ImportancePrimary open-angle glaucoma (POAG) is a heritable disease. A polygenic risk score (PRS) threshold may be used to identify individuals at low risk of disease onset.ObjectiveTo assess the utility of a POAG PRS to identify ocular hypertensive individuals at low risk of disease onset.Design, Setting, and ParticipantsThis is a post hoc analysis of the Ocular Hypertension Treatment Study (OHTS), a multicenter randomized clinical trial across 22 centers in the US conducted among 1636 participants with ocular hypertension from February 1994 to April 2019 with available genetic data. Of the 1636 original participants, 1077 had available genetic data; after excluding 67 for missing data, data quality concerns, or ancestry other than European or African, 1010 were included in the present analysis. Data for this report were analyzed from November 2023 to June 2024.ExposureFrom 1994-2002, participants were randomized to receive topical intraocular pressure (IOP)–lowering medications. From 2002 onwards, all participants were given topical IOP-lowering medications.Main Outcome and MeasureTwenty-year conversion rates by POAG PRS threshold, baseline randomization status, and OHTS clinical risk tertile.ResultsAmong the 1010 participants in this study, 563 (65.8%) were female, and the mean (SD) age was 55.9 (9.4) years. In a mixed-effects logistic regression model adjusted for OHTS risk factors for conversion to POAG and randomization status, a PRS under the 48th percentile was associated with a 1.49 times higher likelihood of disease-free status after 20 years of follow-up (95% CI, 1.04-2.15; P = .03; unadjusted hazard ratio [HR], 1.64; 95% CI, 1.13-2.38; P = .009), compared with high polygenic risk. When we stratified the trial cohort into nongenetic OHTS clinical risk tertiles, the largest differences in survival probability at 20 years based on PRS threshold was observed in eyes in the highest tertile, initial observation group (20-year conversion rate: 61.1% in the high polygenic risk group vs 23.8% in the low polygenic risk group; 95% CI, −63.0 to −11.6; P = .01), with randomization to early treatment partially mitigating the effect of high genetic risk (20-year conversion rate: 37.3% in the high polygenic risk group vs 24.1% in the low polygenic risk group; 95% CI, −35.6 to 9.3%; P = .32).Conclusions and RelevanceThese findings support considering use of a POAG PRS threshold to identify individuals at low risk of disease onset, with those below the PRS threshold more likely to have lower conversion rates over 20 years. Among those considered at highest risk based on the OHTS clinical risk model, early treatment may partially offset the association with high genetic risk but provide limited benefit for those with low genetic risk.Trial RegistrationClinicalTrials.gov Identifier: NCT00000125

中文翻译：

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原发性开角型青光眼多基因风险评分和发病风险


重要性原发性开角型青光眼 （POAG） 是一种遗传性疾病。多基因风险评分 （PRS） 阈值可用于识别发病风险低的个体。目的评估 POAG PRS 识别低发病风险眼高血压个体的效用。设计、设置和参与者这是对高眼压症治疗研究 （OHTS） 的事后分析，这是一项在美国 22 个中心进行的多中心随机临床试验，于 1994 年 2 月至 2019 年 4 月对 1636 名高眼压症参与者进行了研究，并拥有可用的遗传数据。在 1636 名原始参与者中，1077 名有可用的遗传数据;在因数据缺失、数据质量问题或非欧洲或非洲血统而排除 67 人后，本分析包括 1010 人。本报告的数据是从 2023 年 11 月到 2024 年 6 月进行的分析。暴露从 1994 年到 2002 年，参与者被随机分配接受局部眼压 （IOP） 降低药物。从 2002 年开始，所有参与者都接受了局部降眼压药物。主要结果和测量按 POAG PRS 阈值、基线随机化状态和 OHTS 临床风险三分位数划分的 20 年转化率。结果在本研究的 1010 名参与者中，563 名 （65.8%） 为女性，平均 （SD） 年龄为 55.9 （9.4） 岁。在针对转换为 POAG 和随机化状态的 OHTS 危险因素进行调整的混合效应 logistic 回归模型中，第 48 个百分位数以下的 PRS 与随访 20 年后无病状态的可能性高 1.49 倍相关（95% CI，1.04-2.15;P = .03;未调整的风险比 [HR]，1.64;95% CI，1.13-2.38;P = .009），与高多基因风险相比。 当我们将试验队列分层为非遗传性 OHTS 临床风险三分位数时，根据 PRS 阈值，在最高三分位数初始观察组的眼睛中观察到 20 年生存概率的最大差异（20 年转化率：高多基因风险组为 61.1%，低多基因风险组为 23.8%;95% CI， −63.0 至 −11.6;P = .01），随机化至早期治疗部分减轻了高遗传风险的影响（20 年转化率：高多基因组为 37.3%，低多基因组为 24.1%;95% CI，-35.6 至 9.3%;P = .32）。结论和相关性这些发现支持考虑使用 POAG PRS 阈值来识别发病风险低的个体，低于 PRS 阈值的人更有可能在 20 年内具有较低的转化率。在根据 OHTS 临床风险模型被认为风险最高的人群中，早期治疗可能会部分抵消与高遗传风险的关联，但对低遗传风险人群的益处有限。试验注册临床试验。gov 标识符： NCT00000125