This application proposes to conduct several timely and cost-efficient blood-based and diet-based studies to expand upon recent randomized trial findings for age-related macular degeneration (AMD) in the Women's Antioxidant Folic Acid Cardiovascular Study (WAFACS). WAFACS was a randomized, double-blind, placebo-controlled trial conducted among female health professionals aged 40 years or older who were at high risk of cardiovascular events. The findings for AMD in WAFACS, based on an average of 7.3 years of treatment and follow-up of 5,205 women in the folic acid arm, indicate a statistically-significant 34% reduced risk of confirmed AMD (55 cases vs. 82 cases) for those assigned to active treatment with folic acid (2.5 mg/d), vitamin B6 (50 mg/d), and vitamin B12 (1 mg/d). Supplementation with folic acid and B vitamins is known to reduce plasma levels of homocysteine. Therefore, a primary aim of this proposal is to address the causal relevance of homocysteine to AMD by conducting the first prospective studies of plasma homocysteine and AMD in women and men utilizing available data from WAFACS, the Women's Health Study, and Physicians'Health Study II. A total of 829 cases of confirmed AMD have been documented among participants with baseline blood specimens in these cohorts and are available for analysis. We will also utilize archived blood specimens collected at baseline and at follow-up for 300 participants in WAFACS to examine the effect of folic acid/B6/B12 supplementation on four biomarkers of inflammation and endothelial dysfunction found to be associated with risks of AMD in observational studies. Finally, we will explore whether the reduced risk of AMD observed in WAFACS reflects the homocysteine-lowering effect of folic acid and B vitamins by utilizing archived blood specimens collected at baseline to contrast the magnitude of risk reduction in women with baseline homocysteine level above, as compared to below, the median value. We will also explore the modifying effect of baseline levels of plasma folate, vitamin B6, and vitamin B12 on the effectiveness of folic acid/B6/B12 supplementation. This proposal represents an extraordinarily cost-efficient opportunity to extend the promising overall findings for AMD in WAFACS to important blood-based and diet-based subgroups. The information derived from these studies will address important gaps in knowledge regarding the homocysteine-AMD hypothesis, and should contribute to the efficient design of future trials in other populations to critically evaluate the possible beneficial effect of folic acid and B vitamin supplementation in AMD.

Public Health Relevance

Recent randomized trial findings from the Women's Antioxidant Folic Acid Cardiovascular Study indicate that supplementation with folic acid and B vitamins may reduce the risk of AMD in persons with no previous diagnosis. Supplementation with folic acid and B vitamins is known to lower plasma homocysteine levels. We propose studies to address the causal relevance of homocysteine to AMD, and to extend these promising findings for AMD to important blood- based and diet-based subgroups.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY018820-04
Application #
8320301
Study Section
Special Emphasis Panel (ZEY1-VSN (03))
Program Officer
Wideroff, Louise
Project Start
2009-09-30
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$209,563
Indirect Cost
$43,243
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Christen, William G; Cook, Nancy R; Chiuve, Stephanie E et al. (2018) Prospective study of plasma homocysteine, its dietary determinants, and risk of age-related macular degeneration in men. Ophthalmic Epidemiol 25:79-88
Christen, William G; Chasman, Daniel I; Cook, Nancy R et al. (2018) Homocysteine, B Vitamins, MTHFR Genotype, and Incident Age-related Macular Degeneration. Ophthalmol Retina 2:508-510
Christen, William G; Cook, Nancy R; Ridker, Paul M et al. (2015) Prospective study of plasma homocysteine level and risk of age-related macular degeneration in women. Ophthalmic Epidemiol 22:85-93