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Genetic association and stress mediated down-regulation in trabecular meshwork implicates MPP7 as a novel candidate gene in primary open angle glaucoma

BACKGROUND: Glaucoma is the largest cause of irreversible blindness affecting more than 60 million people globally. The disease is defined as a gradual loss of peripheral vision due to death of Retinal Ganglion Cells (RGC). The RGC death is largely influenced by the rate of aqueous humor production...

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Autores principales: Vishal, Mansi, Sharma, Anchal, Kaurani, Lalit, Alfano, Giovanna, Mookherjee, Suddhasil, Narta, Kiran, Agrawal, Jyoti, Bhattacharya, Iman, Roychoudhury, Susanta, Ray, Jharna, Waseem, Naushin H., Bhattacharya, Shomi S., Basu, Analabha, Sen, Abhijit, Ray, Kunal, Mukhopadhyay, Arijit
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4802647/
https://www.ncbi.nlm.nih.gov/pubmed/27001270
http://dx.doi.org/10.1186/s12920-016-0177-6
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author Vishal, Mansi
Sharma, Anchal
Kaurani, Lalit
Alfano, Giovanna
Mookherjee, Suddhasil
Narta, Kiran
Agrawal, Jyoti
Bhattacharya, Iman
Roychoudhury, Susanta
Ray, Jharna
Waseem, Naushin H.
Bhattacharya, Shomi S.
Basu, Analabha
Sen, Abhijit
Ray, Kunal
Mukhopadhyay, Arijit
author_facet Vishal, Mansi
Sharma, Anchal
Kaurani, Lalit
Alfano, Giovanna
Mookherjee, Suddhasil
Narta, Kiran
Agrawal, Jyoti
Bhattacharya, Iman
Roychoudhury, Susanta
Ray, Jharna
Waseem, Naushin H.
Bhattacharya, Shomi S.
Basu, Analabha
Sen, Abhijit
Ray, Kunal
Mukhopadhyay, Arijit
author_sort Vishal, Mansi
collection PubMed
description BACKGROUND: Glaucoma is the largest cause of irreversible blindness affecting more than 60 million people globally. The disease is defined as a gradual loss of peripheral vision due to death of Retinal Ganglion Cells (RGC). The RGC death is largely influenced by the rate of aqueous humor production by ciliary processes and its passage through the trabecular meshwork (TM) in the anterior part of the eye. Primary open angle glaucoma (POAG), the most common subtype, is a genetically complex disease. Multiple genes and many loci have been reported to be involved in POAG but taken together they explain less than 10 % of the patients from a genetic perspective warranting more studies in different world populations. The purpose of this study was to perform genome-wide search for common variants associated with POAG in an east-Indian population. METHODS: The study recruited 746 POAG cases and 697 controls distributed into discovery and validation cohorts. In the discovery phase, genome-wide genotype data was generated on Illumina Infinium 660 W-Quad platform and the significant SNPs were genotyped using Illumina GGGT assay in the second phase. Logistic regression was used to test association in the discovery phase to adjust for population sub-structure and chi-square test was used for association analysis in validation phase. Publicly available expression dataset for trabecular meshwork was used to check for expression of the candidate gene under cyclic mechanical stress. Western blot and immunofluorescence experiments were performed in human TM cells and murine eye, respectively to check for expression of the candidate gene. RESULTS: Meta-analysis of discovery and validation phase data revealed the association of rs7916852 in MPP7 gene (p = 5.7x10(−7)) with POAG. We have shown abundant expression of MPP7 in the HTM cells. Expression analysis shows that upon cyclic mechanical stress MPP7 was significantly down-regulated in HTM (Fold change: 2.6; p = 0.018). MPP7 protein expression was also found to be enriched in the ciliary processes of the murine eye. CONCLUSION: Using a genome-wide approach we have identified MPP7 as a novel candidate gene for POAG with evidence of its expression in relevant ocular tissues and dysregulation under mechanical stress possibly mimicking the disease scenario. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12920-016-0177-6) contains supplementary material, which is available to authorized users.
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spelling pubmed-48026472016-03-22 Genetic association and stress mediated down-regulation in trabecular meshwork implicates MPP7 as a novel candidate gene in primary open angle glaucoma Vishal, Mansi Sharma, Anchal Kaurani, Lalit Alfano, Giovanna Mookherjee, Suddhasil Narta, Kiran Agrawal, Jyoti Bhattacharya, Iman Roychoudhury, Susanta Ray, Jharna Waseem, Naushin H. Bhattacharya, Shomi S. Basu, Analabha Sen, Abhijit Ray, Kunal Mukhopadhyay, Arijit BMC Med Genomics Research Article BACKGROUND: Glaucoma is the largest cause of irreversible blindness affecting more than 60 million people globally. The disease is defined as a gradual loss of peripheral vision due to death of Retinal Ganglion Cells (RGC). The RGC death is largely influenced by the rate of aqueous humor production by ciliary processes and its passage through the trabecular meshwork (TM) in the anterior part of the eye. Primary open angle glaucoma (POAG), the most common subtype, is a genetically complex disease. Multiple genes and many loci have been reported to be involved in POAG but taken together they explain less than 10 % of the patients from a genetic perspective warranting more studies in different world populations. The purpose of this study was to perform genome-wide search for common variants associated with POAG in an east-Indian population. METHODS: The study recruited 746 POAG cases and 697 controls distributed into discovery and validation cohorts. In the discovery phase, genome-wide genotype data was generated on Illumina Infinium 660 W-Quad platform and the significant SNPs were genotyped using Illumina GGGT assay in the second phase. Logistic regression was used to test association in the discovery phase to adjust for population sub-structure and chi-square test was used for association analysis in validation phase. Publicly available expression dataset for trabecular meshwork was used to check for expression of the candidate gene under cyclic mechanical stress. Western blot and immunofluorescence experiments were performed in human TM cells and murine eye, respectively to check for expression of the candidate gene. RESULTS: Meta-analysis of discovery and validation phase data revealed the association of rs7916852 in MPP7 gene (p = 5.7x10(−7)) with POAG. We have shown abundant expression of MPP7 in the HTM cells. Expression analysis shows that upon cyclic mechanical stress MPP7 was significantly down-regulated in HTM (Fold change: 2.6; p = 0.018). MPP7 protein expression was also found to be enriched in the ciliary processes of the murine eye. CONCLUSION: Using a genome-wide approach we have identified MPP7 as a novel candidate gene for POAG with evidence of its expression in relevant ocular tissues and dysregulation under mechanical stress possibly mimicking the disease scenario. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12920-016-0177-6) contains supplementary material, which is available to authorized users. BioMed Central 2016-03-22 /pmc/articles/PMC4802647/ /pubmed/27001270 http://dx.doi.org/10.1186/s12920-016-0177-6 Text en © Vishal et al. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Vishal, Mansi
Sharma, Anchal
Kaurani, Lalit
Alfano, Giovanna
Mookherjee, Suddhasil
Narta, Kiran
Agrawal, Jyoti
Bhattacharya, Iman
Roychoudhury, Susanta
Ray, Jharna
Waseem, Naushin H.
Bhattacharya, Shomi S.
Basu, Analabha
Sen, Abhijit
Ray, Kunal
Mukhopadhyay, Arijit
Genetic association and stress mediated down-regulation in trabecular meshwork implicates MPP7 as a novel candidate gene in primary open angle glaucoma
title Genetic association and stress mediated down-regulation in trabecular meshwork implicates MPP7 as a novel candidate gene in primary open angle glaucoma
title_full Genetic association and stress mediated down-regulation in trabecular meshwork implicates MPP7 as a novel candidate gene in primary open angle glaucoma
title_fullStr Genetic association and stress mediated down-regulation in trabecular meshwork implicates MPP7 as a novel candidate gene in primary open angle glaucoma
title_full_unstemmed Genetic association and stress mediated down-regulation in trabecular meshwork implicates MPP7 as a novel candidate gene in primary open angle glaucoma
title_short Genetic association and stress mediated down-regulation in trabecular meshwork implicates MPP7 as a novel candidate gene in primary open angle glaucoma
title_sort genetic association and stress mediated down-regulation in trabecular meshwork implicates mpp7 as a novel candidate gene in primary open angle glaucoma
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4802647/
https://www.ncbi.nlm.nih.gov/pubmed/27001270
http://dx.doi.org/10.1186/s12920-016-0177-6
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