Associations Between Methylenetetrahydrofolate Reductase Polymorphisms, Serum Homocysteine Levels, and Incident Cortical Cataract

Ava Grace Tan; Annette Kifley; Paul Mitchell; Elena Rochtchina; Victoria M Flood; Robert G Cumming; Gyungah Jun; Elizabeth G Holliday; Rodney J Scott; Yik Ying Teo; Barbara E K Klein; Ching-Yu Cheng; Sudha K Iyengar; Jie Jin Wang

doi:10.1001/jamaophthalmol.2016.0167

Associations Between Methylenetetrahydrofolate Reductase Polymorphisms, Serum Homocysteine Levels, and Incident Cortical Cataract

JAMA Ophthalmol. 2016 May 1;134(5):522-528. doi: 10.1001/jamaophthalmol.2016.0167.

Authors

Affiliations

¹ Centre for Vision Research, Department of Ophthalmology, The Westmead Institute for Medical Research, The University of Sydney, Westmead Hospital, Westmead, New South Wales, Australia.
² Faculty of Health Sciences, The University of Sydney, Sydney, New South Wales, Australia3St Vincent's Hospital, Sydney, New South Wales, Australia.
³ School of Public Health, The University of Sydney, Sydney, New South Wales, Australia.
⁴ Department of Medicine, School of Medicine, Boston University, Boston, Massachusetts6Andover Product Creation Innovation System, Eisai Inc, Andover, Massachusetts.
⁵ Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia.
⁶ School of Biomedical Sciences, University of Newcastle, Newcastle, New South Wales, Australia9Hunter Medical Research Institute, Newcastle, New South Wales, Australia 10Pathology North, Newcastle, New South Wales, Australia.
⁷ Saw Swee Hock School of Public Health, National University of Singapore, Singapore12Department of Statistics and Applied Probability, National University of Singapore, Singapore.
⁸ Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison.
⁹ Singapore Eye Research Institute, Singapore National Eye Centre, Singapore15Duke-NUS Medical School, Singapore16Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
¹⁰ Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio18Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio19University Hospitals Eye Institute, Cleveland, Ohio20Departm.

PMID: 26986182
DOI: 10.1001/jamaophthalmol.2016.0167

Abstract

Importance: Methylenetetrahydrofolate reductase (MTHFR) polymorphisms have been shown to influence homocysteine levels; homocysteine has been implicated as a cataractogenic stressor.

Objective: To investigate the associations of MTHFR polymorphisms and serum homocysteine levels with incident cortical cataract in an older population.

Design, setting, and participants: From 1992 to 1994, a population-based cohort study, the Blue Mountains Eye Study, was conducted with 3654 residents (82.4% of eligible participants) of the Blue Mountains region aged 49 years and older. At the second (1997-1999, 5-year follow-up) and third (2002-2004, 10-year follow-up) surveys, 2334 (75.8% of survivors) and 1952 (76.7% of survivors) were examined, respectively. For this report, the second survey serves as baseline when homocysteine levels were assessed, and 5-year incidence of cataract refers to incidence estimated from the second to the third survey. After excluding participants with no follow-up data or DNA or who had previous cortical cataract or cataract surgery, 757 participants were included in gene and environment analyses. This current project on associations with cataract was designed initially March 19, 2013, and completed April 14, 2014. Cataract was assessed using the Wisconsin Cataract Grading system. Two MTHFR polymorphisms, C677T (rs1801133) and A1298C (rs1801131), were included. Serum homocysteine levels were assessed following standard methods.

Main outcomes and measures: Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals for incident cortical cataract, after adjusting for age, sex, smoking status, hypertension, diabetes, education, and myopia. Path analysis was performed to explore a possible pathway of MTHFR polymorphisms via homocysteine levels to cortical cataract.

Results: The mean (SD) age of the 1726 participants in the Blue Mountains Eye Study 2 cohort with normal homocysteine levels was 68.3 (8.1) years and 73.2 (8.5) years for those with elevated homocysteine levels. Both the C677T polymorphism (CT/TT vs CC: OR = 1.50; 95% CI = 1.01-2.23) and elevated homocysteine levels (>15 µmol/L: OR = 2.24; 95% CI = 1.38-3.63) were independently associated with increased risk of cortical cataract. Path analysis showed that the genetic effect on cortical cataract was partially mediated via homocysteine levels. Combined CT/TT genotypes and elevated homocysteine levels were associated with a 3-fold risk of cortical cataract (OR = 3.74; 95% CI = 1.79-7.80). The synergy index of both exposures was 1.34 (95% CI = 0.44-4.01).

Conclusions and relevance: MTHFR polymorphism and elevated homocysteine levels contributed separately and jointly to increased risk of cortical cataract. If these findings are confirmed, homocysteine levels may be a therapeutic target to reduce risk of cortical cataract in persons carrying genetic risk.