Polygenic-Variant Testing Can Help Improves Glaucoma-Risk Prediction

By David Douglas

July 22, 2021

NEW YORK (Reuters Health) - Polygenic risk scores can improve risk stratification in people at increased odds of developing open-angle glaucoma (OAG), according to researchers in Australia.

"Early diagnosis of glaucoma can lead to vision-saving treatment, and genetic information can potentially give us an edge in making earlier diagnoses, and better treatment decisions," Dr. Owen M. Siggs of Flinders University, in Bedford Park, told Reuters Health by email.

In a paper in JAMA Ophthalmology, Dr. Siggs and colleagues note that current glaucoma screening guidelines target high-risk groups, including first-degree relatives or those of a certain age or ancestry.

Beyond those traditional risk factors, they say, genetic risk stratification may be a valuable screening adjunct. Heterozygous variants in the MYOC gene (in particular p.Gln368Ter) are the most common known single-gene cause of primary OAG, accounting for up to 4% of all cases,

To investigate further, the researchers examined clinical and genetic data on 2,507 patients in the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG). Further information was gained via data on genetic and health information on more than 411,000 participants in the UK Biobank.

Using ANZRAG, the team defined the contribution of known monogenic variants. Those with a pathogenic or likely pathogenic variant in a Mendelian glaucoma gene (MYOC, CYP1B1, OPTN, or TBK1) were identified as having monogenic variants, while the remainder were classified as nonmonogenic.

To define the effect of polygenic risk, the team set a threshold for high polygenic risk as the top 5% of an unselected and ancestrally matched population. In the UK Biobank this corresponded to a significant increase in the odds of developing glaucoma of 2.77, comparable with those heterozygous for MYOC p.Gln368Ter in the same population cohort who had an glaucoma OR of 4.19.

In ANZRAG, a high polygenic risk was more than six times more common than MYOC p.Gln368Ter heterozygosity (15.7% vs. 2.6%); in the general population, it was more than 15 times more common (5.0% vs. 0.32%).

In addition, in the ANZRAG population, mean age at glaucoma diagnosis did not differ between those at high polygenic risk and those heterozygous for MYOC p.Gln368Ter.

"Genetic testing is not currently a routine part of glaucoma diagnosis and care, but our test has the potential to change that," said Dr. Siggs. "We're now in a strong position to start testing this in clinical trials."

Commenting on the findings by email, Dr. Louis R. Pasquale, a professor of Ophthalmology at Icahn School of Medicine at Mount Sinai, in New York City, told Reuters Health, "It is remarkable that a panel of common gene variants confer an increased risk for glaucoma comparable to the risk associated with a rare mutation whose biology is fairly well understood. It provides hope that we will ultimately understand glaucoma, which is a complex, multifactorial disease."

SOURCE: https://bit.ly/3iy7yZj JAMA Ophthalmology, online July 15, 2021.

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