Li Keva, Tolman Nicholas, Segrè Ayellet V, Stuart Kelsey V, Zeleznik Oana A, Vallabh Neeru A, Hu Kuang, Zebardast Nazlee, Hanyuda Akiko, Raita Yoshihiko, Montgomery Christa, Zhang Chi, Hysi Pirro G, Do Ron, Khawaja Anthony P, Wiggs Janey L, Kang Jae H, John Simon Wm, Pasquale Louis R
bioRxiv. 2025 Mar 10:2025.01.18.633745. doi: 10.1101/2025.01.18.633745.
A glaucoma polygenic risk score (PRS) can effectively identify disease risk, but some individuals with high PRS do not develop glaucoma. Factors contributing to this resilience remain unclear. Using 4,658 glaucoma cases and 113,040 controls in a cross-sectional study of the UK Biobank, we investigated whether plasma metabolites enhanced glaucoma prediction and if a metabolomic signature of resilience in high-genetic-risk individuals existed. Logistic regression models incorporating 168 NMR-based metabolites into PRS-based glaucoma assessments were developed, with multiple comparison corrections applied. While metabolites weakly predicted glaucoma (Area Under the Curve=0.579), they offered marginal prediction improvement in PRS-only-based models (P=0.004). We identified a metabolomic signature associated with resilience in the top glaucoma PRS decile, with elevated glycolysis-related metabolites-lactate (P=8.8E-12), pyruvate (P=1.9E-10), and citrate (P=0.02)-linked to reduced glaucoma prevalence. These metabolites combined significantly modified the PRS-glaucoma relationship (P =0.011). Higher total resilience metabolite levels within the highest PRS quartile corresponded to lower glaucoma prevalence (Odds Ratio =0.71, 95% Confidence Interval=0.64-0.80). As pyruvate is a foundational metabolite linking glycolysis to tricarboxylic acid cycle metabolism and ATP generation, we pursued experimental validation for this putative resilience biomarker in a human-relevant Mus musculus glaucoma model. Dietary pyruvate mitigated elevated intraocular pressure (P=0.002) and optic nerve damage (P<0.0003) in mice. These findings highlight the protective role of pyruvate-related metabolism against glaucoma and suggest potential avenues for therapeutic intervention.
青光眼多基因风险评分（PRS）可有效识别疾病风险，但一些PRS高的个体并未患青光眼。导致这种抗逆性的因素尚不清楚。在英国生物银行的一项横断面研究中，我们使用了4658例青光眼病例和113040例对照，调查血浆代谢物是否能增强青光眼预测，以及高遗传风险个体中是否存在抗逆性的代谢组学特征。我们开发了将168种基于核磁共振的代谢物纳入基于PRS的青光眼评估的逻辑回归模型，并进行了多重比较校正。虽然代谢物对青光眼的预测作用较弱（曲线下面积=0.579），但在仅基于PRS的模型中，它们提供了边际预测改善（P=0.004）。我们在青光眼PRS最高十分位数中确定了一种与抗逆性相关的代谢组学特征，与糖酵解相关的代谢物乳酸（P=8.8×10⁻¹²）、丙酮酸（P=1.9×10⁻¹⁰）和柠檬酸（P=0.02）升高与青光眼患病率降低有关。这些代谢物的组合显著改变了PRS与青光眼的关系（P=0.011）。在PRS最高四分位数中，总抗逆性代谢物水平越高，青光眼患病率越低（优势比=0.71，95%置信区间=0.64 - 0.80）。由于丙酮酸是连接糖酵解与三羧酸循环代谢和ATP生成的基础代谢物，我们在与人相关的小家鼠青光眼模型中对这种假定的抗逆性生物标志物进行了实验验证。饮食中的丙酮酸减轻了小鼠的眼压升高（P=0.002）和视神经损伤（P<0.0003）。这些发现突出了丙酮酸相关代谢对青光眼的保护作用，并提示了潜在的治疗干预途径。
