ImportancePrimary open-angle glaucoma (POAG) is a highly heritable disease, with 127 identified risk loci to date. Polygenic risk score (PRS) may provide a clinically useful measure of aggregate genetic burden and improve patient risk stratification.ObjectiveTo assess whether a PRS improves prediction of POAG onset in patients with ocular hypertension.Design, Setting, and ParticipantsThis was a post hoc analysis of the Ocular Hypertension Treatment Study. Data were collected from 22 US sites with a mean (SD) follow-up of 14.0 (6.9) years. A total of 1636 participants were followed up from February 1994 to December 2008; 1077 participants were enrolled in an ancillary genetics study, of which 1009 met criteria for this analysis. PRS was calculated using summary statistics from the largest cross-ancestry POAG meta-analysis, with weights trained using 8 813 496 variants from 449 186 cross-ancestry participants in the UK Biobank. Data were analyzed from July 2022 to December 2023.ExposuresFrom February 1994 to June 2002, participants were randomized to either topical intraocular pressure–lowering medication or close observation. After June 2002, both groups received medication.Main Outcomes and MeasuresOutcome measures were hazard ratios for POAG onset. Concordance index and time-dependent areas under the receiver operating characteristic curve were used to compare the predictive performance of multivariable Cox proportional hazards models.ResultsOf 1009 included participants, 562 (55.7%) were female, and the mean (SD) age was 55.9 (9.3) years. The mean (SD) PRS was significantly higher for 350 POAG converters (0.24 [0.95]) compared with 659 nonconverters (−0.12 [1.00]) (P < .001). POAG risk increased 1.36% (95% CI, 1.08-1.64) with each higher PRS decile, with conversion ranging from 9.52% (95% CI, 7.09-11.95) in the lowest PRS decile to 21.81% (95% CI, 19.37-24.25) in the highest decile. Comparison of low-risk and high-risk PRS tertiles showed a 2.0-fold increase in 20-year POAG risk for participants of European and African ancestries. In the subgroup randomized to delayed treatment, each increase in PRS decile was associated with a 0.52-year (95% CI, 0.01-1.03) decrease in age at diagnosis (P = .047). No significant linear association between PRS and age at POAG diagnosis was present in the early treatment group. Prediction models significantly improved with the addition of PRS as a covariate (C index = 0.77) compared with the Ocular Hypertension Treatment Study baseline model (C index = 0.75) (P < .001). Each 1-SD higher PRS conferred a mean hazard ratio of 1.25 (95% CI, 1.13-1.44) for POAG onset.Conclusions and RelevanceHigher PRS was associated with increased risk for POAG in patients with ocular hypertension. The inclusion of a PRS improved the prediction of POAG onset.Trial RegistrationClinicalTrials.gov Identifier: NCT00000125

中文翻译：

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高眼压治疗研究中青光眼发病的多基因风险评分

重要性原发性开角型青光眼 (POAG) 是一种高度遗传性疾病，迄今为止已识别出 127 个风险位点。多基因风险评分 (PRS) 可以提供临床上有用的总体遗传负担测量并改善患者风险分层。目的评估 PRS 是否可以改善高眼压患者 POAG 发病的预测。设计、设置和参与者这是一项事后分析高眼压治疗研究。数据收集自 22 个美国研究中心，平均 (SD) 随访时间为 14.0 (6.9) 年。1994年2月至2008年12月共对1636名参与者进行了随访；1077 名参与者参加了一项辅助遗传学研究，其中 1009 名参与者符合该分析的标准。PRS 是使用最大的跨血统 POAG 荟萃分析的汇总统计数据计算的，并使用来自英国生物银行 449 186 名跨血统参与者的 8 813 496 个变体训练权重。数据分析时间为 2022 年 7 月至 2023 年 12 月。 暴露时间：1994 年 2 月至 2002 年 6 月，参与​​者被随机分配接受局部降眼压药物治疗或密切观察。2002 年 6 月后，两组均接受药物治疗。主要结果和测量结果测量为 POAG 发病的风险比。使用一致性指数和接受者操作特征曲线下的时间相关面积来比较多变量 Cox 比例风险模型的预测性能。结果 1009 名参与者中，562 名（55.7%）为女性，平均（SD）年龄为 55.9 岁（ 9.3）年。与 659 个非转化者 (−0.12 [1.00]) 相比，350 个 POAG 转化者 (0.24 [0.95]) 的平均 (SD) PRS 显着更高 (磷< .001）。PRS 十分位数每升高一个，POAG 风险就会增加 1.36%（95% CI，1.08-1.64），转换范围从最低 PRS 十分位数的 9.52%（95% CI，7.09-11.95）到 21.81%（95% CI，19.37-11.95）。 24.25）位于最高十分位。低风险和高风险 PRS 三分位数的比较显示，欧洲和非洲血统的参与者 20 年 POAG 风险增加了 2.0 倍。在随机分配延迟治疗的亚组中，PRS 十分位数的每增加都与诊断时年龄的 0.52 年（95% CI，0.01-1.03）降低相关（磷=.047)。在早期治疗组中，PRS 与 POAG 诊断时的年龄之间不存在显着的线性相关性。与高眼压治疗研究基线模型（C 指数 = 0.75）相比，添加 PRS 作为协变量（C 指数 = 0.77）后预测模型显着改善（磷< .001）。PRS 每升高 1-SD，POAG 发病的平均风险比为 1.25（95% CI，1.13-1.44）。结论和相关性较高的 PRS 与高眼压患者 POAG 风险增加相关。PRS 的纳入改善了 POAG 发病的预测。试验注册ClinicalTrials.gov 标识符：NCT00000125