Abstract
Purpose :
The mitochondrial genes TXNRD2 and ME3 are associated with POAG risk in genome-wide association studies (GWAS). These genes may functionally contribute to POAG by altering NADPH levels and oxidative stress response. To assess the impact of these variants, we investigated whether a genetic risk score (GRS) of TXNRD2 and ME3 variants correlates with patient clinical phenotypes.
Methods :
2617 POAG cases from the NEIGHBORHOOD consortium were included in this study. All single nucleotide polymorphisms (SNPs) in the TXNRD2 and ME3 loci associated with POAG (p<0.05) were identified using GWAS data. Of these, 20 TXNRD2 and 24 ME3 SNPs were selected for analysis after adjusting for linkage disequilibrium. After aligning alleles for risk, a GRS was constructed for each POAG case using the unweighted sum of POAG risk alleles; this was performed for TXNRD2 SNPs, ME3 SNPs, and TXNRD2+ME3 SNPs combined. The clinical features of individuals in the top 1, 5, 10 and 25% of genetic risk were compared to individuals in the bottom 1, 5, 10 and 25%, respectively. Clinical features examined included age at diagnosis, intraocular pressure (IOP), cup-to-disc ratio (CDR), visual field mean deviation (MD), incidence of paracentral field loss, and need for glaucoma surgery.
Results :
Individuals in the top 1% of TXNRD2 GRS had higher mean maximal IOP compared to the bottom 1% (19.9 mmHg in top 1% vs 15.6 mmHg in bottom 1%, p<0.05). Individuals in the top 1% of ME3 and TXNRD2+ME3 GRS had greater incidence of paracentral visual field loss (72.7-89% in top 1% vs 14.3-33% in bottom 1%, p<0.05 for both). Individuals in the top 5% of ME3 and top 10% of TXNRD2+ME3 GRS had greater mean maximal CDR (0.83 in top 5/10% vs 0.80 in bottom 5/10%, p<0.05). There was a trend toward significance for age at diagnosis in the top 10% of TXNRD2+ME3 GRS (63.8 years in top 10% vs 65.6 years in bottom 10%, p=0.053).
Conclusions :
POAG patients with higher GRS for TXNRD2 and ME3 variants have greater maximal IOP and CDR as well as greater incidence of paracentral field loss. These data suggest that TXNRD2 and ME3 functionally contribute to POAG development and disease severity, potentially through a mechanism that involves NADPH levels. Future prospective clinical studies and translational mechanistic studies will help enable precision medicine approaches to POAG risk stratification and treatment.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.