Cho E, Hung S, Willett WC, et al. Prospective study of dietary fat and the risk of age-related macular degeneration. Am J Clin Nutr 2001;73:209-218.

BACKGROUND: The relation between intakes of total fat and specific types of fat and age-related macular degeneration (AMD) remains unclear.

OBJECTIVE: Our objective was to examine prospectively the association between fat intake and AMD.

DESIGN: We conducted a prospective follow-up study of participants in the Nurses' Health Study and the Health Professionals Follow-up Study. At baseline (1984 for women and 1986 for men), the study included 42743 women and 29746 men aged > or = 50 y with no diagnosis of AMD who were followed until 1996. Fat intake was assessed with a food-frequency questionnaire.

RESULTS: We accrued 567 patients with AMD with a visual loss of 20/30 or worse. The pooled multivariate relative risk (RR) for the highest compared with the lowest quintile of total fat intake was 1.54 (95% CI: 1.17, 2.01; P for trend = 0.008). Linolenic acid was positively associated with risk of AMD (top versus bottom quintile of RR: 1.49; 95% CI: 1.15, 1.94; P for trend = 0.0009). Docosahexaenoic acid had a modest inverse relation with AMD (top versus bottom quintile of RR: 0.70; 95% CI: 0.52, 0.93; P for trend = 0.05), and >4 servings of fish/wk was associated with a 35% lower risk of AMD compared with < or = 3 servings/mo (RR: 0.65; 95% CI: 0.46, 0.91; P for trend = 0.009).

CONCLUSIONS: Total fat intake was positively associated with risk of AMD, which may have been due to intakes of individual fatty acids, such as linolenic acid, rather than to total fat intakes per se. A high intake of fish may reduce the risk of AMD.

PMID: 11157315

Miljanovi B, Trivedi KA, et al. Relation between dietary n?3 and n?6 fatty acids and clinically diagnosed dry eye syndrome in women. Am J Clinical Nutrition, 2005;82(4):887-893.

Background: Dry eye syndrome (DES) is a prevalent condition, but information on risk or protective factors is lacking.

Objective: We aimed to determine the association between the dietary intake and ratio of n?3 and n?6 fatty acids (FAs) and DES occurrence.

Design: Of the 39876 female health professionals in the Women?s Health Study (WHS), 32470 women aged 45?84 y who provided information on diet and DES were cross-sectionally studied. We assessed FA intakes by using a validated food-frequency questionnaire and assessed DES by using self-reports of clinically diagnosed cases. Of the sample, 1546 (4.7%) subjects reported DES. We used logistic regression models to estimate the odds ratios (ORs) and 95% CIs to describe the relation of FA intake with DES.

Results: After adjustment for demographic factors, hormone therapy, and total fat intake, the OR for the highest versus the lowest quintile of n?3 FAs was 0.83 (95% CI: 0.70, 0.98; P for trend = 0.05). A higher ratio of n?6 to n?3 FA consumption was associated with a significantly increased risk of DES (OR: 2.51; 95% CI: 1.13, 5.58) for >15:1 versus <4:1 (P for trend = 0.01). In addition, tuna consumption [1 serving was 113 g (4 oz)] was inversely associated with DES (OR: 0.81; 95% CI: 0.66, 0.99 for 2?4 servings/wk; OR: 0.32; 95% CI: 0.13, 0.79 for 5?6 servings/wk versus 1 serving/wk; P for trend = 0.005).

Conclusions: These results suggest that a higher dietary intake of n?3 FAs is associated with a decreased incidence of DES in women. These findings are consistent with anecdotal clinical observations and postulated biological mechanisms.

Lu M, Cho E, et al. Prospective Study of Dietary Fat and Risk of Cataract Extraction among US Women. Am J of Epidemiology, 2005; 161(10):948-959

The authors examined prospectively the association between dietary fat intake and cataract extraction in adult women from the Nurses' Health Study.

A total of 71,083 women were followed prospectively for up to 16 years between 1984 and 2000.

Dietary fat was assessed by repeated food frequency questionnaires. Incident cases of cataract extraction were determined by a biennial questionnaire.

The multivariate-adjusted relative risk for the highest compared with the lowest quintile of total fat intake was 1.10 (95% confidence interval (CI): 0.99, 1.22; ptrend = 0.01).

Women in the highest quintile of long-chain omega-3 fatty acid had a 12% lower risk of cataract extraction compared with those in the lowest quintile (relative risk = 0.88, 95% CI: 0.79, 0.98; ptrend = 0.02).

Total fish intake was inversely associated with cataract (for intake of 3/week vs. <1/month: relative risk = 0.89, 95% CI: 0.81, 0.98; ptrend = 0.01).

The authors' findings suggest that higher intake of long-chain omega-3 fatty acid (eicosapentaenoic acid and docosahexaenoic acid) and consumption of fish may modestly reduce the risk of cataract.

Seddon, JM, Rosner, B et al. Dietary Fat and Risk for Advanced Age-Related Macular Degeneration. Arch Ophthalmol. 2001; 119:1191-1199.

Objective: To evaluate the relationship between intake of total and specific types of fat and risk for advanced age-related macular degeneration (AMD), the leading cause of irreversible blindness in adults.

Design: A multicenter eye disease case-control study.

Setting: Five US clinical ophthalmology centers.

Patients: Case subjects included 349 individuals (age range, 55-80 years) with the advanced, neovascular stage of AMD diagnosed within 1 year of their enrollment into the study who resided near a participating clinical center. Control subjects included 504 individuals without AMD but with other ocular diseases. Controls were from the same geographic areas as cases and were frequency-matched to cases by age and sex.

Main Outcome: Measures Relative risk for AMD according to level of fat intake, controlling for cigarette smoking and other risk factors.

Results: Higher vegetable fat consumption was associated with an elevated risk for AMD. After adjusting for age, sex, education, cigarette smoking, and other risk factors, the odds ratio (OR) was 2.22 (95% confidence interval [CI], 1.32-3.74) for persons in the highest vs those in the lowest quintiles of intake (P for trend, .007). The risk for AMD was also significantly elevated for the highest Vs lowest quintiles of intake of monounsaturated (OR, 1.71) and polyunsaturated (OR, 1.86) fats (Ps for trend, .03 and .03, respectively). Higher consumption of linoleic acid was also associated with a higher risk for AMD (P for trend, .02). Higher intake of -3 fatty acids was associated with a lower risk for AMD among individuals consuming diets low in linoleic acid, an -6 fatty acid (P for trend, .05; P for continuous variable, .03). Similarly, higher frequency of fish intake tended to reduce risk for AMD when the diet was low in linoleic acid (P for trend, .05). Conversely, neither n-3 fatty acids nor fish intake were related to risk for AMD among people with high levels of linoleic acid intake.

Conclusion: Higher intake of specific types of fat including vegetable, monounsaturated, and polyunsaturated fats and linoleic acid rather than total fat intake may be associated with a greater risk for advanced AMD. Diets high in -3 fatty acids and fish were inversely associated with risk for AMD when intake of linoleic acid was low.

Seddon JM, Cote J, Rosner B. Progression of age-related macular degeneration: Association with dietary fat, trans-unsaturated fat, nuts, and fish intake. Arch Ophthalmol 2003 December;121:1728-1737.

BACKGROUND: Individuals with early or intermediate stages of age-related macular degeneration (AMD) make up a large, growing segment of the elderly population. Evidence is sparse regarding modifiable factors that may decrease the risk of progression to the advanced forms of AMD.

OBJECTIVE: To advise patients with a high risk for advanced forms of AMD about preventive measures through our evaluation of the relationship between dietary fat intake and the progression of early or intermediate AMD to the advanced stages of the disease associated with visual loss.

DESIGN: A prospective cohort study with an average follow-up time of 4.6 years.

SETTING: A hospital-based clinical retinal practice specializing in macular degeneration. Patients: The 261 participants were aged 60 years and older and had some sign of nonexudative AMD and visual acuity of 20/200 or better in at least 1 eye. Main Outcome Measure: Progression to advanced AMD, which was defined as having geographic atrophy or neovascular disease.

RESULTS: Higher total fat intake increased the risk of progression to the advanced forms of AMD, with a relative risk (RR) of 2.90 (95% confidence interval, 1.15-7.32) for the highest fat-intake quartile relative to the lowest fat-intake quartile, after controlling for other factors (P trend =.01).

Animal fat intake was associated with a 2-fold increased risk of progression (RR, 2.29 for the highest quartile compared with the lowest quartile; 95% confidence interval, 0.91-5.72), although the trend for increasing risk with higher animal fat intake was not significant (P=.09). Higher vegetable fat intake had a stronger relationship with increased risk of AMD progression with an RR of 3.82 (95% confidence interval, 1.58-9.28) for the highest quartile compared with the lowest quartile (P trend =.003). Saturated, monounsaturated, polyunsaturated, and transunsaturated fats increased the likelihood of progression (RR, 2.09 and P trend =.08; RR, 2.21 and P trend =.04; RR, 2.28 and P trend =.04; RR, 2.39 and P trend =.008, respectively).

Higher fish intake was associated with a lower risk of AMD progression among subjects with lower linoleic acid intake. Processed baked goods, which are higher in some of these fats, increased the rate of AMD progression approximately 2-fold, and nuts were protective.

CONCLUSIONS: Among individuals with the early or intermediate stages of AMD, total and specific types of fat intake, as well as some fat-containing food groups, modified the risk of progression to advanced AMD. Fish intake and nuts reduced risk. Since advanced AMD is associated with visual loss and reduced quality of life, these preventive measures deserve additional research and greater emphasis.

PMID: 14662593

Seddon JM, George S, Rosner B. Cigarette Smoking, Fish Consumption, Omega-3 Fatty Acid Intake, and Associations With Age-Related Macular Degeneration. The US Twin Study of Age-Related Macular Degeneration. Arch Ophthalmol, 2006;124(7):995-1001.

Objective:
To evaluate modifiable risk and protective factors for age-related macular degeneration (AMD) among elderly twins.

Methods:
The US Twin Study of Age-Related Macular Degeneration comprises elderly male twins from the National Academy of Sciences?National Research Council World War II Veteran Twin Registry. To determine genetic and environmental risk factors for AMD, twins were surveyed for a prior diagnosis of AMD and underwent an eye examination, fundus photography, and food frequency and risk factor questionnaires. This environmental component of the study includes 681 twins: 222 twins with AMD (intermediate or late stages) and 459 twins with no maculopathy or early signs.

Risk for AMD according to cigarette smoking and dietary fat intake was estimated using logistic regression analyses.

Results:
Current smokers had a 1.9-fold increased risk (95% confidence interval, 0.99-3.68, P = .06) of AMD while past smokers had about a 1.7-fold increased risk (95% confidence interval, 1.2-2.6, P = .009). Increased intake of fish reduced risk of AMD, particularly for 2 or more servings per week (P trend = .04).

Dietary omega-3 fatty intake was inversely associated with AMD (odds ratio, 0.55; 95% confidence interval, 0.32-0.95) comparing the highest vs lowest quartile.

Reduction in risk of AMD with higher intake of omega-3 fatty acids was seen primarily among subjects with low levels (below median) of linoleic acid intake, an omega-6 fatty acid (P trend<.001).
The attributable risk percentage was 32% for smoking and the preventive fraction was 22% for higher omega-3 intake.

Conclusions:
This study of twins provides further evidence that cigarette smoking increases risk while fish consumption and omega-3 fatty acid intake reduce risk of AMD.

Chua B, Flood V, et al. Dietary Fatty Acids and the 5-Year Incidence of Age-Related Maculopathy. Arch Ophthalmol, 2006;124(7):981-986.

Objective:
To assess longitudinal associations between dietary fat and incident age-related maculopathy (ARM) in an older, population-based, historical cohort.

Methods:
A total of 3654 persons, 49 years or older, participated in the Blue Mountains Eye Study (1992-1994); 2335 (75.1% of survivors) were reexamined after 5 years (1997-1999). Dietary data were collected from 2895 people (79%) at baseline by means of a semiquantitative food frequency questionnaire to calculate dietary fat intakes. Presence of ARM was graded from retinal photographs (Wisconsin ARM Grading System). Logistic regression adjusted for age, sex, vitamin C intake, and smoking.

Results:
Participants with the highest vs lowest quintiles of n-3 polyunsaturated fat intake had lower risk of incident early ARM (odds ratio [95% confidence interval], 0.41 [0.22-0.75).

A 40% reduction of incident early ARM was associated with fish consumption at least once a week (odds ratio [95% confidence interval], 0.58 [0.37-0.90]), whereas fish consumption at least 3 times per week could reduce the incidence of late ARM (odds ratio [95% confidence interval], 0.25 [0.06-1.00]).

We found no association between incident ARM and butter, margarine, or nut consumption.

Conclusions:
A regular diet high in n-3 polyunsaturated fat, especially from fish, suggests protection against early and late ARM in this older Australian cohort. Our study could not confirm deleterious effects of higher polyunsaturated fat intakes reported by other clinic-based studies.

Trivedi KA, Dana MR, Gilbard JP, et al. Dietary Omega-3 Fatty Acid Intake and Risk of Clinically Diagnosed Dry Eye Syndrome in Women. Invest Ophthalmol Vis Sci 2003;44: E-Abstract 811.

Purpose: To determine the association between dietary intake of omega-3 fatty acids and risk of dry eye syndrome (DES).

Methods: A total of 32,470 female health professionals aged between 45 and 84 years who provided information on diet and DES were chosen from the 39,876 women participating in the Women's Health Study. Intake of omega-3 fatty acids was assessed by a validated food frequency questionnaire. DES was assessed using self-reports of clinically diagnosed DES. We used logistic regression models to estimate the odds ratios (OR) and 95% confidence intervals (CI) to describe the relationships of omega-3 fatty acid intake and DES. We also analyzed the relationship between consumption of fish and DES in a similar way.

Results: After adjusting for age, other demographic factors, postmenopausal hormone therapy, and total fat intake, the OR (CI) for the highest versus the lowest dietary intake of omega-3 fatty acids was 0.83 (0.70-0.98), P for trend=0.04. In addition, we observed a significant association between tuna fish consumption and DES (OR=0.82, CI=0.67-1.00 for 2 to 4 servings/week, and OR=0.34, CI=0.13-0.81 for 5 to 6 four-ounce servings/week versus <2 servings/week; P for trend=0.004). Results were similar in other models additionally controlling for diabetes, hypertension, and connective tissue diseases.

Conclusion: These results suggest that women with a higher dietary intake of omega-3 fatty acids are at decreased risk of developing DES.

Although this is the first study that has evaluated this relationship, and confirmation from other studies is needed, the findings are consistent with clinical observations and postulated biological mechanisms. Thus, further research on the role of omega-3 fatty acids in the prevention and/or treatment of DES would be of interest.

Nicolas G Bazan. Cell survival matters: docosahexaenoic acid signaling, neuroprotection and photoreceptors. Trends Neurosci, 2006; doi:10.1016/j.tins.2006.03.005

Recent data have provided important clues about the molecular mechanisms underlying certain retinal degenerative diseases, including retinitis pigmentosa and age-related macular degeneration.

Photoreceptor cell degeneration is a feature common to these diseases, and the death of these cells in many instances seems to involve the closely associated retinal pigment epithelial (RPE) cells.

Under normal circumstances, both cell types are subject to potentially damaging stimuli (e.g. sunlight and high oxygen tension). However, the mechanism or mechanisms by which homeostasis is maintained in this part of the eye, which is crucial for sight, are an unsolved riddle.

The omega-3 fatty acid family member docosahexaenoic acid (DHA), which is enriched in these cells, is the precursor of neuroprotectin D1 (NPD1). NPD1 inhibits oxidative-stress-mediated proinflammatory gene induction and apoptosis, and consequently promotes RPE cell survival.

This enhanced understanding of the molecular basis of endogenous anti-inflammatory and neuroprotective signaling in the RPE presents an opportunity for the development of therapies for retinal degenerative diseases.

PMID: 16580739

Elner VM. Retinal pigment epithelial acid lipase activity and lipoprotein receptors: Effects of dietary omega-3 fatty acids. Trans AM Ophthalmol Soc 2002 January 1;100:301-338.

PURPOSE: To show that fish oil-derived omega-3 polyunsaturated fatty acids, delivered to the retinal pigment epithelium (RPE) by circulating low-density lipoproteins (LDL), enhance already considerable RPE lysosomal acid lipase activity, providing for more efficient hydrolysis of intralysosomal RPE lipids, an effect that may help prevent development of age-related macular degeneration (ARMD).

METHODS: Colorimetric biochemical and histochemical techniques were used to demonstrate RPE acid lipase in situ, in vitro, and after challenge with phagocytic stimuli. Receptor-mediated RPE uptake of fluorescently labeled native, aceto-acetylated, and oxidized LDL was studied in vitro and in vivo. LDL effects on RPE lysosomal enzymes were assessed. Lysosomal enzyme activity was compared in RPE cells from monkeys fed diets rich in fish oil to those from control animals and in cultured RPE cells exposed to sera from these monkeys.

RESULTS: RPE acid lipase activity was substantial and comparable to that of mononuclear phagocytes. Acid lipase activity increased significantly following phagocytic challenge with photoreceptor outer segment (POS) membranes. Receptor-mediated RPE uptake of labeled lipoproteins was determined in vitro. Distinctive uptake of labeled lipoproteins occurred in RPE cells and mononuclear phagocytes in vivo. Native LDL enhanced RPE lysosomal enzyme activity. RPE lysosomal enzymes increased significantly in RPE cells from monkeys fed fish oil-rich diets and in cultured RPE cells exposed to their sera.

CONCLUSIONS: RPE cells contain substantial acid lipase for efficient metabolism of lipids imbibed by POS phagocytosis and LDL uptake.

Diets rich in fish oil-derived omega-3 fatty acids, by enhancing acid lipase, may reduce RPE lipofuscin accumulation, RPE oxidative damage, and the development of ARMD.

PMID: 12545699