title: Genetic association and stress mediated down-regulation in trabecular meshwork implicates MPP7 as a novel candidate gene in primary open angle glaucoma.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Molecular and Human Genetics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, 700032, India.|Genomics & Molecular Medicine, CSIR-Institute of Genomics & Integrative Biology, Mathura Road (near Sukhdev Vihar), New Delhi, 110025, India.
authors.forename: Mansi
authors.initials: M
authors.lastname: Vishal
authors.affiliation: Genomics & Molecular Medicine, CSIR-Institute of Genomics & Integrative Biology, Mathura Road (near Sukhdev Vihar), New Delhi, 110025, India.|Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110025, India.
authors.forename: Anchal
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Genomics & Molecular Medicine, CSIR-Institute of Genomics & Integrative Biology, Mathura Road (near Sukhdev Vihar), New Delhi, 110025, India.
authors.forename: Lalit
authors.initials: L
authors.lastname: Kaurani
authors.affiliation: UCL Institute of Ophthalmology, London, EC1V 9EL, UK.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Alfano
authors.affiliation: Molecular and Human Genetics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, 700032, India.
authors.forename: Suddhasil
authors.initials: S
authors.lastname: Mookherjee
authors.affiliation: Genomics & Molecular Medicine, CSIR-Institute of Genomics & Integrative Biology, Mathura Road (near Sukhdev Vihar), New Delhi, 110025, India.|Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110025, India.
authors.forename: Kiran
authors.initials: K
authors.lastname: Narta
authors.affiliation: Genomics & Molecular Medicine, CSIR-Institute of Genomics & Integrative Biology, Mathura Road (near Sukhdev Vihar), New Delhi, 110025, India.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Agrawal
authors.affiliation: Premas Biotech Pvt. Ltd, Gurgaon, Haryana, 122050, India.
authors.forename: Iman
authors.initials: I
authors.lastname: Bhattacharya
authors.affiliation: Cancer Biology and Inflammatory disorder division, CSIR-Indian Institute of Chemical Biology, Kolkata, 700032, India.
authors.forename: Susanta
authors.initials: S
authors.lastname: Roychoudhury
authors.affiliation: S. N. Pradhan Centre for Neurosciences, University of Calcutta, Kolkata, 700019, India.
authors.forename: Jharna
authors.initials: J
authors.lastname: Ray
authors.affiliation: UCL Institute of Ophthalmology, London, EC1V 9EL, UK.
authors.forename: Naushin H
authors.initials: NH
authors.lastname: Waseem
authors.affiliation: UCL Institute of Ophthalmology, London, EC1V 9EL, UK.
authors.forename: Shomi S
authors.initials: SS
authors.lastname: Bhattacharya
authors.affiliation: National Institute of Biomedical Genomics, Kalyani, 741251, India.
authors.forename: Analabha
authors.initials: A
authors.lastname: Basu
authors.affiliation: Dristi Pradip, Kolkata, 700068, India.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Sen
authors.affiliation: Molecular and Human Genetics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, 700032, India. kunalray@gmail.com.|Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110025, India. kunalray@gmail.com.
authors.forename: Kunal
authors.initials: K
authors.lastname: Ray
authors.affiliation: Genomics & Molecular Medicine, CSIR-Institute of Genomics & Integrative Biology, Mathura Road (near Sukhdev Vihar), New Delhi, 110025, India. arijit@igib.res.in.|Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110025, India. arijit@igib.res.in.|UCL Institute of Ophthalmology, London, EC1V 9EL, UK. arijit@igib.res.in.
authors.forename: Arijit
authors.initials: A
authors.lastname: Mukhopadhyay
mesh_terms: D000818:Animals; D002924:Ciliary Body / Q000378:metabolism; D015331:Cohort Studies; D015536:Down-Regulation / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D056726:Genetic Association Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005902:Glaucoma, Open-Angle / Q000235:genetics*; D006801:Humans; D007194:India; D008565:Membrane Proteins / Q000235:genetics*; D008810:Mice, Inbred C57BL; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015203:Reproducibility of Results; D013314:Stress, Mechanical; D014129:Trabecular Meshwork / Q000378:metabolism* / Q000473:pathology
chemical_list: C482290:MPP7 protein, human; D008565:Membrane Proteins
keywords: GEO; GWA; HTM; IOP; LD; MPP7; POAG; SNP