268His might be involved in the pathogenesis of KC, which may help in the genetic counselling of patients and their family.

Identification of Novel Mutations in ABCA4 Gene: Clinical and Genetic Analysis of Indian Patients with Stargardt Disease.

Stargardt disease (STGD) is the leading cause of juvenile macular degeneration associated with progressive central vision loss, photophobia, and colour vision abnormalities. In this study, we have described the clinical and genetic features of Stargardt patients from an Indian cohort. The next generation sequencing was carried out in five clinically confirmed unrelated patients and their family members using a gene panel comprising 184 retinal specific genes. Sequencing results were analyzed by read mapping and variant calling in genes of interest, followed by their verification and interpretation. Genetic analysis revealed ABCA4 mutations in all of the five unrelated patients. Among these, four patients were found with compound heterozygous mutations and another one had homozygous mutation. All the affected individuals showed signs and symptoms consistent with the disease phenotype. We report two novel ABCA4 mutations in Indian patients with STGD disease, which expands the existing spectrum of disease-causing variants and the understanding of phenotypic and genotypic correlations. Screening for causative mutations in patients with STGD using panel of targeted gene sequencing by NGS would be a cost effective tool, might be helpful in confirming the precise diagnosis, and contributes towards the genetic counselling of asymptomatic carriers and isolated patients.

Association of PEDF polymorphisms with age-related macular degeneration and polypoidal choroidal vasculopathy: a systematic review and meta-analysis.

This study assesses the association of the pigment epithelium-derived factor (PEDF) gene with age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV). Publications in MEDLINE and EMBASE up to 21/08/2014 were searched for case-control association studies of PEDF with AMD and/or PCV. Reported studies giving adequate genotype and/or allele information were included. Pooled odds ratios (OR) and 95% confidence intervals (CI) of each polymorphism were estimated. Our literature search yielded 297 records. After excluding duplicates and reports with incomplete information, 8 studies were eligible for meta-analysis, involving 2284 AMD patients versus 3416 controls, and 317 PCV patients versus 371 controls. Four PEDF polymorphisms were meta-analyzed: rs1136287, rs12150053, rs12948385 and rs9913583, but none was significantly associated with AMD or PCV. The most-investigated polymorphism, rs1136287, had a pooled-OR of 1.02 (95% CI: 0.94-1.11, P = 0.64) for AMD. In subgroup analysis by ethnicity, no significant association was identified. Polymorphisms present in single report showed no association. Therefore, existing data in literature does not support the role of PEDF in the genetic susceptibility of AMD and PCV, although replication in specific populations is warranted. Since the pooled-sample size for PCV was small, there is a need of PEDF genotyping in larger samples of PCV.

Biosynthetic and functional defects in newly identified SLC4A11 mutants and absence of COL8A2 mutations in Fuchs endothelial corneal dystrophy.

Late-onset Fuchs endothelial corneal dystrophy (FECD) shows genetic heterogeneity. Identification of SLC4A11 as a candidate gene for congenital hereditary endothelial dystrophy with similar corneal endothelial defects as FECD and reduced mRNA expression of SLC4A11 in the endothelium of FECD cases suggested that this gene may also be involved in pathogenesis of FECD. Mutations in SLC4A11 give rise to SLC4A11 protein marked by retention in the endoplasmic reticulum as a result of mis-folding. We screened 45 sporadic late-onset, 4 early-onset FECD patients and an early-onset autosomal dominant FECD family. We identified three previously unreported missense mutations: c.719G>C (p.W240S), c.1519G>A (p.V507I) and c.1304C>T (p.T434I) in unrelated individuals. These SLC4A11 mutants, expressed in HEK293 cells, had defects in either their cell surface expression or functional activity (rate of osmotically driven water flux). SLC4A11 mutations contribute to 11% (5/45) of sporadic late-onset FECD in the cohort studied. COL8A2, which causes some cases of early-onset FECD, was also screened in this cohort. No mutations were identified in COL8A2, in neither the late-onset cohort nor the early-onset family, suggesting genetic heterogeneity in this FECD family.