Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: Higher GRS8 was associated with XFGS/XFG (GRS8 RR(Quintile(Q)5vs.Q1) = 3.82, 95% CI: 1.76, 8.29). GRS8 significantly (p = 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 p < 0.001). CONCLUSIONS: XFS GRS8 improved XFGS/XFG prediction, and a higher XFS GRS8 was associated with altered levels of fatty acyl and bile acid metabolite classes.