Abstract
Purpose :
LOXL1 single nucleotide polymorphisms (SNPs) and other genetic loci have been identified for exfoliation syndrome (XFS) or glaucoma (XFG). To better understand the biological underpinnings of this genetic susceptibility to XFG, we created a XFG genetic risk score (GRS) and explored the metabolomics of a high XFG GRS.
Methods :
We included participants with metabolite and genetic data from Nurses’ Health Study (NHS), NHS2, and Health Professionals Follow-up Study, who were free of cancer and glaucoma as of blood draw (1989-1990, 1996-1999, 1993-1995, respectively). Plasma metabolites (n=258) were measured via liquid chromatography-mass spectrometry and standardized. A weighted GRS was calculated by multiplying estimated coefficients to the number of risk alleles for 8 SNPs from the largest GWAS of XFG, including LOXL1 SNPs (rs3825942, rs1048661). We calculated area under the curve (AUC) and receiver operating characteristic (ROC) curves for the GRS and used linear regression models, adjusted for age, sex, and fasting status, to estimate mean differences in metabolite levels by GRS and LOXL1 SNPs status.
Results :
Among 7956 participants (mean [SD] age: 55.9 [9.4] years), 78.1% were women. Since blood draw, we identified 90 incident XFG cases through 2019. The AUC for predicting XFG increased from 0.71 (95% CI: 0.66, 0.76) to 0.83 (95% CI: 0.79, 0.86; p<0.001) when GRS was added to a model with age and sex. We confirmed the higher risk of XFG with the GRS and both LOXL1 SNPs: e.g., we observed a 4.36-fold increase in odds (per 1 SD increase in GRS; 95% CI: 2.93, 6.47). For metabolomics, the top 2 metabolites nominally significantly associated with 1 SD increase in GRS were carnitine (CAR(2:0), diff=-0.031, 95% CI: -0.053, -0.009) and methylxanthine, a caffeine-related metabolite (diff=0.025, 95% CI: 0.001, 0.049), which were also top metabolites associated with rs3825942. For rs1048661, of 20 metabolites that were nominally significant, we observed positive associations for 17 lipid metabolites (7 triglycerides, 6 phosphatidylethanolamines, 3 phosphatidylcholines, 1 sphingomyelins). We observed similar results in secondary analyses excluding XFG cases.
Conclusions :
Higher XFG GRS, mostly weighted by LOXL1 SNPs showed associations with select carnitines, methylxanthines and lipids.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.