DES is a significant public health problem affecting over 10 million Americans (19
). However, few risk or protective factors for DES have been identified and none relate thus far to diet. The present study indicates that women with a higher dietary intake of n-3 FA have a lower prevalence of DES, including a 68% reduction in women who consumed ≥5-6 113 g (4-ounce) servings per week compared to ≤1 servings per week of tuna fish, one of the largest contributors of n-3 FA in the typical American diet. In contrast, we did not observe any independent relationship of n-6 FA intake with DES; however, a high ratio of n-6/n-3 FA (>15:1) was associated with a greater than two-fold higher prevalence of DES.
The central role of inflammation in the development of DES (21
), and the known anti-inflammatory potential of n-3 FA are consistent with the correlations observed in the present study. Essential fatty acids are natural modulators of inflammatory activity via their metabolism to eicosanoids, locally acting hormone-like lipids involved in the control of inflammatory and immune responses. Eicosanoids are derived from three fatty acid precursors, dihomogammalinoleic acid (20:3, n-6 DGLA), arachidonic acid (20:4, n-6 AA), and EPA. The modulation of inflammatory activity is based on the balance of these precursors. One of the possible ways in which n-3 FA can reduce inflammatory activity is through their ability to suppress the biosynthesis of AA-derived eicosanoids. Since the balance of n-3 and n-6 FA in cellular membranes is largely dependent on dietary intake (22
); high intakes of n-3 FA result in replacement of the usually more abundant AA with EPA and DHA. Eicosanoids derived from AA such as prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) are vigorously pro-inflammatory, whereas the 3-series prostaglandins and 5-series leukotrienes from EPA are 10 to 100-fold less biologically active (23
). A higher intake of n-3 FA also reduces the desaturation and elongation of LA to AA (24
). Further, n-3 FA suppress COX-2 and have greater affinity resulting in higher formation of EPA-derived as compared to AA-derived eicosanoids (26
). When the ratio of n-6/n-3 FA is approximately 4/1 or lower, there is also competitive inhibition of the conversion of DGLA to AA (22
); resulting in enhanced metabolism of DGLA to the 1-series prostaglandins including PGE1, which has a number of anti-inflammatory actions (29
Apart from the importance of FA in modulating inflammatory response, their eicosanoid metabolites have a variety of other actions. Particularly salient to DES, PGE1 appears to be an important stimulator of aqueous tear secretion (30
). Early studies hypothesized that aqueous tear deficiency in Sjogren's-related DES was the result of PGE1 precursor deficiency due to impaired delta-6 desaturase activity and a resultant reduction of the metabolism of LA to gamma-linoleic acid (18:3, n-6 GLA) (31
). GLA is elongated to DGLA, which forms PGE1. Investigators hypothesized that supplementation with GLA directly could correct this deficiency (31
). However, a recent randomized trial of GLA versus placebo among 90 Sjogren's syndrome patients showed no significant difference between the active treatment and placebo groups in signs and symptoms of DES (32
). In contrast, another randomized trial of 28.5mg LA plus 15mg GLA twice a day versus placebo among 26 patients with aqueous deficient DES resulted in reported reductions in DES symptoms, lissamine green staining, and ocular surface inflammation (33
). An additional trial among 60 subjects undergoing photorefractive keratectomy, reported significant beneficial effects of a once daily dose of 28.5 mg LA plus 15.1 mg GLA on tear function tests and ocular symptoms (34
). Observational studies have also suggested a link between n-3 FA and DES in Sjogren's syndrome. In a cross-sectional study of 41 patients with primary Sjogren's syndrome (35
), fatty acid levels within erythrocyte phospholipids, plasma phospholipids, plasma triglycerides and plasma cholesterol esters were investigated for associations with immunopathological and clinical disease parameters. In this study, DHA was inversely correlated with the clinical DES status, a finding that is in general agreement with those of the present study. In a separate study, 68 women with Sjogren's syndrome were found to have a lower dietary intake of n-3 FA compared to age-matched controls (36
N-3 FA may also have a direct effect on the polar portion of the lipid layer of tear film by increasing the amount of n-3 FA present or by affecting the ratio of n-6/n-3 FA (37
). Finally, n-3 FA intake may decrease endogenous estrogen production (38
), which may impact risk of DES (39
One of the main limitations of our study lies in our questionnaire-based assessment of DES. Additionally, we could not differentiate between evaporative versus aqueous deficient subtypes of DES. However, previous studies have suggested the validity of the type of assessment we used (19
) and our own validation study among 53 patients demonstrated good sensitivity and specificity versus commonly used clinical tests for DES (18
). Although our classification of DES was certainly not perfect, misclassification would tend to bias estimates toward the null, unless it was associated with the exposure of interest. Although it is theoretically possible that women who consume higher amounts of n-3 FA are less likely to receive a diagnosis of DES, this seems particularly unlikely since increased consumption was correlated with factors such as older age and diabetes, which are associated with an increased risk of DES. Moreover, control for frequency of eye examinations (i.e. opportunity for diagnosis) did not eliminate the association between n-3 FA and DES. Confounding by unmeasured factors, such as medication use, is another concern. Although we could not address this directly as information on medication use was not available, control for major diseases such diabetes mellitus, hypertension and connective tissue diseases did not alter the observed associations.
Confounding due to differential use of contact lenses or artificial tears across levels of FA intake is also unlikely given that neither of these factors was related to FA intake in a subgroup of 341 women for whom we had this information (each P for trend > 0.6; data not shown). Nonetheless, as in any epidemiological study, it remains possible that the relationships we observed could be explained by other differences between the women who consumed greater versus lesser amounts of n-3 FA.
Our study has several significant advantages including a large sample size, nationwide sampling of the study participants, control of most known or potential confounders, and use of a well-validated means of assessing dietary intake of essential fatty acids. Studies have shown that estimates of nutrient intake derived from the SFFQ are reflective of long-term dietary intake (14
). Additionally, a positive association between the n-6/n-3 ratio and DES in the setting of a healthy population such as the WHS, where 99% of participants had a n-6/n-3 ratio below the mean for a typical Western diet (41
), and 90% of them had a ratio below current recommendations (42
), may point to an even greater influence of FA imbalances on DES in the general population.
To our knowledge, this is the first study of dietary intake of n-3 and/or n-6 FA, as they may relate to prevention of DES. Historically, there were appreciable amounts of n-3 FA in the diet provided by wild plants and wild game, and humans are thought to have evolved eating a ratio of n-6 FA to n-3 FA of close to 1:1. Many natural sources of n-3 FA have now been depleted from the diet, coupled with an oversupply of n-6 FA, particularly in last half of century, which has resulted in distortion of n-6/n-3 ratio to current levels, typically in the range of 12-16:1. Given the biology and importance of these fatty acids, and their opposing biological effects, it seems quite likely that such an imbalance would be related to some pathology (22
In the present study, women with a higher intake of n-3 FA appear to have a lower risk of DES. Further, a high ratio of n-6/n-3 FA is associated with increased risk of DES. This is the first report of such an association. In light of the plausibility of hypothesized biological mechanisms, these findings suggest that increasing dietary intake of n-3 FA may reduce the risk of DES, an important and prevalent cause of ocular complaints.