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    Genetic Test Outlines POAG Risk Categories

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    A multicountry team has de­veloped a genetic test that stratifies individuals with glaucoma into risk groups.1 The researchers’ polygenic risk score (PRS), or genetic profiling strategy, determines how likely a patient is to develop primary open-angle glaucoma (POAG)—and indicates which patients should be offered early treatment and/or monitoring.

    The PRS predicted that individuals in the top decile were at a 15-fold increased risk of advanced glaucoma and 21.5-fold increased risk of advanced high-tension glau­coma, relative to those in the bottom decile. What’s more, those in the highest decile reached an absolute risk for glaucoma 10 years earlier than did participants at the bottom.

    “Traditionally, genetic testing in glaucoma has focused on rare mutations such as the Gln368Ter vari­ant in the MYOC gene. Our work provides the utility of mass screening,” said Xikun Han, MSc, at the QIMR Berghofer Medical Research Institute in Brisbane, Australia. “Also, importantly, the prediction can be done before damage begins, and people who are stratified into the high-risk group can take the necessary precautions.”

    POAG Risk

    POAG RISK. The risk calculator was found to be predictive of a number of factors, including earlier age of glaucoma diagnosis, increased likelihood of disease progression in early-stage disease, and greater need for incisional surgery in advanced disease.

    A new approach. Unlike existing risk calculators, which rely on general information such as age and intraoc­ular pressure (IOP), the PRS is based on an individual’s profile of all known risk loci for glaucoma. In this study, the researchers identified 107 new gene variants associated with glaucoma that increase the individual’s risk of devel­oping POAG.

    To create the PRS, the researchers identified vertical cup/disc ratio risk variants from optic nerve photographs of 67,040 participants in the U.K. Biobank, which holds genotyping on 500,000 volunteer participants between the ages of 40 and 69. Thus, this investi­gation is the largest genome-wide asso­ciation study of optic nerve morphol­ogy to date. In addition to information from the U.K. Biobank, they used other large biobanks to provide risk variants for IOP and POAG.

    Age and family history mattered. The PRS, which could be approved for general use in one or two years, was sig­nificantly associated with age at POAG diagnosis. Individuals in the top 10% of PRS distribution were, on average, diagnosed seven years earlier than were those in the bottom 10%.

    In addition, those in the highest decile had twice as many family mem­bers affected by glaucoma as did those at the bottom. Moreover, a higher PRS was associated with a greater need for trabeculectomy.

    Room for improvement. The researchers noted that their risk calculator needs to be tested in other populations—and that it could be evaluated prospectively in a longitu­dinal intervention study. In an effort to improve the PRS’ predictive power, the researchers hope to collect DNA from 20,000 people with glaucoma or a family history of glaucoma. “While a more accurate PRS is unlikely to move high-risk individuals to a low-risk cat­egory, the current PRS is less accurate for those in the moderately high-risk category,” Mr. Han said. “An improved genetic test will help split up this group more effectively, enabling more precise guidance to be given to a larger number of people.”

    —Miriam Karmel


    1 Craig JE et al. Nat Genet. Published online Jan. 20, 2020.


    Relevant financial disclosures—Mr. Han: None.

    For full disclosures and the disclosure key, see below.

    Full Financial Disclosures

    Dr. Dishler Carl Zeiss: C.

    Dr. Douglas Horizon Therapeutics: C.

    Mr. Han Support from the University of Queensland Research Training Scholarship and Queensland Institute of Medical Researcher Berghofer PhD Top Up Scholar­ship.

    Dr. Lam None.

    Disclosure Category



    Consultant/Advisor C Consultant fee, paid advisory boards, or fees for attending a meeting.
    Employee E Employed by a commercial company.
    Speakers bureau L Lecture fees or honoraria, travel fees or reimbursements when speaking at the invitation of a commercial company.
    Equity owner O Equity ownership/stock options in publicly or privately traded firms, excluding mutual funds.
    Patents/Royalty P Patents and/or royalties for intellectual property.
    Grant support S Grant support or other financial support to the investigator from all sources, including research support from government agencies (e.g., NIH), foundations, device manufacturers, and/or pharmaceutical companies.


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