How Does a High IOP Cause Vision Loss

How Does a High IOP Cause Vision Loss?

Since the 1800s it has been known that high intraocular pressure (IOP) can result in permanent loss of vision. More recently it has been discovered that Glaucoma results from a selective loss of a particular cell in the eye called the Retinal Ganglion Cell. What has not been known, however, is why an elevated IOP would result in damage or death of the Retinal Ganglion Cells (RGCs). Plenty of theories have been suggested. Extremely high eye pressures, for example, could physically damage RGCs or cut off the blood supply to the optic nerve and retina. The problem with these theories is that most people with glaucoma lose vision with eye pressure that is well below what would be necessary to cause physical tissue damage or loss of blood supply.

It’s in the Genes

The risk of developing glaucoma is higher among those with family members who have glaucoma. This has led to the search for the genes that might be associated with glaucoma. Two such genes are SIX6 and p16INKda.[1] Genes can have intimidating names and I personally find it difficult to keep such odd letter-number combinations straight in my own head. So, I secretly rename them in playful ways that will help me remember what they do. For example, in my head SIX6 is “Agent 66” and p16INK4a is “Pinky”.

SIX6 (”Agent 66”) is involved in eye development.[2] One variation of this gene, in particular, has a strong association with primary open angle glaucoma.[3]

When p16INK4a (”Pinky”) is expressed a cell will stop growing.[4] Cells, like businesses, must “grow or die”. So, when a cell stops growing it’s essentially on its way out. This is called “cellular senescence”. Expression of p16INK4a, then, is a death sentence for a cell. Indeed, removal of cells expressing p16INK4a from laboratory mouse tissue can “prevent or delay age-related deterioration”.[5] Of particular interest is that in a rat model of glaucoma p16INK4a was significantly elevated.[6]

It appears that when the IOP is increased SIX6 is activated within Retinal Ganglion Cells. The proteins created by the SIX6 gene interact with p16INK4a.[7] Expression of p16INK4a then results in a cascade of protein interactions that lead to cellular senescence and eventually cell death.

The mission of Agent 66, if accepted, is to contact the hitman, Pinky – who then sees to it that the Retinal Ganglion Cell is put to sleep…permanently.

So it appears that we may finally have a mechanism to explain how elevated IOP can result in the death of Retinal Ganglion Cells leading to permanent loss of vision. Why is knowing this mechanism important? Because now that the genes and their associated protein products are known, therapies might be developed to target these pathways. Such therapies could have the potential to slow or halt vision loss even in if the IOP could not be controlled.

But wait, there’s more…

SIX6 and p16INK4a are far from the only genes that have been associated with glaucoma. Many others have been found that are associated with particular families or types of glaucoma. To review them all would test the wakefulness of even the most interested reader. If you’re interested in the alphabet soup of genes associated with glaucoma a quick Google search should quickly overwhelm you.


[1] Burdon, KP, Macgregor S, Hewitt AW, et al. Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMC01 and CDKN2B-AS1. Nat Genet. 2011;43:574-578.

Wiggs JL, Yaspan BL, Hauser MA, et al. Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. PLos Genet. 2012;8:e1002654.

[2] Anderson AM, Weasner BM, Weasner BP, Kumar JP. Dual transcriptional activities of SIX proteins define their roles in normal and ectopic eye development. Development. 2012;139:991-1000.

[3] Carnes MU, Liu YP, Allingham RR, et al. NEIGHBORHOOD Consortium Investigators. Discovery and functional annotation of SIX6 variants in primary open-angle glaucoma. PLoS Genet. 2014;10:e1004372.

Iglesias AI, Springelkamp H, van den Hout MC, et al. Exome sequencing and functional analyses suggest that SIX6 is a gene involved in an altered proliferation-differentiation balance early in life and optic nerve degeneration at old age. Hum Mol Genet. 2014;23:1320-1332.

Osman W, Low SK, Takahashi A, et al. A genome-wide association study in the Japanese population confirms 9p21 and 14q23 as susceptibility loci for primary open angle glaucoma. Hum Mol Genet. 2102;21:2836-2842.

[4] Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol. 2013;75:685-705.

Krishnamurthy J, Torrice C, Ramsey MR, et al. Ink4a/Arf expression is a biomarker of aging. J Clin Invest. 2004;114:1299-1307.

Naylor RM, Baker DJ, van Deursen JM. Senescent cells: a novel therapeutic target for aging and age-related diseases. Clin Pharmacol Ther. 2013;93:105-116.

[5] Baker DJ, Wijshake T, Tchkonia T, et al. Clearance of p16INK4a-positive senescent cells delays ageing-associated disorders. Nature. 2011;479:232-236.

[6] Burdon, KP, Macgregor S, Hewitt AW, et al. Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMC01 and CDKN2B-AS1. Nat Genet. 2011;43:574-578.

[7] Skowronska-Krawczyk D, Zhao L, Zhu J, et al. P16INK4a Upregulation Mediated by SIX6 Defines Retinal Ganglion Cell Pathogenesis in Glaucoma. Mol Cell. 2015;59:931-940.

Don’t delay getting checked for glaucoma.

Make an appointment with an eye doctor in your area now.  If you live in the greater Los Angeles area and would like Dr. Richardson to evaluate your eyes for glaucoma call 626-289-7856 now. No referral required. Appointments are available, Tuesday through Saturday.

David Richardson, MD

David Richardson, MD

Medical Director, San Marino Eye

David Richardson, M.D. is recognized as one of the top cataract and glaucoma surgeons in the US and is among an elite group of glaucoma surgeons in the country performing the highly specialized canaloplasty procedure. Morever, Dr. Richardson is one of only a few surgeons in the greater Los Angeles area that performs MicroPulse P3™ "Cyclophotocoagulation" (MP3) glaucoma laser surgery. Dr. Richardson graduated Magna Cum Laude from the University of Southern California and earned his Medical Degree from Harvard Medical School. He completed his ophthalmology residency at the LAC+USC Medical Center/ Doheny Eye Institute. Dr. Richardson is also an Ambassador of Glaucoma Research Foundation.

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