Juramt Namuunaa, Zeleznik Oana A, Pasquale Louis R, Wiggs Janey L, Kang Jae H
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Metabolites. 2025 Aug 30;15(9):582. doi: 10.3390/metabo15090582.
Exfoliation syndrome (XFS) is a form of deleterious ocular aging mediated by genetic and environmental factors that frequently produces glaucoma (XFG). We aimed to develop a genetic risk score (GRS), assess its clinical utility, and identify metabolites/metabolite classes associated with a high GRS.
For 39,472 Nurses' Health Studies (NHS, 1980-2018; NHS2, 1989-2019) and Health Professionals Follow-up Study (1986-2018) participants aged ≥ 40 years reporting eye exams and no baseline glaucoma, we formed an eight-single nucleotide polymorphism Genetic Risk Score (GRS8) using loci with genome-wide associations with XFS. We estimated relative risks (RR) for incident XFG suspect (XFGS)/XFG (n = 118 cases) and Harrell's C statistics. Among 7547 participants with plasma metabolites measured via liquid chromatography-mass spectrometry, we evaluated the relation between GRS8 and 427 individual metabolites and 20 metabolite classes, adjusting for multiple comparisons.
Higher GRS8 was associated with XFGS/XFG (GRS8 RR = 3.82, 95% CI: 1.76, 8.29). GRS8 significantly ( = 0.04) improved model prediction from C-index of 88% (95% CI: 0.84, 0.92) to 93% (95% CI: 0.91, 0.95) when added to a basic risk model including age, sex, period at risk, intraocular pressure, and glaucoma family history. Metabolite class analyses revealed positive associations of bile acids and inverse associations of fatty acyls with GRS8 (adjusted < 0.001).
XFS GRS8 improved XFGS/XFG prediction, and a higher XFS GRS8 was associated with altered levels of fatty acyl and bile acid metabolite classes.
剥脱综合征（XFS）是一种由遗传和环境因素介导的有害眼部衰老形式，常导致青光眼（XFG）。我们旨在开发一种遗传风险评分（GRS），评估其临床效用，并确定与高GRS相关的代谢物/代谢物类别。
对于39472名年龄≥40岁、报告有眼部检查且无基线青光眼的护士健康研究（NHS，1980 - 2018年；NHS2，1989 - 2019年）和卫生专业人员随访研究（1986 - 2018年）的参与者，我们使用与XFS全基因组关联的位点构建了一个包含八个单核苷酸多态性的遗传风险评分（GRS8）。我们估计了发生XFG疑似病例（XFGS）/XFG（n = 118例）的相对风险（RR）和Harrell's C统计量。在7547名通过液相色谱 - 质谱法测量血浆代谢物的参与者中，我们评估了GRS8与427种个体代谢物和20种代谢物类别的关系，并对多重比较进行了校正。
较高的GRS8与XFGS/XFG相关（GRS8 RR = 3.82，95%置信区间：1.76，8.29）。当将GRS8添加到包括年龄、性别、风险期、眼压和青光眼家族史的基本风险模型中时，GRS8显著（P = 0.04）将模型预测的C指数从88%（95%置信区间：0.84，0.92）提高到93%（95%置信区间：0.91，0.95）。代谢物类别分析显示胆汁酸与GRS8呈正相关，脂肪酰与GRS8呈负相关（校正P < 0.001）。
XFS GRS8改善了XFGS/XFG的预测，且较高的XFS GRS8与脂肪酰和胆汁酸代谢物类别的水平改变有关。
