Mitochondrial TXNRD2 and ME3 Genetic Risk Scores Are Associated with Specific Primary Open-Angle Glaucoma Phenotypes

Inas F Aboobakar; Tyler G Kinzy; Yan Zhao; Baojian Fan; Louis R Pasquale; Ayub Qassim; Antonia Kolovos; Joshua M Schmidt; Jamie E Craig; Jessica N Cooke Bailey; Janey L Wiggs; NEIGHBORHOOD Consortium

doi:10.1016/j.ophtha.2023.02.018

Mitochondrial TXNRD2 and ME3 Genetic Risk Scores Are Associated with Specific Primary Open-Angle Glaucoma Phenotypes

Ophthalmology. 2023 Jul;130(7):756-763. doi: 10.1016/j.ophtha.2023.02.018. Epub 2023 Feb 20.

Authors

Collaborators

NEIGHBORHOOD Consortium:
R Rand Allingham⁶, Murray Brilliant⁷, Donald L Budenz⁸, Jessica N Cooke Bailey⁹, John H Fingert¹⁰, Douglas Gaasterland¹¹, Teresa Gaasterland¹², Jonathan L Haines⁹, Michael A Hauser¹³, Richard K Lee¹⁴, Paul R Lichter¹⁵, Yutao Liu¹⁶, Syoko Moroi¹⁵, Jonathan Myers¹⁷, Louis R Pasquale¹⁸, Margaret Pericak-Vance¹⁹, Anthony Realini²⁰, Doug Rhee²¹, Julia E Richards¹⁵, Robert Ritch²², Joel S Schuman²³, William K Scott¹⁹, Kuldev Singh²⁴, Arthur J Sit²⁵, Douglas Vollrath²⁶, Robert N Weinreb²⁷, Janey L Wiggs²⁸, Gadi Wollstein²³, Donald J Zack²⁹

Affiliations

¹ Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts.
² Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio.
³ Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, New York.
⁴ Department of Ophthalmology, Flinders Health and Medical Research Institute, Flinders University, Adelaide, South Australia, Australia.
⁵ Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts. Electronic address: janey_wiggs@meei.harvard.edu.
⁶ Department of Ophthalmology, Duke University Medical Center, Durham, NC USA.
⁷ Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI USA.
⁸ Department of Ophthalmology, University of North Carolina, Chapel Hill, NC USA.
⁹ Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH USA.
¹⁰ Department of Ophthalmology, University of Iowa, College of Medicine, Iowa City, IA USA.
¹¹ Eye Doctors of Washington, Chevy Chase, MD USA.
¹² Scripps Genome Center, University of California at San Diego, San Diego, CA USA.
¹³ Departments of Medicine and Ophthalmology, Duke University, Durham, NC USA.
¹⁴ Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL USA.
¹⁵ Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI USA.
¹⁶ Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, Georgia USA; James and Jean Culver Vision Discovery Institute, Georgia Regents University, Augusta, GA USA.
¹⁷ Wills Eye Hospital, Philadelphia, PA USA.
¹⁸ Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA.
¹⁹ Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL USA.
²⁰ Department of Ophthalmology, West Virginia University Eye Institute, Morgantown, WV USA.
²¹ Department of Ophthalmology, Case Western Reserve University School of Medicine, Cleveland, OH USA.
²² Einhorn Clinical Research Center, Department of Ophthalmology, New York Eye and Ear Infirmary of Mount Sinai, New York, NY USA.
²³ Department of Ophthalmology, NYU School of Medicine, New York, NY USA.
²⁴ Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA USA.
²⁵ Department of Ophthalmology, Mayo Clinic, Rochester, MN USA.
²⁶ Department of Genetics, Stanford University School of Medicine, Palo Alto, CA USA.
²⁷ Hamilton Glaucoma Center, Shiley Eye Institute, University of California, San Diego, CA USA.
²⁸ Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
²⁹ Wilmer Eye Institute, Johns Hopkins University Hospital, Baltimore, MD USA.

Abstract

Purpose: Genetic variants in regions that include the mitochondrial genes thioredoxin reductase 2 (TXNRD2) and malic enzyme 3 (ME3) are associated with primary open-angle glaucoma (POAG) in genome-wide association studies (GWASs). 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: A total of 2617 patients with POAG and 2634 control participants from the National Eye Institute Glaucoma Human Genetics Collaboration Hereditable Overall Operational Database (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 database. Genetic risk scores were constructed for each individual using the unweighted sum of TXNRD2, ME3, and TXNRD2 + ME3 combined risk alleles. Age- and sex-adjusted odds ratios (ORs) for POAG diagnosis were calculated per decile for each GRS. Additionally, the clinical features of patients with POAG in the top 1%, 5%, and 10% of each GRS were compared with those in the bottom 1%, 5%, and 10%, respectively.

Main outcome measures: Primary open-angle glaucoma OR per GRS decile, maximum treated intraocular pressure (IOP), and prevalence of paracentral visual field loss among patients with POAG with high versus low GRSs.

Results: A larger SNP effect size strongly correlated with higher TXNRD2 and lower ME3 expression levels (r = 0.95 and r = -0.97, respectively; P < 0.05 for both). Individuals in decile 10 of the TXNRD2 + ME3 GRS had the highest odds of POAG diagnosis (OR, 1.79 compared with decile 1; 95% confidence interval, 1.39-2.30; P < 0.001). Patients with POAG in the top 1% of the TXNRD2 GRS showed higher mean maximum treated IOP compared with the bottom 1% (19.9 mmHg vs. 15.6 mmHg; adjusted P = 0.03). Patients with POAG in the top 1% of the ME3 and TXNRD2 + ME3 GRS showed a higher prevalence of paracentral field loss than the bottom 1% (72.7% vs. 14.3% for ME3 GRS and 88.9% vs. 33.3% for TXNRD2+ME3 GRS; adjusted P = 0.03 for both).

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

Financial disclosure(s): Proprietary or commercial disclosure may be found after the references.

Keywords: genetic risk score; glaucoma genetics; mitochondria; precision medicine.

MeSH terms

Cross-Sectional Studies
Genetic Predisposition to Disease
Genome-Wide Association Study*
Glaucoma, Open-Angle* / diagnosis
Glaucoma, Open-Angle* / genetics
Humans
Intraocular Pressure
Phenotype
Risk Factors
Thioredoxin Reductase 2 / genetics

Substances

TXNRD2 protein, human
Thioredoxin Reductase 2

Abstract

MeSH terms

Substances

Grants and funding