Prospective Study of Zinc Intake and the Risk of Age-Related Macular Degeneration

doi:10.1016/S1047-2797(01)00217-4

Annals of Epidemiology

Volume 11, Issue 5, July 2001, Pages 328-336

https://doi.org/10.1016/S1047-2797(01)00217-4 Get rights and content

Abstract

PURPOSE: Zinc is found in high concentrations in the retina and is hypothesized to reduce the risk of age-related macular degeneration (AMD). Any long-term benefit associated with dietary zinc intake has not been evaluated.

METHODS: We followed 66,572 women and 37,636 men who were ⩾ 50 years old and had no diagnosis of AMD or cancer. Zinc intake from food, multivitamins, and supplements was assessed with a semiquantitative food-frequency questionnaire at baseline (in 1984 for women and in 1986 for men) and repeated during follow-up (twice for women, once for men).

RESULTS: During 10 years of follow-up for women and 8 years of follow-up for men, we confirmed 384 incident cases of AMD (195 cases of the early form and 189 cases of the late form) associated with a visual acuity loss of 20/30 or worse. After multivariate adjustment for potential risk factors, the pooled relative risk was 1.13 (95% confidence interval [CI], 0.82 to 1.57; p-value, test for trend, 0.74) among participants in the highest quintile of total zinc intake (energy-adjusted median; 25.5 mg/day for women and 40.1 mg/day for men) compared with those in the lowest quintile (energy-adjusted median; 8.5 mg/day for women and 9.9 mg/day for men). The relative risk for highest compared with lowest quintile was 1.04 (95% CI, 0.59 to 1.83; p-value, test for trend, 0.54) for zinc intake from food. Subjects who took zinc supplements had a pooled multivariate relative risk of 1.04 (95% CI, 0.75 to 1.45).

CONCLUSIONS: In these two large prospective studies, moderate zinc intake, either in food or in supplements, was not associated with a reduced risk of AMD.

Introduction

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss and affects the quality of life in the elderly population 1, 2, 3. No effective treatment for AMD has been developed, and, with the exception of smoking avoidance, no preventive strategy has been established.

Zinc, a cofactor for many enzymes, is concentrated in the retina (4). Although the role of zinc in the retina is not clear, it may be related to its antioxidant function as a cofactor for superoxide dismutase and catalase. In one randomized clinical trial, zinc supplements protected subjects against the progression of AMD (5), but subsequent studies have yielded conflicting results 6, 7, 8, 9. Most of these studies have been limited by a short follow-up period.

We, therefore, evaluated the relation between zinc intake (from food, multivitamins, and supplements) and the incidence of AMD in two large prospective studies: one in women participating in the Nurses' Health Study (NHS) and the other in men participating in the Health Professionals Follow-up Study (HPFS).

Section snippets

Study Populations

The NHS was established in 1976, when 121,700 female registered nurses aged 30 to 55 years were enrolled (10). The HPFS began in 1986 with an enrollment of 51,529 male health professionals 40 to 75 years of age (11). The HPFS cohort consisted primarily of dentists and veterinarians but also included pharmacists, optometrists, osteopathic physicians, and podiatrists. Members of both cohorts provided information on various life-style factors and the diagnosis of major illnesses biennially since

Results

During 10 years of follow-up (509,394 person-years) for women and 8 years of follow-up (230,730 person-years) for men, we identified 384 incident cases of AMD; 230 of these cases were in women and 154 in men. The early and late forms of AMD accounted for 195 cases (51%) and 189 cases (49%), respectively. Participants with a high intake of total zinc tended to smoke less, to have a higher intake of lutein/zeaxanthin, and (among women) to use postmenopausal hormones more (Table 1). As expected,

Discussion

Results from these two large prospective studies do not support a lowered risk of AMD associated with higher zinc intake. Overall, zinc intake from food or from supplements had no apparent association with total AMD or with either subtype of AMD. The results were similar in the two cohorts; none of the results of tests for between-study heterogeneity was significant.

Although the retina has a high concentration of zinc, its primary function in vision is not well understood (4). Zinc is a

Acknowledgements

This study was supported by research Grants CA 40356, CA 55075, EY 09611, and HL 35464 from the National Institutes of Health. We are indebted to Maureen Ireland, Paula Masto, Kerry Demers, Laura Sampson, Karen Corsano, Elaine Coughlan-Havas, and Jaylyn Olivo for their unfailing help. We also gratefully acknowledge Dr. Frank E. Speizer, Principal Investigator of the Nurses' Health Study, for his input.

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Subsequently, Klein et al reported a weak association between late AMD and the incidental use of vitamins A, C, and E and zinc [41]. Furthermore, a prospective study performed by Cho et al failed to identify an association between zinc intake (food or supplements) and AMD risk [59]. Interestingly, different results were provided by the Blue Mountains Eye Study.
The actions of nutrients and related compounds on age-related macular degeneration (AMD) are explained in this review. The findings from 80 studies published since 2003 on the association between diet and supplements in AMD were reviewed. Antioxidants and other nutrients with an effect on AMD susceptibility include carotenoids (lutein and zeaxanthin, β-carotene), vitamins (vitamin A, E, C, D, B), mineral supplements (zinc, copper, selenium), dietary fatty acids [monounsaturated fatty acids, polyunsaturated fatty acids (PUFA both omega-3 PUFA and omega-6 PUFA), saturated fatty acids and cholesterol], and dietary carbohydrates. The literature revealed that many of these antioxidants and nutrients exert a protective role by functioning synergistically. Specifically, the use of dietary supplements with targeted actions can provide minimal benefits on the onset or progression of AMD; however, this does not appear to be particularly beneficial in healthy people. Furthermore, some supplements or nutrients have demonstrated discordant effects on AMD in some studies. Since intake of dietary supplements, as well as exposure to damaging environmental factors, is largely dependent on population habits (including dietary practices) and geographical localization, an overall healthy diet appears to be the best strategy in reducing the risk of developing AMD. As of now, the precise mechanism of action of certain nutrients in AMD prevention remains unclear. Thus, future studies are required to examine the effects that nutrients have on AMD and to determine which factors are most strongly correlated with reducing the risk of AMD or preventing its progression.
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An increase in transferrin receptor could raise cellular iron uptake and hence intracellular levels.253 The changes detected in retinal iron and zinc homeostasis in AMD have led to the idea that iron chelators and zinc supplements may be beneficial in the treatment of this debilitating disease.22,54,156,248,250,363 Several authors123,261,383 suggest that therapy with iron chelators such as deferoxamine, deferasirox, and deferiprone may help in the treatment of retinal diseases associated with iron overload.
The essential trace metals iron, zinc, and copper play important roles both in retinal physiology and disease. They are involved in various retinal functions such as phototransduction, the visual cycle, and the process of neurotransmission, being tightly bound to proteins and other molecules to regulate their structure and/or function or as unbound free metal ions. Elevated levels of “free” or loosely bound metal ions can exert toxic effects, and in order to maintain homeostatic levels to protect retinal cells from their toxicity, appropriate mechanisms exist such as metal transporters, chaperones, and the presence of certain storage molecules that tightly bind metals to form nontoxic products. The pathways to maintain homeostatic levels of metals are closely interlinked, with various metabolic pathways directly and/or indirectly affecting their concentrations, compartmentalization, and oxidation/reduction states. Retinal deficiency or excess of these metals can result from systemic depletion and/or overload or from mutations in genes involved in maintaining retinal metal homeostasis, and this is associated with retinal dysfunction and pathology. Iron accumulation in the retina, a characteristic of aging, may be involved in the pathogenesis of retinal diseases such as age-related macular degeneration (AMD). Zinc deficiency is associated with poor dark adaptation. Zinc levels in the human retina and RPE decrease with age in AMD. Copper deficiency is associated with optic neuropathy, but retinal function is maintained. The changes in iron and zinc homeostasis in AMD have led to the speculation that iron chelation and/or zinc supplements may help in its treatment.
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A prospective study of 104,208 elderly men and women showed that there was no association between risk for AMD and ten years of zinc intake (RR = 1.13; 95% CI: 0.82, 1.57) (Cho et al., 2001b) (Fig. 74). Compared to those with the lowest amount of zinc intake from food, those with the highest food intake did not have a reduced risk of AMD (RR = 1.04; 95% CI: 0.59, 1.83) (Cho et al., 2001b) (Fig. 74). There was also no association between AMD risk and zinc supplementation (RR = 1.04; 95% CI: 0.75, 1.45) (Cho et al., 2001b) (Fig. 74).
Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly worldwide. It affects 30–50 million individuals and clinical hallmarks of AMD are observed in at least one third of persons over the age of 75 in industrialized countries (Gehrs et al., 2006). Costs associated with AMD are in excess of $340 billion US (American-Health-Assistance-Foundation, 2012). The majority of AMD patients in the United States are not eligible for clinical treatments (Biarnes et al., 2011, Klein et al., 2011). Preventive interventions through dietary modulation are attractive strategies because many studies suggest a benefit of micro- and macronutrients with respect to AMD, as well as other age-related debilities, and with few, if any, adverse effects (Chiu, 2011). Preservation of vision would enhance quality of life for millions of elderly people, and alleviate the personal and public health financial burden of AMD (Frick et al., 2007, Wood et al., 2011). Observational studies indicate that maintaining adequate levels of omega-3 fatty acids (i.e. with 2 servings/week of fish) or a low glycemic index diet may be particularly beneficial for early AMD and that higher levels of carotenoids may be protective, most probably, against neovascular AMD. Intervention trials are needed to better understand the full effect of these nutrients and/or combinations of nutrients on retinal health. Analyses that describe effects of a nutrient on onset and/or progress of AMD are valuable because they indicate the value of a nutrient to arrest AMD at the early stages. This comprehensive summary provides essential information about the value of nutrients with regard to diminishing risk for onset or progress of AMD and can serve as a guide until data from ongoing intervention trials are available.
Diet and Supplements in the Prevention and Treatment of Eye Diseases
2012, Nutrition in the Prevention and Treatment of Disease, Third Edition
Pharmacotherapy of age-related macular degeneration
2012, Retina Fifth Edition

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Original reportProspective Study of Zinc Intake and the Risk of Age-Related Macular Degeneration

Abstract

Introduction

Section snippets

Study Populations

Results

Discussion

Acknowledgements

The Beaver Dam Eye Study. Ophthalmology

Lancet

Control Clin Trials

Surv Ophthalmol

Is the incidence of registrable age-related macular degeneration increasing?

Br J Ophthalmol

Epidemiology of age-related macular degeneration

Ocular zinc concentration

Invest Ophthalmol

Oral zinc in macular degeneration

Arch Ophthalmol

Risk factors for neovascular age-related macular degeneration

Arch Ophthalmol

Oral zinc and the second eye in age-related macular degeneration

Invest Ophthalmol Vis Sci

Association of zinc and antioxidant nutrients with age-related maculopathy

Arch Ophthalmol

Associations between antioxidant and zinc intake and the 5-year incidence of early age-related maculopathy in the Beaver Dam Eye Study

Am J Epidemiol

The Nurses' Health StudyA cohort of U.S. women followed since 1976

J Am Med Womens' Assoc

Original report
Prospective Study of Zinc Intake and the Risk of Age-Related Macular Degeneration