Department of Ophthalmology, Columbia University Medical Center, New York, New York.
Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts.
JAMA Ophthalmol. 2024 Apr 1;142(4):356-363. doi: 10.1001/jamaophthalmol.2024.0151.
Primary 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.
To assess whether a PRS improves prediction of POAG onset in patients with ocular hypertension.
DESIGN, SETTING, AND PARTICIPANTS: This 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.
From 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.
Outcome 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.
Of 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.
Higher PRS was associated with increased risk for POAG in patients with ocular hypertension. The inclusion of a PRS improved the prediction of POAG onset.
ClinicalTrials.gov Identifier: NCT00000125.
原发性开角型青光眼 (POAG) 是一种高度遗传性疾病，迄今为止已确定了 127 个风险位点。多基因风险评分 (PRS) 可能提供一种有用的临床综合遗传负担衡量标准，并改善患者风险分层。
评估 PRS 是否可以提高对高眼压患者 POAG 发病的预测。
设计、地点和参与者：这是对眼压升高治疗研究的事后分析。数据来自 22 个美国站点，平均（SD）随访时间为 14.0（6.9）年。共有 1636 名参与者从 1994 年 2 月至 2008 年 12 月进行随访；1077 名参与者参加了辅助遗传学研究，其中 1009 名符合本分析标准。PRS 是使用来自 UK Biobank 的 449186 名跨种族参与者的 8813496 个变体的最大跨种族 POAG 荟萃分析的汇总统计数据计算得出的，权重使用英国生物库的 8813496 个变体进行训练。数据分析于 2022 年 7 月至 2023 年 12 月进行。
从 1994 年 2 月至 2002 年 6 月，参与者被随机分配到局部眼内压降低药物治疗或密切观察。2002 年 6 月后，两组均接受药物治疗。
结局指标是 POAG 发病的风险比。一致性指数和时间依赖性接收器工作特征曲线下面积用于比较多变量 Cox 比例风险模型的预测性能。
在 1009 名纳入的参与者中，562 名（55.7%）为女性，平均（SD）年龄为 55.9（9.3）岁。350 名 POAG 转化者的平均（SD）PRS 显著高于 659 名非转化者（-0.12[1.00]）（P<.001）。随着每个更高的 PRS 十分位数的增加，POAG 风险增加 1.36%（95%置信区间，1.08-1.64%），转换范围从最低 PRS 十分位数的 9.52%（95%置信区间，7.09-11.95%）到最高十分位数的 21.81%（95%置信区间，19.37-24.25%）。对低风险和高风险 PRS 三分位数的比较显示，欧洲和非洲血统的参与者在 20 年内 POAG 风险增加了 2 倍。在随机分配到延迟治疗的亚组中，每个 PRS 十分位数的增加与诊断时年龄（95%置信区间，0.01-1.03）的 0.52 岁（95%置信区间，0.01-1.03）减少相关（P=.047）。在早期治疗组中，PRS 与 POAG 诊断年龄之间没有明显的线性关联。与眼压升高治疗研究基线模型（C 指数=0.75）相比，添加 PRS 作为协变量的预测模型显著改善（C 指数=0.77）（P<.001）。每个 1-SD 更高的 PRS 使 POAG 发病的平均风险比增加 1.25（95%置信区间，1.13-1.44）。
较高的 PRS 与高眼压患者 POAG 风险增加相关。PRS 的纳入提高了 POAG 发病的预测。
ClinicalTrials.gov 标识符：NCT00000125。
