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Banerjee D.,CSIR - Central Electrochemical Research Institute | Banerjee D.,U.S. National Institutes of Health | Banerjee A.,CSIR - Central Electrochemical Research Institute | Banerjee A.,Bangabasi College | And 8 more authors.
PLoS ONE | Year: 2013

Primary open angle glaucoma (POAG) is a multi-factorial optic disc neuropathy characterized by accelerating damage of the retinal ganglion cells and atrophy of the optic nerve head. The vulnerability of the optic nerve damage leading to POAG has been postulated to result from oxidative stress and mitochondrial dysfunction. In this study, we investigated the possible involvement of the mitochondrial genomic variants in 101 patients and 71 controls by direct sequencing of the entire mitochondrial genome. The number of variable positions in the mtDNA with respect to the revised Cambridge Reference Sequence (rCRS), have been designated "Segregating Sites". The segregating sites present only in the patients or controls have been designated "Unique Segregating Sites (USS)". The population mutation rate (θ = 4Neμ) as estimated by Watterson's θ (θw), considering only the USS, was significantly higher among the patients (p = 9.8×10-15) compared to controls. The difference in θw and the number of USS were more pronounced when restricted to the coding region (p<1.31×10-21 and p = 0.006607, respectively). Further analysis of the region revealed non-synonymous variations were significantly higher in Complex I among the patients (p = 0.0053). Similar trends were retained when USS was considered only within complex I (frequency 0.49 vs 0.31 with p<0.0001 and mutation rate p-value <1.49×10-43) and ND5 within its gene cluster (frequency 0.47 vs 0.23 with p<0.0001 and mutation rate p-value <4.42×10-47). ND5 is involved in the proton pumping mechanism. Incidentally, glaucomatous trabecular meshwork cells have been reported to be more sensitive to inhibition of complex I activity. Thus mutations in ND5, expected to inhibit complex I activity, could lead to generation of oxidative stress and favor glaucomatous condition. © 2013 Banerjee et al. Source

Banerjee D.,CSIR - Central Electrochemical Research Institute | Bhattacharjee A.,CSIR - Central Electrochemical Research Institute | Ponda A.,CSIR - Central Electrochemical Research Institute | Sen A.,Dristi Pradip | Ray K.,CSIR - Central Electrochemical Research Institute
Molecular Vision | Year: 2012

Purpose: Mutations in the myocilin gene (MYOC) account for 2%-4% of primary open angle glaucoma (POAG) cases. To date, a limited number of Indian POAG patients have been analyzed for the contribution of the gene towards the disease pathogenesis. In this study we provided a comprehensive analysis of a total of 765 eastern Indian POAG patients. Methods: In the present study 450 POAG patients and 208 ethnically matched controls were screened for the coding region of MYOC by using the polymerase chain reaction-direct sequencing approach; 315 POAG patients were analyzed in a previous study. Thus, our total patient cohort considering both the studies was 765. In addition, 1 kb upstream region of the gene was also examined for variants in a subset of 250 patients and 100 control samples. Results: Analysis of MYOC coding regions in 450 POAG patients revealed 10 novel variations including 2 frame-shift (R125SfsX158 and D273DfsX344) and 3 nonsynonymous changes (Arg33Lys, Ser331Leu, and Asp395Glu), 3 reported mutations and 4 reported polymorphisms. Gln48His, which has to date been reported only from Indian subcontinent, was identified in 4 individuals among 450 patients, taking the count to 7 individuals among 765 patients harboring the same mutation in eastern Indian cohort. Screening of 1 kb upstream region of MYOC in limited number of individuals yielded 5 variants but none are likely to contribute to the pathogenesis of the disease. Conclusions: MYOC mutations were found to account for 3% of POAG cases in our entire cohort (n=765) and Gln48His is the most common defect. This study, for the first time, reports the presence of deletion mutations in Indian patients, and represents the largest study performed in a single cohort in the Indian population. © 2012 Molecular Vision. Source

Mookherjee S.,Indian Institute of Chemical Technology | Banerjee D.,Indian Institute of Chemical Technology | Chakraborty S.,Indian Institute of Chemical Technology | Banerjee A.,Indian Institute of Chemical Technology | And 3 more authors.
BMC Medical Genetics | Year: 2010

Background: Recent studies suggest that glaucoma is a neurodegenerative disease in which secondary degenerative losses occur after primary insult by raised Intraocular pressure (IOP) or by other associated factors. It has been reported that polymorphisms in the IL1A and IL1B genes are associated with Primary Open Angle Glaucoma (POAG). The purpose of our study was to investigate the role of these polymorphisms in eastern Indian POAG patients.Methods: The study involved 315 unrelated POAG patients, consisting of 116 High Tension Glaucoma (HTG) patients with intra ocular pressure (IOP) > 21 mmHg and 199 non-HTG patients (presenting IOP < 20 mmHg), and 301 healthy controls from eastern India. Genotypes were determined by polymerase chain reaction and restriction digestion for three single nucleotide polymorphisms (SNPs): IL1A (-889C/T; rs1800587), IL1B (-511C/T; rs16944) and IL1B (3953C/T; rs1143634). Haplotype frequency was determined by Haploview 4.1 software. The association of individual SNPs and major haplotypes was evaluated using chi-square statistics. The p-value was corrected for multiple tests by Bonferroni method.Results: No significant difference was observed in the allele and genotype frequencies for IL1A and IL1B SNPs between total pool of POAG patients and controls. However, on segregating the patient pool to HTG and non-HTG groups, weak association was observed for IL1A polymorphism (-889C/T) where -889C allele was found to portray risk (OR = 1.380; 95% CI = 1.041-1.830; p = 0.025) for non-HTG patients. Similarly, 3953T allele of IL1B polymorphism (+3953C/T) was observed to confer risk to HTG group (OR = 1.561; 95% CI = 1.022-2.385; p = 0.039). On haplotype analysis it was observed that TTC was significantly underrepresented in non-HTG patients (OR = 0.538; 95% CI = 0.356- 0.815; p = 0.003) while TCT haplotype was overrepresented in HTG patients (OR = 1.784; 95% CI = 1.084- 2.937; p = 0.022) compared to control pool. However, after correction for multiple tests by Bonferroni method, an association of only TTC haplotype with non-HTG cases sustained (pcorrected= 0.015) and expected to confer protection.Conclusion: The study suggests that the genomic region containing the IL1 gene cluster influences the POAG pathogenesis mostly in non-HTG patients in eastern India. A similar study in additional and larger cohorts of patients in other population groups is necessary to further substantiate the observation. © 2010 Mookherjee et al; licensee BioMed Central Ltd. Source

Basu K.,Jawaharlal Nehru University | Sen A.,Dristi Pradip | Ray K.,CSIR - Central Electrochemical Research Institute | Ghosh I.,Jawaharlal Nehru University | And 2 more authors.
Disease Markers | Year: 2012

Hyaluronan (HA) plays a significant role in maintaining aqueous humor outflow in trabecular meshwork, the primary ocular tissue involved in glaucoma. We examined potential association of the single nucleotide polymorphisms (SNPs) of the HA synthesizing gene-hyaluronan synthase 2 (HAS2), hyaluronan binding protein 1 (HABP1) and HA catabolic gene hyaluronidase 3 (HYAL3) in the primary open angle glaucoma (POAG) patients in the Indian population. Thirteen tagged SNPs (6 for HAS2, 3 for HABP1 and 4 for HYAL3) were genotyped in 116 high tension (HTG), 321 non-high tension glaucoma (NHTG) samples and 96 unrelated, age-matched, glaucoma-negative, control samples. Allelic and genotypic association were analyzed by PLINK v1.04; haplotypes were identified using PHASE v2.1 and gene-gene interaction was analyzed using multifactor dimensionality reduction (MDR) v2.0. An allelic association (rs6651224; p= 0.03; OR: 0.49; 95% CI: 0.25-0.94) was observed at the second intron (C>G) of HAS2 both for NHTG and HTG. rs1057308 revealed a genotypic association (p=0.03) at the 5' UTR of HAS2 with only HTG. TCT haplotype (rs1805429-rs2472614-rs8072363) in HABP1 and TTAG and TTGA (rs2285044-rs3774753-rs1310073-rs1076872) in HYAL3 were found to be significantly high (p< 0.05) both for HTG and NHTG compared to controls. Gene-gene interaction revealed HABP1 predominantly interacts with HAS2 in HTG while it associates with both HYAL3 and HAS2 in NHTG. This is the first genetic evidence, albeit from a smaller study, that the natural polymorphisms in the genes involved in hyaluronan metabolism are potentially involved in glaucomatous neurodegeneration. © 2012-IOS Press and the authors. All rights reserved. Source

Kaurani L.,CSIR - Central Electrochemical Research Institute | Vishal M.,CSIR - Central Electrochemical Research Institute | Kumar D.,CSIR - Central Electrochemical Research Institute | Sharma A.,CSIR - Central Electrochemical Research Institute | And 13 more authors.
Investigative Ophthalmology and Visual Science | Year: 2014

Purpose. Large copy number variations (CNV) can contribute to increased burden for neurodegenerative diseases. In this study, we analyzed the genome-wide burden of large CNVs > 100 kb in primary open angle glaucoma (POAG), a neurodegenerative disease of the eye that is the largest cause of irreversible blindness. Methods. Genome-wide analysis of CNVs > 100 kb were analyzed in a total of 1720 individuals, including an Indian cohort (347 POAG cases and 345 controls) and a Caucasian cohort (624 cases and 404 controls). All the CNV data were obtained from experiments performed on Illumina 660W-Quad (infinium) arrays. Results. We observed that for both the populations CNVs > 1 Mb was significantly enriched for gene-rich regions unique to the POAG cases (P < 10-11). In the Indian cohort CNVs > 1 Mb (39 calls) in patients influenced 125 genes while in controls 31 such CNVs influenced only 5 genes with no overlap. In both cohorts we observed 1.9-fold gene enrichment in patients for deletions compared to duplications, while such a bias was not observed in controls (0.3-fold). Overall duplications > 1 Mb were more than deletions (Del/Dup = 0.82) confirming that the enrichment of gene-rich deletions in patients was associated with the disease. Of the 39 CNVs > 1 Mb from Indian patients, 28 (72%) also were implicated in other neurodegenerative disorders, like autism, schizophrenia, sensorineural hearing loss, and so forth. We found one large duplication encompassing CNTN4 gene in Indian and Caucasian POAG patients that was absent in the controls. Conclusions. To our knowledge, our study is the first report on large CNV bias for gene-rich regions in glaucomatous neurodegeneration, implicating its impact across populations of contrasting ethnicities. We identified CNTN4 as a novel candidate gene for POAG. © 2014 The Association for Research in Vision and Ophthalmology, Inc. Source

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