HARVARD DEPARTMENT OF OPHTHALMOLOGY
Category : Clinical Research Candidate : Inas Aboobakar Poster #: C1
Genetic Risk Scores of Mitochondrial TXNRD2 and ME3 Variants are Associated with Specific Primary Open-angle Glaucoma Phenotypes
Inas F . Aboobakar , Tyler G . Kinzy , Baojian Fan , Louis R . Pasquale , Jessica N . Cooke-Bailey , Janey L . Wiggs , NEIGHBORHOOD CONSORTIUM
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 genetic risk scores ( GRSs ) of TXNRD2 and ME3 variants are associated with specific glaucoma phenotypes .
Methods : 2617 POAG cases and 2634 controls from the NEIGHBORHOOD consortium were studied . 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 .
Results : Increased SNP effect size strongly correlated with higher TXNRD2 and lower ME3 expression levels ( r = 0.72 and -0.97 , respectively ). Individuals in decile 10 of TXNRD2 + ME3 GRS had the highest odds of POAG diagnosis ( OR = 1.79 , 95 % CI 1.39-2.30 , p < 0.001 ). Individuals in the top 1 % of TXNRD2 GRS had higher mean maximal IOP compared to the bottom 1 % ( 19.9 mmHg vs 15.6 mmHg , p = 0.01 ). Individuals in the top 1 % of ME3 and TXNRD2 + ME3 GRS had higher prevalence of paracentral field loss compared to the bottom 1 % ( 72.7-89 % vs 14.3-33 %, p = 0.02 and 0.01 , respectively ).
Conclusions : Individuals with higher GRSs have higher odds of POAG diagnosis , with a greater effect seen for TXNRD2 + ME3 combined compared to either gene alone . Moreover , POAG patients with higher GRSs have higher IOP and greater prevalence of paracentral field loss . These data suggest that TXNRD2 and ME3 functionally contribute to POAG development and disease severity , potentially through a mechanism involving NADPH levels and mitochondrial dysfunction .