Manzoor Ahmad Malik

Epigenetic regulation of human retinoblastoma

Retinoblastoma is a rare type of eye cancer of the retina that commonly occurs in early childhood and mostly affects the children before the age of 5. It occurs due to the mutations in the retinoblastoma gene (RB1) which inactivates both alleles of the RB1. RB1 was first identified as a tumor suppressor gene, which regulates cell cycle components and associated with retinoblastoma. Previously, genetic alteration was known as the major cause of its occurrence, but later, it is revealed that besides genetic changes, epigenetic changes also play a significant role in the disease. Initiation and progression of retinoblastoma could be due to independent or combined genetic and epigenetic events. Remarkable work has been done in understanding retinoblastoma pathogenesis in terms of genetic alterations, but not much in the context of epigenetic modification. Epigenetic modifications that silence tumor suppressor genes and activate oncogenes include DNA methylation, chromatin remodeling, histone modification and noncoding RNA-mediated gene silencing. Epigenetic changes can lead to altered gene function and transform normal cell into tumor cells. This review focuses on important epigenetic alteration which occurs in retinoblastoma and its current state of knowledge. The critical role of epigenetic regulation in retinoblastoma is now an emerging area, and better understanding of epigenetic changes in retinoblastoma will open the door for future therapy and diagnosis.

Candidate genes involved in the susceptibility of primary open angle glaucoma.

PURPOSE Glaucoma is a common disease often identified by high intraocular pressure, characteristic optic neuropathy and vision loss. It is currently a leading cause of blindness worldwide with no known cure. Primary open angle glaucoma (POAG) is the most common type of glaucoma worldwide. It is a multifactorial disease where both genetic as well as environmental factors are involved in the pathogenesis. RESULTS Till date, at least 29 genetic loci have been found to be linked to POAG. However, the role of only three underlying genes Myocilin (MYOC), Optineurin (OPTN) and WD repeat Domain 36, (WDR36) is well established. Also, the role of Cytochrome P450, family 1, subfamily B, polypeptide 1 (CYP1B1), Glutathione S-transferase mu 1 (GSTM1) and Neurotrophin (NTF4) has been fairly identified. Association studies have found that 66 loci with 76 genes associated to POAG till date, but even more studies are required to confirm their role in the disease pathology. Gene mutations in various populations have been identified by genetic studies to establish that about 5% of POAG is currently attributed to single-gene or Mendelian forms of glaucoma and others caused by the combined effects of many genetic and environmental risk factors, each of which do not act alone to cause glaucoma. CONCLUSION Although the clinical progression of the disease is well defined, the molecular events responsible for glaucoma are poorly understood and thus the etiology of POAG remains a mystery. Despite strong genetic influence in POAG pathogenesis, only a small part of the disease can be explained in terms of genetic aberration. This review is an overview and update on the latest research and progress of genetic studies associated with POAG.

Genetic determinants of uveal melanoma

Melanoma of the uveal tract is the most common primary intraocular tumor in adults. With advances in genetic research and the open source access of genetic databases, new insights are emerging into the molecular changes of this cancer. As with most other tumors, the driving force behind such research is the hope of finding and developing new modalities for therapeutic purposes, prognosticating disease and understanding risk factors for metastasis. With advances in proteomics, cytogenetics and gene profiling, the stage is set to unearth the underlying genetic basis which can in the future be a target of therapeutic modalities. This article describes the cytogenetic, molecular pathogenesis, and prognostic factors along with the most important findings and their attribution to current and future management of uveal melanoma.

Vascular endothelial growth factor (VEGF-634G/C) polymorphism and retinopathy of prematurity: a meta-analysis

PURPOSE Vascular endothelial growth factor polymorphism (VEGF-634G/C, rs 2010963) has been considered a risk factor for the development of retinopathy of prematurity (ROP). However, the results remain controversial. Therefore, the aim of the present meta-analysis was to determine the association between VEGF-634G/C polymorphism and ROP risk. METHODS Published literature from PubMed and other databases were retrieved. All studies evaluating the association between VEGF-634G/C polymorphism and ROP risk were included. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using random or fixed effects model. A total of six case-control studies including 355 cases and 471 controls were included. RESULTS By pooling all the studies, we found that VEGF-634G/C polymorphism was not associated with ROP risk at co-dominant and allele levels and no association was also found in dominant and recessive models. While stratifying on ethnicity level no association was observed in Caucasian and Asian population. DISCUSSION This meta-analysis suggests that VEGF-634G/C polymorphism may not be associated with ROP risk, the association between single VEGF-634G/C polymorphism and ROP risk awaits further investigation.

Glutathione S-transferase (GSTM1, GSTT1) polymorphisms and JOAG susceptibility: A case control study and meta-analysis in glaucoma

PURPOSE Glutathione S transferase (GST) polymorphisms have been considered risk factors for the development of glaucoma. The aim of the present study was to investigate the association of glutathione S-transferase GSTT1 and GSTM1 genotypes with juvenile open-angle glaucoma (JOAG) in Indian patients. METHODS A case-control study was performed to investigate the associations of GSTM1 and GSTT1 in juvenile open-angle glaucoma. The genotype of GSTM1 and GSTT1 were determined in 73 juvenile open-angle glaucoma patients, and 70 controls matched by age and sex by polymerase chain reaction method. We also performed a meta-analysis of sixteen published studies on GSTM1 and GSTT1 and evaluated the association between the GSTM1 and GSTT1 polymorphisms and glaucoma (JOAG & POAG). Published literature from PubMed and other databases were retrieved. All studies evaluating the association between GSTM1 and GSTT1 polymorphisms and glaucoma (JOAG & POAG) risk were included. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using random- or fixed-effects model. RESULTS In the present study, we observed there is no association of GSTM1 (OR=0.680; 95% CI=0.323-1.433; p=0.311) or GSTT1 (OR=0.698; 95% CI=0.307-1.586; p=0.391) with JOAG. In the present meta-analysis, significantly increased glaucoma (JOAG & POAG) risk was found among subjects carrying GSTM1 null genotype (OR=1.177; 95% CI=1.028-1.348; p=0.018) but not among subjects carrying GSTT1 deletion genotype (OR=1.186; 95% CI=0.992-1.417; p=0.061). CONCLUSIONS The present case-control study found that GSTM1 and GSTT1 polymorphism are not associated with JOAG risk in North Indian population. The present meta-analysis suggested that there might be a significant association of GSTM1 null genotype with glaucoma (JOAG & POAG) risk. To the best of our knowledge, this is the first study in the world to investigate role of GSTM1 and GSTT1 polymorphisms with JOAG susceptibility. Given the limited sample size, the associations between GST polymorphism and glaucoma risk needs further investigation.

Inferior rectus muscle ocular cysticercosis: A case report

Cysticercosis is a systemic parasitic disease caused by the larval form of cestode Taenia solium. It has a worldwide distribution and is potentially harmful with variable clinical manifestations. The most commonly involved sites include eye, brain, bladder wall, and heart. Ocular cysticercosis can be extraocular or intraocular and may present with varied clinical symptoms. We report the condition in a thirteen year old female child who presented with mild lower lid swelling and diplopia in upgaze, wherein cysticercus cellulosae cyst was found within the mass of the right inferior rectus muscle. It becomes important to report this case because of the relative rarity of the condition these days, unusual site of the cyst and the young age of the patient.

A novel duplication in the PAX6 gene in a North Indian family with aniridia

Mutations in paired box gene 6 (PAX6) are the major cause of aniridia that may be associated with several other developmental anomalies of the eye, including microcornea in rare cases. Therefore, the purpose of this study was to identify the underlying genetic cause in a two-generation North Indian family diagnosed with aniridia. All the participants enrolled in the study, including the aniridia family and 20 healthy individuals (controls), underwent a comprehensive ophthalmic examination. Mutation screening was performed for the PAX6 gene by direct sequencing of the polymerase chain reaction products. A novel PAX6 duplication in exon 5 at position c.474dupC was identified in all three affected individuals from the family but not in the unaffected family members or unrelated controls. We reported a novel duplication in the PAX6 gene capable of causing the classic aniridia phenotype. This is the first report on the duplication in a North Indian family with autosomal dominant aniridia.

Genetic variants associated with primary open angle glaucoma in Indian population

Glaucoma is a very common disorder of the eye wherein the disturbance of the structural or functional integrity of the optic nerve causes characteristic atrophic changes in the optic nerve, which may lead to specific visual field defects over time. Primary open angle glaucoma (POAG) is most frequent among the three principle glaucoma subtypes. With well-established role of genes like Myocilin (MYOC), Optineurin (OPTN) and WD repeat Domain 36, (WDR36), at least 29 genetic loci have been found till date to be linked to POAG. Moreover, association studies have found 66 loci with 76 genes associated to POAG till date with conflicting results. This particular study is to summarize the current knowledge regarding the change in glaucoma prevalence worldwide and in India from 1993 onwards and compiles all the studied genes that are involved in POAG pathogenesis in Indian population.

Association between VEGF polymorphisms (−460 T/C and +936 C/T) and retinopathy of prematurity risk: A meta-analysis

Purpose Vascular endothelial growth factor (VEGF) contributes to the development of retinopathy of prematurity (ROP). A number of studies investigated the association of ROP with VEGF −460 T/C and +936 C/T polymorphisms but the results were conflicting. In order to derive a more precise estimation of the associations, we performed a meta-analysis of the relationship between VEGF −460 T/C and +936 C/T polymorphisms with ROP in all published studies. Methods A literature search was performed systematically using electronic databases. Published literature from PubMed and other databases was retrieved. The odds ratio (OR) with 95% confidence interval (CI) was used to estimate the pooled effect. Each −460 T/C and +936 C/T polymorphism included four case-control studies including case/control 249/308 and 179/250 respectively. Results Through literature search, we found that both VEGF −460 T/C and +936 C/T polymorphisms were not associated with ROP risk at allelic, co-dominant, dominant and recessive models. Conclusions This meta-analysis suggests that the VEGF −460 T/C and +936 C/T polymorphism might contribute to genetic susceptibility of ROP. The association between VEGF −460 T/C and +936 C/T polymorphism and ROP risk awaits further investigation.