Mitochondrial TXNRD2 and ME3 genetic risk scores are associated with specific primary open-angle glaucoma phenotypes.

PURPOSE: Genetic variants in regions that include the mitochondrial genes TXNRD2 and ME3 are associated with primary open-angle glaucoma (POAG) in genome-wide association studies (GWAS). To assess their clinical impact, we investigated whether TXNRD2 and ME3 genetic risk scores (GRSs) are associated with specific glaucoma phenotypes.

DESIGN: Cross-sectional study PARTICIPANTS: 2617 POAG cases and 2634 controls from the NEIGHBORHOOD consortium.

METHODS: All POAG-associated single nucleotide polymorphisms (SNPs) in the TXNRD2 and ME3 loci were identified using GWAS data (p<0.05). Of these, 20 TXNRD2 and 24 ME3 SNPs were selected after adjusting for linkage disequilibrium. The correlation between SNP effect size and gene expression levels was investigated using the Gene-Tissue Expression (GTEx) database. GRSs were constructed for each individual using the unweighted sum of TXNRD2, ME3, and TXNRD2+ME3 combined risk alleles. Age and gender-adjusted odds ratios (ORs) for POAG diagnosis were calculated per decile for each GRS. Additionally, the clinical features of POAG cases in the top 1, 5, and 10% of each GRS were compared to the bottom 1, 5, and 10%, respectively.

MAIN OUTCOME MEASURES: POAG OR per GRS decile; maximal treated intraocular pressure (IOP) and prevalence of paracentral visual field loss among POAG cases with high vs. low GRSs.

RESULTS: Increased SNP effect size strongly correlated with higher TXNRD2 and lower ME3 expression levels (r=0.95 and -0.97, respectively, p<0.05 for both). Individuals in decile 10 of TXNRD2+ME3 GRS had the highest odds of POAG diagnosis (OR=1.79 compared to decile 1, p<0.001). POAG cases in the top 1% of TXNRD2 GRS had higher mean maximal treated IOP compared to the bottom 1% (19.9 mmHg vs 15.6 mmHg, adjusted p=0.03). POAG cases in the top 1% of ME3 and TXNRD2+ME3 GRS had a higher prevalence of paracentral field loss compared to the bottom 1% (72.7-88.9% vs 14.3-33.3%; adjusted p=0.03 for both).

CONCLUSIONS: POAG patients with higher TXNRD2 and ME3 GRSs had higher treated IOP and a greater prevalence of paracentral field loss. Functional studies exploring how these variants impact mitochondrial function in glaucoma patients are warranted.