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Eldon Geisert, Steven Hart, XiangDi Wang, Janey Wiggs, ; Mouse Genomic Loci Modulating Ganglion Cell Loss in Glaucoma. Invest. Ophthalmol. Vis. Sci. 2013;54(15):6226.
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There is considerable evidence for differential susceptibility of retinal ganglion cells (RGCs) to injury. In human populations RGCs in some individuals are resistant to death even with extremely high intraocular pressures (IOPS), while in other individuals with relatively normal IOPs, the RGCs die. The current study examines the genetic basis of RGC susceptibility to acute elevated IOP in the BXD RI strain set, a mouse genetic reference panel.
To induce an acute elevation in IOP, we used a previously developed method (Samsel et al, IOVS; 52:1671-1675). The animals were deeply anesthetized and a 20 µl injection of 5µm magnetic microspheres was made into the anterior chamber of the right eye. A hand held 0.5 Tesla magnet was used to pull the microspheres into the trabecular meshwork and impede drainage in the eye. Left eyes served as non-injected controls. The IOP was then measured over the next 21 days. For an animal to be included in the study the bead injected eye had to have an IOP above 25 mm Hg for two consecutive days. We quantified RGC loss by counting axons within the optic nerves of the injected eye and control eye for 24 BXD strains of mice (total of 49 mice).
The injections resulted in an average increase in IOP of 11.8 mm Hg in the injected eye as compared to the contralateral control eye (average IOP of 12 mmHg). The eye with elevated IOP had an average loss of 17.4% of the axons relative to the non-injected control eye. We used this strain-specific quantitative data to map loci modulating axonal loss and identified a significant QTL on Chr 18. Potential candidate genes in the Chr 18 peak were defined by determining genes with cisQTLs in the peak using the ONC Retina Database and bioinformatic tools on GeneNetwork.org. For the locus on Chr 18, 7 candidates were identified (Adnp2, C16orf25, Pias2, Katnal2, Hdhd2, Skorz and Smad2) and were analzyed for association with human glaucoma using the results of the NEIGHBOR/GLAUGEN meta-analysis. Of these 7, one gene, SMAD2, had a significant P value (p = 0.013 when Bonferroni corrected for 7 candidates) associated with normal tension glaucoma patients but not with POAG populations.
This novel approach has identified a potential risk factor for normal tension glaucoma (SMAD2). SMAD2 is part of the signaling pathway for TGFβ, which is known to have a prominent association with glaucoma.
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