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Editors Selection IGR 19-2
Basic Science: A New Gene Modulating IOP
Comment by Kent Taylor on:
75367 Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility, Chintalapudi SR; Maria D; Di Wang X et al., Nature communications, 2017; 8: 1755
Chintalapudi et al. selected the best possible tools across both mice and humans to find a possible therapeutic for POAG. Tool #1 consisted of the BXD inbred mouse panel. This panel was generated by crossing C57BL/6J (B6) and DBA/2J (D2) mouse strains followed by successive inbreeding of strains from the second generation (F2) until each strain was homozygous at every chromosomal point, but was also a mosaic of the B6 and D2 chromosomal segments. IOP varied two fold across the panel, mapping IOP mouse chromosome 5. Tool #2 consisted of extensive bioinformatics data. The authors narrowed their list of 25 candidate genes to CACNA2D1. Tool #3 consisted of the human genome-wide association study (GWAS). The NEIGHBORHOOD consortium confirmed the association of CACNA2D1 with POAG and IOP. Tool #4 consisted of returning to the mouse as an experimental system, using histology to confirm a role for CACNA2D1 in POAG-related tissues and then turning a known affinity of pregabalin for CACNA2D1 into testing the ability of pregabalin drops to lower IOP in both B6 and D2 strains.
One critique of the paper would be that the human GWAS results for CACNA2D1 are modest considering the size of NEIGHBORHOOD, but just as different mouse strains show different IOP, perhaps additional GWAS in other ethnic groups will add to the confirmation of the role of CACNA2D1 in POAG.
The approach outlined in this paper shows the synergy possible by combining a quantitative phenotype such as IOP, a well-characterized series of mouse strains such as the BXD series, and a large human GWAS for POAG and POAG-related endophenotypes such as NEIGHBORHOOD. The paper is a model for the type of collaboration necessary to move glaucoma therapeutics rapidly forward.
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