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

Genetic association and stress mediated down-regulation in trabecular meshwork implicates MPP7 as a novel candidate gene in primary open angle glaucoma - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

BMC Medical Genomics

, 9:15

First Online: 22 March 2016Received: 20 September 2015Accepted: 11 March 2016


BackgroundGlaucoma 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.

MethodsThe 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.

ResultsMeta-analysis of discovery and validation phase data revealed the association of rs7916852 in MPP7 gene p = 5.7x10 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.

ConclusionUsing 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.

KeywordsPOAG IOP MPP7 GWA HTM LD GEO SNP AbbreviationsPOAGprimary open angle glaucoma

IOPintra-ocular pressure

RGCretinal ganglion cells

GWAgenome-wide association

MPP7membrane protein palmitoylated 7

GEOgene expression omnibus

HTMhuman trabecular meshwork

CCTCentral Corneal Thickness

LDlinkage disequilibrium

CMScyclic mechanical stress

Electronic supplementary materialThe 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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