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Two Risk Genes Interact to Cause Primary Open-Angle Glaucoma

NEW YORK (GenomeWeb) – Two risk genes interact to cause the development of primary open-angle glaucoma, according to a new study from researchers at the University of California, San Diego.

Primary open-angle glaucoma, one of the leading causes of blindness in Western countries and the leading cause among African Americans, is marked by increased intraocular pressure and the slow, progressive degeneration of retinal ganglion cells.

Through a combination of genetic association and functional studies, UCSD's Kang Zhang and his colleagues found that a SIX6 risk variant increases the expression of p16INK4a, another risk gene, and leads to the senescence of retinal ganglion cells. These findings, which were reported in Molecular Cell today, could lead to new treatments for glaucoma, the researchers said.

"Glaucoma is currently treated by lowering intraocular pressure; however, lowering IOP can only slow down progression — it does not prevent retinal ganglion cell death and blindness," Zhang said in a statement. "Inhibiting [the risk gene product] P16 can be an important drug target for treatment of glaucoma."

Through genetic association studies, the researchers found that a missense variant in SIX6 is strongly associated with primary open-angle glaucoma. In addition, they reported that this variant was more common among patients than controls in a Caucasian cohort of 1,130 glaucoma patients and 4,306 controls, as well as in a Mexican replication cohort.

SIX6, they added, is part of the SIX/Sine oculis family of homeobox transcription factors that are involved in retinal development.

The p16INK4a gene also exhibited a strong association with glaucoma risk, and together, variants in the two genes increase the risk of developing glaucoma some 2.7 times, the researchers reported.

Using RT-qPCR, theyfound that human lymphoblastoid cells carrying the SIX6 risk allele had higher expression levels of SIX6 and p16INK4a mRNA, 1.4-fold and 2.3-fold, respectively.

By tagging different versions of the SIX6 protein, the researchers further noted that they could bind to the p16INK4a promoter. According to Zhang and his colleagues, this indicates that SIX6 is a direct activator of the p16INK4a gene and that the disease risk variant has more potential to activate p16INK4a expression than the wildtype gene.

In a mouse model of glaucoma, the investigators found that both SIX6 and p16INK4a mRNA levels increased significantly in mouse retinas five days after intraocular pressure was increased, as compared to control eyes. In all of the five mice tested, senescent cells accumulated more in IOP-treated retinas as compared to untreated retinas.

The researchers also found that retinal ganglion cells were the primary affected cells in the model.

Lacking SIX6 or p16 is protective against retinal ganglion cell death, they added, and  haploinsufficiency of SIX6 in their mouse model of glaucoma was protective against senescence in retinal ganglion cells.

Meanwhile, knocking out p16INK4a could prevent retinal ganglion cell death in their mouse model of glaucoma, suggesting, along with other findings, that p16INK4a expression is a major cause of cellular senescence in glaucoma.

This, the researchers said, suggests a disease model in which elevated intraocular pressure leads to the upregulation of p16INK4a through increased expression of SIX6 — particularly the His variant — and its binding to the p16INK4a promoter. Increased p16INK4a expression, then, causes retinal ganglion cells to enter senescence, and prolonged senescence, in turn, leads to retinal ganglion cell death and, eventually, to blindness.

This, Zhang and his colleagues added, could help explain how increased intraocular pressure, a common risk factor for the disease, can cause glaucoma.

It also suggests new possible therapeutic targets. "We were surprised by how important P16 is in this disease process and excited about the prospect of developing a new class of drugs to treat glaucoma, which affects tens of millions of people," Zhang said. "We plan to do some preclinical studies to test the efficacy and safety for treatment of glaucoma with reagents targeting P16, and if they are effective, we may contemplate a human clinical trial in the future."

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