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Glaucoma Risk Factor Linked to More Than 100 Genetic Loci in Europeans

NEW YORK (GenomeWeb) – A genome-wide analysis has linked hundreds of genetic loci — including nearly six dozen novel ones — to intraocular pressure, a key risk factor for primary open-angle glaucoma.

Primary open-angle glaucoma affects nearly 3 million adults in the US and often has no warning symptoms, according to the American Academy of Ophthalmology. But, as people's intraocular pressures increases, so does their risk of developing glaucoma.

In a meta-analysis of nearly 140,000 people of European ancestry, an international team of researchers identified 112 loci — 68 of which were novel — linked to intraocular pressure, as they reported today in Nature Genetics. A number of these loci indicate the involvement of the angiopoietin-receptor tyrosine kinase (ANG-TEK) signaling pathway in regulating intraocular pressure. The researchers used these loci to develop a model to predict who might be at risk of developing glaucoma.

"Knowing someone's genetic risk profile might allow us to predict what risk of glaucoma he or she carries so that in the future we can focus scarce health care resources on those most at risk," lead author Pirro Hysi from King's College London said in a statement.

With data from the UK Biobank and EPIC-Norfolk studies and combined results from the International Glaucoma Genetics Consortium, Hysi and colleagues conducted a GWAS of intraocular pressure. Within the UK Biobank cohort of 103,382 individuals, they first identified 74 unique autosomal genetic regions associated with intraocular pressure. They then replicated these results within the other two studies and performed a combined meta-analysis of 139,555 people of European ancestry. In all, the researchers uncovered associations at 112 unique autosomal genomic regions.

While some of the loci the researchers uncovered had previously been linked to intraocular pressure — such as TMCO1, GAS7, and ABCA2 — 68 loci were novel.

A number of loci the researchers found could be traced to genes involved in the ANG-TEK signaling pathway, which mediates the development of blood and lymphatic vessels. The researchers noted that TEK receptors are also highly expressed in endothelial cells of Schlemm's canal, which helps drain fluid from the eye.

Two loci they uncovered contain the angiopoietin genes ANGPT1 and ANGPT2, which encode primary TEK receptor tyrosine kinase ligands, while they noted other associations at LRIG1, a regulator of tyrosine kinases, and at the tyrosine kinase FER. This suggested to the researchers that ANG-TEK signaling is critical for regulating intraocular pressure and could represent a therapeutic target.

They also found associations near genes important in mitochondrial function and adenosine-receptor signaling.

At the same time, Hysi and colleagues looked into whether these loci associated with intraocular pressure were also linked to primary open-angle glaucoma within 3,853 cases and 33,480 controls from the NEIGHBORHOOD study and a separate set of 1,500 cases and 331,078 controls from the UK Biobank study. Four dozen loci were nominally associated with glaucoma, and 14 loci were significantly associated after Bonferroni correction, they reported.

Using 120 significant variants from conditional analyses, the researchers also built a regression-based model to predict primary open-angle glaucoma risk. When they tested it on NEIGHBORHOOD and UK Biobank study participants, the researchers found that their model could predict whether someone might develop glaucoma with about 75 percent accuracy.

"These results help us to better understand the previously unknown mechanisms that cause this damaging disease," first author Anthony Khawaja from Moorfields Eye Hospital said. "By understanding how glaucoma develops we can, in time, get ahead of the curve of the condition and support both those living with the disease and those who may develop it."

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