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We examined the association between caffeine and caffeinated beverage consumption in relation to the risk of exfoliation glaucoma or exfoliation glaucoma suspect (EG/EGS).
We followed 78,977 women from the Nurses' Health Study (NHS) and 41,202 men from the Health Professionals Follow-up Study (HPFS) who were at least 40 years of age, did not have glaucoma, and reported undergoing eye examinations from 1980 (NHS) or 1986 (HPFS) to 2008. Information on consumption of caffeine-containing beverages and potential confounders were repeatedly ascertained in validated follow-up questionnaires. Confirmation with medical record review revealed 360 incident EG/EGS cases. Multivariate rate ratios (RRs) for EG/EGS were calculated in each cohort and then pooled using meta-analytic techniques.
Compared with participants whose cumulatively updated total caffeine consumption was <125 mg/day, participants who consumed ≥500 mg/day had a trend toward increased risk of EG/EGS that was not statistically significant (RR = 1.43; 95% confidence interval [CI], 0.98–2.08); P trend = 0.06). Compared to abstainers, those who drank ≥3 cups of caffeinated coffee daily were at increased risk of EG/EGS (RR = 1.66; 95% CI, 1.09–2.54; P trend = 0.02). These results were not materially altered after adjustment for total fluid intake. Associations were stronger among women with a family history of glaucoma (P interaction = 0.06 for coffee; P interaction = 0.03 for caffeine). We did not find associations with consumption of other caffeinated products (caffeinated soda, caffeinated tea, decaffeinated coffee or chocolate) and risk of EG/EGS (P trend ≥0.31).
We observed a positive association between heavier coffee consumption with risk of EG/EGS in this large prospective study.
Exfoliation glaucoma (EG) is the leading cause of secondary open-angle glaucoma worldwide.1 In EG, disarrayed extracellular deposits and admixed pigment lodge in the trabecular meshwork to produce elevated intraocular pressure (IOP) and optic neuropathy. An association between the lysyl oxidase like 1 (LOXL1) gene variants and exfoliation syndrome (ES) was discovered in Iceland where the disease burden is very high2; yet the prevalence of LOXL1 polymorphisms from Scandinavian countries is similar to that of other countries with widely varying disease prevalence.3–10 While genetic variants other than LOXL1 polymorphisms might contribute to ES and EG,11 these data suggest that environmental factors could also play a role in this syndrome. Established risk factors for ES and EG includes older age12,13 and female sex.12–14 Recent studies also indicate that relative to living in the middle or southern United States, residing in the northern tier of the continental United States is associated with increased risk of ES and EG.14,15 Only sparse data are available for other modifiable risk factors for ES and EG.16
Coffee consumption is highest in Scandinavian countries,17 making caffeine or coffee consumption an attractive candidate as a modifiable lifestyle risk factor in ES and EG. Coffee consumption has been shown to increase plasma homocysteine (Hcy) levels in several randomized clinical trials.18–20 Hcy levels in plasma,21–26 aqueous humor,27 and tear fluid28 are consistently elevated in ES patients compared to those in control subjects. Elevated Hcy may enhance exfoliation material formation by contributing to vascular damage,29 oxidative stress,30,31 and extracellular matrix alterations.32 Noncaffeine components in coffee may be responsible for increased Hcy levels,33,34 although the exact mechanisms involved are unclear. While coffee consumption can also lead directly to modest, transient elevations in IOP,35–38 it is unlikely that caffeine's effect on aqueous humor dynamics contributes to the ocular accumulation of exfoliation material and subsequent EG.
Because caffeinated drinks are widely consumed among older persons at risk of EG (e.g., 80% of US adults over the age of 50 consume caffeine daily),39 it is important to investigate the relationship between caffeinated product consumption and risk of EG or exfoliation glaucoma suspect (EG/EGS) status. We examined caffeinated product consumption relative to the risk of EG/EGS, using prospectively and repeatedly acquired dietary data among 78,977 women in the Nurses' Health Study (NHS) and 41,202 men in the Health Professionals Follow-up Study (HPFS), who were followed for up to 28 years.
The NHS started in 1976 with the enrollment of 121,700 US registered female nurses aged 30 to 55 years, who replied to a mailed health questionnaire.40 The HPFS commenced in 1986 when 51,529 male health professionals agreed to join a similarly designed prospective cohort analysis.41 Participants were monitored using biennial questionnaires covering health status, lifestyle tendencies, and dietary habits. Follow-up rates were high (>85% of the total possible person-time). The Human Research Committees of Brigham and Women's Hospital and Massachusetts Eye and Ear Infirmary approved this study; furthermore, the research adhered to the Declaration of Helsinki tenets.
The NHS study period began in 1980 and the HPFS in 1986 (when we began to assess dietary habits) and lasted until 2008. A participant began to contribute person-time in 2-year increments after age 40 (as glaucoma risk increases after this age) and only during periods in which they indicated having had an eye examination. Participants contributed person-time from the return date of the first questionnaire until the earliest occurrence of either a report of glaucoma, cataract extraction (because it can be difficult to detect exfoliation material after this surgery), cancer (because this diagnosis can profoundly effect lifestyle behaviors), death, loss to follow-up, or 2008.
Participants were excluded from the study at baseline for the following reasons: (1) they did not complete the 1980 or 1986 semiquantitative food frequency questionnaire (SFFQ) (23,239 women; 0 men); (2) the SFFQ dietary data provided seemed implausible (plausible dietary information consisted of >50 of 61 items completed, yielding 500–3500 kcal/day; 5994 women; 1596 men); (3) a cancer diagnosis (excluding nonmelanoma skin cancer) preceded glaucoma (3624 women; 1033 men); (4) a prevalent diagnosis of glaucoma or GS was provided (3624 women; 1033 men); (5) we were unable to contact the participant within 2 years after baseline (740 women; 175 men); (6) an ophthalmic examination was never documented (5804 women; 4282 men); and (7) a previous cataract extraction occurred (173 women; 672 men). In the 1980-to-1982 risk period for NHS and the 1986-to-88 risk period for HPFS, 44,771 women and 29,033 men were eligible for the cohort at risk for glaucoma. At later periods, participants meeting the age and eye examination requirements were allowed to join the cohort. By 2008, a total of 78,977 women and 41,202 men contributed person-time to the cohort at risk for glaucoma.
From participants with self-reported glaucoma, we obtained permission to retrieve medical information to confirm the diagnosis. We sent the diagnosing eye care provider a request to complete a glaucoma questionnaire about maximum IOP, optic nerve features, status of filtration apparatus, and presence of exfoliation material or other secondary causes for elevated IOP. In lieu of completing the questionnaire, eye care providers could send complete medical records. We also requested all visual field (VF) reports supporting the glaucoma diagnosis. A glaucoma specialist (LRP) evaluated the questionnaire and medical record information as well as the VF data in a standardized manner masked to dietary data.
In our study, we could not test the hypothesis of an association between caffeine consumption and ES; however, we evaluated EG/EGS as an outcome, which is an outcome of public health importance. We defined EG/EGS as the presence of ES as documented in the records and at least one of the following occurring in the eye demonstrating exfoliation material on slit lamp examination: (1) a history of IOP >21 mm Hg, (2) a cup:disc ratio of ≥0.6, or (3) VF loss consistent with glaucoma on at least one reliable test. Patients with ES who did not meet these criteria were excluded from analysis because our case identification method was initiated with a questionnaire regarding receiving a glaucoma diagnosis and not on the basis of reporting specific ophthalmic signs.
There were 7330 reports in women and 3089 reports in men of glaucoma diagnoses occurring during the study period. The eye care providers confirmed this diagnosis in 66% of women and 56% of men, as follows: POAG with VF loss (27% in women and 27% in men), only elevated IOP or optic disc cupping (20% in women and 17% in men), and other types of glaucoma or GS (14% in women and 10% in men), and EG/EGS (5% in women and 2% in men). The remaining self-reports (34% in women and 44% of men) could not be confirmed, as the participants themselves (6% in women and 13% of men) or their eye care providers (4% in women and 5% in men) could not be contacted, participants did not give permission to review their records (12% in women and 10% in men), participants indicated the initial report was in error (10% in women and 15% in men), or participants' eye care providers refuted the diagnosis of glaucoma (2% in women and 1% in men).
Of the 330 confirmed EG/EGS cases in women and 74 cases in men, 30 women and 14 men were excluded from the analysis, as EG/EGS occurred among those with previous cancer or cataract extraction, which were censoring criteria; thus, we included 300 women and 60 men who met the criteria for incident EG/EGS.
We collected dietary intake data repeatedly (in 1980, 1984, and 1986 and every 4 years thereafter in the NHS and in 1986 and every 4 years thereafter in the HPFS) during the study period, using the SFFQ. The 1980 SFFQ included 61 food and beverage items; the 1984 SFFQ was expanded to 116 items, and similar versions of it were used from 1986 (126 items) onward in the NHS and HPFS (131 items).
In the FFQ, participants indicated their average intake of a serving of food or beverage over the preceding year. In the NHS, the 1980 FFQ asked about consumption of caffeinated coffee (in cups), caffeinated tea (in cups), and chocolate (in 1-ounce servings). From 1984 in the NHS and from 1986 in the HPFS, the FFQ was expanded to include intake of decaffeinated coffee (in cups) and separate items for caffeinated soda and caffeine-free sodas. The questionnaire provided nine response possibilities for intake frequency for each item ranging from “never or less than once per month” to “6 or more times per day.” We used data from the US Department of Agriculture to convert participants' responses into average daily intake of caffeine in mg/day. We assumed 137 mg of caffeine per cup of coffee, 47 mg of caffeine per cup of tea, 46 mg of caffeine per can or bottle of cola beverage, and 7 mg of caffeine per serving of chocolate.
The reproducibility and validity of the FFQ have been reported previously.41,42 Self-reported intake of caffeinated beverages (cups/day) according to the FFQ was highly correlated with intake from diet records over 4 weeks: the correlations were 0.78 for coffee, 0.93 for tea, and 0.84 for cola drinks in the NHS,43 and in HPFS, the correlations were 0.93 for coffee, 0.77 for tea, and 0.84 for cola drinks.44
We calculated cumulatively updated caffeine intake by averaging the intake from all available dietary assessments up to the start of each 2-year period at risk. As glaucoma is a slowly developing chronic condition, we chose to study cumulatively averaged caffeine intakes as they best represented long-term intake, and average measures have less measurement error than single assessments.45 All caffeine intakes at each questionnaire were adjusted for total energy intake by using the residual method.46
Next, we examined caffeinated beverages and chocolate in association with EG/EGS. Such analyses are useful as products other than caffeine present in caffeinated coffee may contribute to ES. Also, individuals vary their caffeine intake predominately by altering their intake of caffeinated beverages, and thus the net effect of caffeinated beverages on the risk of EG/EGS must be evaluated for possible public health recommendations. Thus, we examined the risk of EG/EGS in relation to categories of cumulatively updated intakes of specific beverages and chocolate, such as caffeinated coffee, tea, caffeinated soda, chocolate, and decaffeinated coffee.
We calculated incidence rates of EG/EGS by dividing the incident cases by person-years accrued for each caffeine or beverage intake category. We adjusted for age using 5-year categories and calculated Mantel-Haenszel age-adjusted incidence rate ratios (RR) and their 95% confidence intervals (CI). For multivariable analyses, we controlled for potential glaucoma risk factors by including them simultaneously in Cox proportional hazards analysis stratified by age in months and the specific 2-year period at risk.47 We conducted tests for trend by including the midpoint values within each intake category.
We first analyzed data from each cohort separately and performed tests for heterogeneity of the cohort specific results to check for appropriateness of pooling the results. Then, we pooled the results using meta-analytic methods incorporating random effects.48
In our multivariable models, we adjusted for the following covariates: (1) established risk factors such as family history of glaucoma (self-report of any glaucoma in biologic parents, siblings or children), major ancestry (Scandinavian Caucasian, southern European Caucasian, other Caucasian, other ancestry); (2) history of cardiovascular disease (myocardial infarction) and other cardiovascular risk factors49,50 (i.e., body mass index in kg/m2, smoking [pack-years], cumulatively updated alcohol intake [g/day], total caloric intake [kcal/day], self-report [yes/no] of hypertension, and diabetes, high cholesterol); and (3) most recently reported continental US residence stratified by latitude (northern tier, above 42°N; middle tier, 37°–42°N; southern tier, below 37°N), which we previously found was a strong risk factor for EG/EGS.14 Updated information for covariates was obtained from the biennial questionnaires; cumulatively updated alcohol and total caloric intake was calculated using responses to the FFQs. Data missing for the covariates were handled with missing indicator variables in models.
First, we examined the influence of timing of exposure by investigating intake only at baseline or at the most recent questionnaire.
In subsequent analyses, we additionally adjusted for cumulatively updated total fluid intake based on intake of nearly 30 different types of beverages. Because drinking a large quantity of fluids, particularly in a short period of time, generally causes IOP elevation,51 we conducted this analysis to determine whether association with caffeine intake depended on total fluid intake. We also determined whether the association between caffeine/coffee intake and EG/EGS was confounded by intake of B vitamins such as folate and vitamins B12 and B6, which may also affect Hcy levels.52
Finally, we examined the associations between caffeine intake and EG/EGS separately among those with and without a self-reported family history of glaucoma. The questions pertaining to family history of glaucoma were first asked of all participants in the 2000 follow-up questionnaire. In stratified analyses described above, we have statistically tested for effect modifications by testing the significance of interaction terms in Cox regression models.
During 1,647,312 person-years of follow-up, we identified 300 incident cases of EG/EGS in the NHS, and during 472,741 person-years of follow-up, we identified 60 incident cases in the HPFS. The basic ocular and demographic attributes of EG/EGS cases are very similar to those previously reported14 and are provided as a supplemental table (see Supplementary Material and Supplementary Table S1, http://www.iovs.org/content/53/10/6427/suppl/DC1). The overall mean cumulatively updated caffeine consumption was 321 mg/day in NHS and 232 mg/day in HPFS. The highest caffeine consumers were somewhat less likely to have hypertension, diabetes, high cholesterol, and myocardial infarction and less likely to report eye examinations (Table 1). The highest consumers of caffeine were more likely to have greater lifetime exposure to cigarette smoking and drink more alcohol (Table 1). All these differences were accounted for in multivariable analyses.
Age-adjusted and multivariable analyses were similar, and results were pooled as they were not heterogeneous between men and women. There was a trend toward a positive association between total caffeine intake and risk of EG/EGS that was not statistically significant in pooled analyses (P trend = 0.06) (Table 2). For example, compared with the reference group consuming <125 mg of caffeine/day, the multivariable (MV) RR of EG/EGS was 1.43 (95% CI, 0.98, 2.08) for ≥500 mg/day. Results were virtually identical to the main results when we added total fluid intake in the models, indicating negligible confounding by total fluid intake. Also, when we explored the influence of the timing of exposure, the association between caffeine intake at baseline and as of the most recent FFQ and risk of EG/EGS were null.
When we examined specific caffeinated beverages, we found that increasing intake of caffeinated coffee was significantly adversely associated with risk of EG/EGS (P trend = 0.02) (Table 2). Compared with subjects who consumed 0 cups of caffeinated coffee per day, consumption of 3 or more cups was associated with a 1.66-fold higher risk of EG/EGS (95% CI, 1.09–2.54). The percentage of those consuming 3 or more cups was 21% in women and 12% in men. In contrast, we observed essentially null associations with intake of decaffeinated coffee (multivariable relative risk [MVRR] of EG/EGS for 1 or more cups = 1.08; 95% CI, 0.57–2.07). We observed no material associations between intake of other caffeinated beverages such as caffeinated soda or tea or chocolate (data not shown).
Because of the possible confounding by other caffeinated beverages or chocolate (e.g., those subjects who consumed 0 cups of caffeinated coffee might all be drinkers of tea only and vice versa), we conducted secondary analyses where we simultaneously entered terms for all four types of beverages and chocolate in the same model. We observed some attenuation in the relative risks; however, the significant adverse associations with caffeinated coffee remained. For example, the pooled MVRR was 1.66 (95% CI, 1.04–2.67) for consumption of 3 or more cups of caffeinated coffee, and the associations with other beverages remained nonsignificant. In addition, there was minimal confounding by total fluid intake or intake of B vitamins.
Associations between intake of caffeine and caffeinated coffee intake and risk of EG/EGS were modified by a self-reported family history of glaucoma among women (men were not included as only 11 cases reported a family history among men, prohibiting informative secondary analyses) (Table 3). For women in the highest category of caffeine consumption, the MVRR for EG/EGS was 2.94 (95% CI, 1.16–7.46) among those with a positive family history, which contrasts with the corresponding MVRR of 1.16 (95% CI, 0.72–1.88) among women with no family history (P interaction = 0.03). We did not observe a significant interaction between folate intake and coffee consumption in relation to the risk of EG/EGS (P > 0.05).
The United States ranks only 25th worldwide in terms of per capita coffee consumption,17 yet in this US-based prospective study, caffeinated coffee consumption was associated with an increased risk of EG/EGS. This trend did not robustly extend to caffeinated product consumption generally. The association between caffeine consumption was modified by a family history of glaucoma, where the increased risk with greater caffeine or caffeinated coffee consumption was stronger among those who might have been more genetically susceptible to developing EG/EGS. Because this is the first prospective study to evaluate long-term caffeine and coffee intake and risk of EG/EGS, our results, particularly for the secondary analyses, must be interpreted cautiously and confirmed with future analyses.
Compared with the null associations with baseline caffeinated coffee consumption or the most recent consumption, the positive association between long-term average consumption of caffeinated coffee in relation to EG/EGS support the hypothesis that habitual caffeinated coffee at ≥3 cups/day may contribute to the gradual ocular accumulation of exfoliation material. The Hcy-elevating effect of coffee consumption represents a biologically plausible link between coffee consumption and ES. After acute ingestion of filtered caffeinated coffee, there is an increase in plasma Hcy,18–20 and polyphenols such as chlorogenic acid, a compound abundant in coffee but not found in other foods, may contribute to this effect.33,34 The Hordaland homocysteine study,53 a population-based study of 11,940 healthy subjects residing in Norway, found that smoking, coffee consumption, and low folate levels are associated with higher serum Hcy levels. Several studies show that Hcy levels are elevated in blood, aqueous humor, and tears taken from ES patients compared to those in controls.21–28 Elevated Hcy levels, in turn, may contribute to vascular leakage and dysfunctional extracellular matrix remodeling in ES.54 Alternatively, elevated Hcy levels are a consequence and not a cause of ES, and some unlinked factor(s) related to heavy coffee consumption may contribute to EG/EGS.
The strength of this study is the prospective design where intake of caffeine and coffee was assessed before disease occurrence, making recall bias highly unlikely. This was a large study with 360 incident cases, among 78,977 women and 41,202 men followed for up to 26 years, with high follow-up rates. Other strengths of our study include repeated dietary and lifestyle risk factor assessment during follow-up. In using detailed questions on extensively validated FFQs, we were able to incorporate caffeine intake from various sources and examine the association with various caffeinated products. Finally, we were able to control for numerous updated covariates, minimizing confounding bias.
Some limitations of our study must be considered. EG/EGS cases were ascertained based on nonstandardized eye examinations performed by eye care providers from throughout the United States. Nonetheless, using this approach, which was needed for practical reasons, we previously confirmed that incident EG/EGS is a strongly age-related condition that produces higher IOPs at diagnosis than incident POAG14; furthermore, we showed that female sex is a risk factor for EG/EGS,14 as observed in the Reykjavik Eye Study, indicating construct validity of the outcome measure.13 Another limitation is that our study population is over 90% Caucasian, and thus, our results may not be generalizable to other more diverse populations. Our study was not designed to capture people with only ES and no signs of glaucoma, and we certainly had under-ascertainment of EG/EGS; yet, our objective was not to ascertain the absolute incidence of EG/EGS (where high sensitivity is important and under-ascertainment may be a detriment); instead, the goal was to ascertain the relative incidence of EG/EGS to identify potential risk factors. In this setting, a low sensitivity of disease identification in epidemiologic studies is acceptable if the disease outcome definition has a high specificity and the under-ascertainment is not systematically different by exposure groups. Indeed, the frequency of disease confirmation among self-reports and the number of reported eye examinations during follow-up were similar by caffeine intake, minimizing the possibility of bias. Finally, it is possible that residual confounding by other factors associated with high coffee consumption may account for these results.
In summary, in this first prospective population-based investigation of the relationship between caffeine and coffee intake and risk of developing EG/EGS, we found that heavier caffeinated coffee consumption was associated with increased risk of EG/EGS. The effect modification by family history on the association with caffeine deserves further study.
Supported by National Institutes of Health and Arthur Ashley Foundation Grants CA87969, EY009611, CA49449, CA055075, EY020928 (JLW), and EY015473 (LRP) and by the Harvard Glaucoma Center of Excellence (LRP and JLW).
Disclosure: L.R. Pasquale, None; J.L. Wiggs, None; W.C. Willett, None; J.H. Kang, None.