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

Abstract

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 = 5.7x10−7) 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.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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-016-0177-6) contains supplementary material, which is available to authorized users.

Plexin domain containing 2 (PLXDC2) gene polymorphism rs7081455 may not influence POAG risk in a Saudi cohort

“…Similarly, there was no association reported in the Chinese [ 9 ], Afro-Caribbean [ 10 ] and Korean [ 11 ] populations. Besides, among the two reports from India, there appeared to be a regional difference, with no association among the South Indian as compared to modest association among the POAG patients from Eastern parts of India [ 12 , 13 ]. The distribution of the risk ‘G’ allele frequency observed in our study and other ethnic groups discussed above are shown in Table 3 .…”

Genetic background modifies vulnerability to glaucoma-related phenotypes in Lmx1b mutant mice

“…Ongoing work is aimed at prioritizing positional candidates. Based on published literature, five of the 442 genes are associated with human glaucoma, elevating them as candidate genes within the interval ( Choquet et al, 2017 ; Craig et al, 2020 ; Vishal et al, 2016 ). However, none of the five corresponding mouse loci have SNPs between B6 and 129 mice that are predicted to impact transcript abundance or protein function ( ; Keane et al, 2011 ).…”

“…However, strain 129 mutant angles were largely open and typically had only mild abnormalities. Mild iridocorneal angle abnormalities have been reported in patients with LMX1B variants and POAG (Lichter et al, 1997;Vollrath et al, 1998) IOP distribution is abnormal in Lmx1b V265D/+ mice of all backgrounds with B6 being most severe at young ages.…”

“…The LIM homeobox transcription factor 1-beta (LMX1B) gene was associated with elevated IOP and POAG through genome wide association studies (GWAS) and has been validated in multiple populations (Choquet et al, 2018;Gao et al, 2018;Gharahkhani et al, 2018;Khawaja et al, 2018;MacGregor et al, 2018;Shiga et al, 2018). Prior to GWAS, dominant mutations in LMX1B were identified to cause nail-patella syndrome (NPS) (Chen et al, 1998;Vollrath et al, 1998). NPS is a developmental disorder with characteristic symptoms including nail dysplasia and abnormally developed limb structures (Farley et al, 1999;Sweeney et al, 2003).…”

Primary open angle glaucoma genetics: The common variants and their clinical associations (Review)

“…Although the number of the subjects enrolled in the study was small, it was demonstrated that the main PoaG-associated susceptibility alleles found in other populations, play a reduced role in populations of African ancestry. Moreover, a GWAS performed in India identified a novel candidate gene for POAG, called membrane palmitoylated protein 7 (MPP7), which is dysregulated under cyclic mechanical stress in the TM, thus causing dysfunction of cell to cell interaction (69), while another study in India led to an novel association of PoaG with opticin (OPTC) gene (70).…”