0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Epidemiology |

Vitamin D Status and Early Age-Related Macular Degeneration in Postmenopausal Women FREE

Amy E. Millen, PhD; Rick Voland, PhD; Sherie A. Sondel, MS; Niyati Parekh, PhD; Ronald L. Horst, PhD; Robert B. Wallace, MD; Gregory S. Hageman, PhD; Rick Chappell, PhD; Barbara A. Blodi, MD; Michael L. Klein, MD; Karen M. Gehrs, MD; Gloria E. Sarto, MD, PhD; Julie A. Mares, PhD ; CAREDS Study Group
[+] Author Affiliations

Author Affiliations: Department of Social and Preventive Medicine, School of Public Health and Health Professions, University at Buffalo, Buffalo, New York (Dr Millen); Department of Ophthalmology and Visual Sciences (Drs Voland and Mares and Ms Sondel), Department of Biostatistics and Medical Informatics, School of Medicine and Public Health, Clinical Science Center (Dr Chappell), and Department of Obstetrics and Gynecology, School of Medicine and Public Health (Dr Sarto), University of Wisconsin, Madison; Department of Nutrition, Food Studies and Public Health, New York University, New York (Dr Parekh); Department of Animal Science, Iowa State University, Ames (Dr Horst); Department of Epidemiology, General Hospital Office, University of Iowa, Iowa City (Dr Wallace); Translational Research Institute, John A. Moran Eye Center, University of Utah, Salt Lake City (Dr Hageman); Fundus Photograph Reading Center, Madison, Wisconsin (Dr Blodi); Department of Ophthalmology, Oregon Health and Science University/Casey Eye Institute, Portland (Dr Klein); and the Center for Retina and Macular Disease, Winter Haven, Florida (Dr Gehrs).


Section Editor: Leslie Hyman, PhD

More Author Information
Arch Ophthalmol. 2011;129(4):481-489. doi:10.1001/archophthalmol.2011.48.
Text Size: A A A
Published online

Objective  The relationship between serum 25-hydroxyvitamin D (25[OH]D) concentrations (nmol/L) and the prevalence of early age-related macular degeneration (AMD) was investigated in participants of the Carotenoids in Age-Related Eye Disease Study.

Methods  Stereoscopic fundus photographs, taken from 2001 to 2004, assessed AMD status. Baseline (1994-1998) serum samples were available for 25(OH)D assays in 1313 women with complete ocular and risk factor data. Odds ratios (ORs) and 95% confidence intervals (CIs) for early AMD (n = 241) of 1287 without advanced disease were estimated with logistic regression and adjusted for age, smoking, iris pigmentation, family history of AMD, cardiovascular disease, diabetes, and hormone therapy use.

Results  In multivariate models, no significant relationship was observed between early AMD and 25(OH)D (OR for quintile 5 vs 1, 0.79; 95% CI, 0.50-1.24; P for trend = .47). A significant age interaction (P = .002) suggested selective mortality bias in women aged 75 years and older: serum 25(OH)D was associated with decreased odds of early AMD in women younger than 75 years (n = 968) and increased odds in women aged 75 years or older (n = 319) (OR for quintile 5 vs 1, 0.52; 95% CI, 0.29-0.91; P for trend = .02 and OR, 1.76; 95% CI, 0.77-4.13; P for trend = .05, respectively). Further adjustment for body mass index and recreational physical activity, predictors of 25(OH)D, attenuated the observed association in women younger than 75 years. Additionally, among women younger than 75 years, intake of vitamin D from foods and supplements was related to decreased odds of early AMD in multivariate models; no relationship was observed with self-reported time spent in direct sunlight.

Conclusions  High serum 25(OH)D concentrations may protect against early AMD in women younger than 75 years.

Age-related macular degeneration (AMD), a chronic, late-onset disease that results in degeneration of the macula, is the leading cause of adult irreversible vision loss in developed countries.1 Age-related macular degeneration affects approximately 9% (8.5 million) of Americans aged 40 years and older.2 Earlier stages of AMD, which increase the odds of developing advanced disease,3 are the most common, affecting 8% of persons aged 43 to 54 years and 30% of those older than 75 years.4 There is no cure for this condition.5 Limited treatment is available to slow its progression, and no established means of prevention exits.5 Therefore, it is important to identify modifiable risk factors that may reduce disease occurrence or prevent progression to advanced stages.

The pathogenesis of AMD is likely to involve a complex interaction of multiple factors including light damage,6 oxidative stress,7 inflammation,8 possible disturbance in the choroidal blood vessels,9 and genetic predisposition.10 Nonmodifiable genetic risk factors,11,12 especially those associated with inflammatory response, and the modifiable risk factor of smoking,12,13 appear to explain a large percentage of the variation in risk of AMD. Recently, a strong protective association between vitamin D status, as reflected by serum concentrations of 25-hydroxyvitamin D (25[OH]D), and the prevalence of early AMD was reported in a nationally representative, cross-sectional study.14 Research suggests that vitamin D affects immune modulation and perhaps the prevention of diseases with inflammatory etiologies.15 Currently there is evidence that vitamin D deficiency and insufficiency exist in individuals worldwide and that the risk of developing many chronic diseases of aging have been shown to be inversely associated with vitamin D status.16

The purpose of this study was to investigate whether the previously observed protective association of vitamin D status and AMD could be confirmed in a second study, the Carotenoids in Age-related Eye Disease Study (CAREDS), in which 25(OH)D concentrations were assessed 6 years prior to AMD status. The CAREDS study is an ancillary study within the Women's Health Initiative Observational Study (WHIOS), which was initiated to investigate relationships of carotenoids in the diet, serum, and retina to AMD17 and cataract.18 Using CAREDS data, the relationship between individually measured serum 25(OH)D concentrations at WHIOS baseline (1993-1998) and the prevalence of early AMD, assessed an average of 6 years later at the CAREDS baseline (2001-2004), was investigated. Additionally, analyses sought to determine whether associations between all sources of vitamin D (sunlight, food, and supplements) and AMD supported associations observed between serum 25 (OH)D and AMD.

THE CAREDS STUDY SAMPLE

The CAREDS population consists of women (ages, 50-79 years) who were enrolled in the observational study of the Women's Health Initiative at 3 of 40 sites: the University of Wisconsin, Madison, the University of Iowa, Iowa City, and the Kaiser Center for Health Research, Portland, Oregon. Participants with baseline WHIOS (1993-1998) intakes of lutein plus zeaxanthin above the 78th and below the 28th percentiles, as assessed at WHIOS baseline (1993-1998), were recruited. Of the 3143 women who fulfilled these criteria, 96 died or were lost to follow-up between the selection year (2000) and enrollment in CAREDS (2001-2004). Those who remained were mailed letters inviting them to participate.

A total of 1042 women declined participation, and 2005 were enrolled (64%). Of those enrolled, 1894 participated in study visits. Gradable fundus photographs were obtained for 1853 participants; an additional 4 participants were included who did not have AMD photographs but had a doctor's confirmation of AMD. One participant was excluded because her lutein data were determined to be unreliable. Sixty-nine participants were further excluded because of missing important AMD risk factor data. Of the remaining 1787 participants, 474 women had insufficient serum for assays, leaving a sample size for the analysis of 1313. All procedures conformed to the Declaration of Helsinki and were approved by the institutional review board at each university.

SERUM ASSAYS

Serum 25(OH)D is the preferred biomarker for vitamin D status, as it reflects vitamin D exposure from both oral sources and sunlight.16 Serum samples were drawn at WHIOS baseline after a fast of 10 or more hours and stored at −80°C.19 From 2004 to 2005, serum lutein and zeaxanthin concentrations were determined at Tufts University, Boston, Massachusetts,17 where samples were stored at −70°C and thawed at room temperature. The remaining serum was refrozen at −70°C and remained frozen until the day of vitamin D assay (in fall 2008), at which time they were thawed at room temperature and assayed within 2 to 3 hours for serum 25(OH)D concentration (nmol/L) using the LIAISON (DiaSorin, Stillwater, Minnesota) chemiluminescence method. Previous research shows that blood 25(OH)D concentrations are minimally affected by multiple freeze-thaw cycles20 or extended years in storage.21,22 C-reactive protein (CRP) (mg/L) concentrations were assessed using the high-sensitivity CRP assay kit (DiaSorin) on separate days from the 25 (OH)D assessment. C-reactive protein has been shown to remain stable for up to 5 freeze/thaw cycles.23 Both 25(OH)D and CRP assays were conducted by Heartland Assays, Inc (Ames, Iowa). The coefficient of variation determined using blind duplicates was 8.9% for 25(OH)D and 18.8% for CRP.

As sun exposure, and thus 25(OH)D concentrations, vary by season at Northern climates, 25(OH)D concentrations were adjusted for month of blood acquisition. Residuals from local regression of 25(OH)D on month of blood draw, with application of the local regression (LOESS) procedure (PROC LOESS in SAS v.9.2, SAS Institute, Cary, North Carolina),24 were added to the overall population mean (57.31 nmol/L). The LOESS method applies a nonparametric curve to smooth the means between adjacent months using weighted polynomial regression. Means for each month determined from the smooth curve are used for the adjustment.

AMD CLASSIFICATION

Prevalent AMD was determined from stereoscopic retinal fundus photographs taken from 2001 through 2004. Of the 1857 participants with ocular data, 5% (n = 95) self-reported a diagnosis of AMD at the WHIOS year 3 follow-up (prior to fundus photography), 94% self-reported no AMD, and 1% (n = 24) had missing data. Photographs were graded by the University of Wisconsin Fundus Reading Center using the Age-Related Eye Disease Study protocol for grading maculopathy.25 Presence of AMD was classified as any, early, or advanced AMD (at least 1 eye). There were 241 cases of early AMD in 1287 women without advanced AMD. Early AMD was further classified as large drusen (≥1 large drusen [≥125 μm] or extensive intermediate drusen [area ≥360 μm when soft indistinct drusen are present or ≥650 μm when soft indistinct drusen are absent]) or pigmentary abnormalities (increased or decreased pigmentation accompanied by at least 1 drusen ≥63 μm). Of this sample, 26 women were classified as having advanced AMD (the presence of geographic atrophy in the center subfield or neovascular or exudative macular degeneration). Owing to the minimal number of advanced AMD outcomes, these analyses focus on early AMD.

SOURCES OF VITAMIN D (DIETARY, SUPPLEMENT, AND SUNLIGHT DATA)

At Women's Health Initiative baseline, vitamin D intake from foods was estimated from a self-administered food frequency questionnaire,26 to assess usual dietary intake during the previous 3 months. An interviewer-administered form was used to collect information on the dose, frequency, and duration of current supplement use at WHIOS baseline.27,28 Total vitamin D intake was calculated by summing vitamin D intake from foods and supplements. Using food frequency questionnaire data, dietary pattern scores were estimated for the 2005 Health Eating Index (HEI 2005) without inclusion of the oil subscore, as previously described.29

At the CAREDS baseline visit, participants were asked to report their sunlight exposure for each city/town in which they resided from 18 years of age to their age at CAREDS. Specifically, for each residence, they were asked to report the number of daytime hours (<1, 1-3, >3) spent in direct sunlight between 10 AM to 4 PM, in the months of April through September, during weekdays and leisure time. They also reported daytime activity on the water for 3 or more hours and whether they used protective gear (hats, sunglasses, and protective lenses). From these data, participants' estimation of reported time spent in direct sunlight at WHIOS baseline, corresponding in time to 25(OH)D assessment, was ascertained, and chronic ocular exposure to visible light in the last 20 years was estimated.30

STATISTICAL ANALYSIS

Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for AMD by quintile of serum 25(OH)D, adjusting for age. Additional adjustment of the age-adjusted model for the following potential confounders of early AMD was investigated: study site, age, race/ethnicity, smoking pack years, recreational physical activity, body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), and family history of AMD. Only BMI and physical activity changed the ORs by 10% or more. Although both measures of adiposity and physical activity have been reported as risk factors for AMD in the literature,31 they are also significant determinants of serum 25(OH)D status.32 Addition of BMI and physical activity to the model could potentially overadjust and explain the relationship of vitamin D status to early AMD. For this reason, the ORs were first investigated adjusted for early AMD risk factors identified a priori that were not strong determinants of serum vitamin D status : smoking pack years, iris pigmentation, self-reported family history of AMD, cardiovascular disease, diabetes, and hormone therapy use. In a second step, this multivariate model was further adjusted for BMI and physical activity. Next, we adjusted the multivariate model for CRP, a marker for systemic inflammation, to explore whether this association was potentially acting through an inflammatory pathway. As an exploratory analysis, we adjusted the multivariate model for other dietary factors highly correlated with 25(OH)D concentrations and associated with AMD in previous CAREDS analyses: dietary intake of lutein and zeaxanthin,17 dietary intake of polyunsaturated fat,33 and overall healthy diet, as indicated by the HEI 2005 score.34

Next, it was investigated whether consistent relationships were observed between early AMD and 2 sources of vitamin D: sunlight exposure and oral intake. The odds of early AMD were estimated among women self-reporting more than 3 and 1 to 3 compared with less than 1 h/d in direct sunlight at WHIOS baseline, and among women in high compared with low quintiles for baseline intake of vitamin D from foods, supplements, and foods and supplements combined.

The effect modification of the associations between serum 25(OH)D status and early AMD by age, BMI, physical activity, lutein plus zeaxanthin intake, a healthy dietary pattern (HEI 2005 score), hormone therapy use, and self-reported family history of AMD was investigated. Effect modification of the association between total vitamin D intake and AMD by sun exposure was also investigated. P < .10 was considered statistically significant. Analyses were conducted stratified by identified effect modifiers.

All analyses were conducted using SAS version 9.2.

PARTICIPANT CHARACTERISTICS

Participants with high compared with low vitamin D status after adjustment for month of blood draw were more likely to be white, have a higher income, consume more alcohol, engage in a higher level of recreational physical activity, report greater ocular visible sun exposure, have a family history of AMD, have a lower BMI, be less hypertensive, and have lower concentrations of CRP (Table 1). Participants with high vitamin D status were also more likely to have higher calorie consumption, lower intake of fat, greater fiber intake, and greater intake of antioxidant nutrients (P ≤ .20). They consumed a greater amount of fruit, milk, and fortified cereal servings, had higher scores on the HEI 2005, and were more likely to use supplements compared with individuals with low vitamin D status (Table 2).

Table Graphic Jump LocationTable 1. Characteristics of Participants in Low and High Quintiles for 25(OH)D, Assessed at Baseline, Adjusted for Month of Blood Drawa
Table Graphic Jump LocationTable 2. Energy, Nutrient Intake, and Serum Nutrient Concentrations, Assessed at Baseline in Participants in the Low and High Quintiles of 25(OH)D, Adjusted for Month of Blood Drawa
SERUM 25(OH)D STATUS AND AMD

Table 3 shows the odds of having AMD among participants in quintiles 2 through 5 compared with 1. In models adjusted for age and further adjusted for a priori early- AMD risk factors (multivariate model), there was no significant relationship between vitamin D status and early or advanced AMD. The same was observed for drusen and pigmentary abnormalities (data not shown). However, the association between early AMD and 25(OH)D concentration was modified by age (P for interaction = .002). The ORs for early AMD among participants younger than 75 years were in the opposite direction of ORs for early AMD among women aged 75 or older, suggesting selective mortality bias in the older age group. Subsequently, further analyses were conducted using the sample of individuals younger than 75 years without advanced disease.

Table Graphic Jump LocationTable 3. Odds Ratios for AMD, Assessed From 2001-2004 Among Participants in Quintiles 2 Through 5 Compared With 1 for 25(OH)D, Assessed in 1993-1998

In the multivariate model, participants younger than 75 years had 48% decreased odds of early AMD (OR for quintile 5 vs 1, 0.52; 95% CI, 0.29-0.91; P for trend = .02) (Table 3). In women younger than 75 years, there were 57% decreased odds of pigmentary abnormalities (OR for quintile 5 vs 1, 0.43; 95% CI, 0.18-0.96; P for trend = .02) and the OR for quintile 5 compared with 1 for large drusen was also less than 1.0 but not statistically significant. Further adjustment of these relationships for BMI and physical activity, determinants of 25(OH)D status as well as potential confounders, attenuated these relationships. Further adjustment of the multivariate model for CRP strengthened relationships.

The inverse association between early AMD and 25(OH)D in women younger than 75 years was not explained by dietary intake of lutein plus zeaxanthin or polyunsaturated fat (Table 4). After adjustment for HEI 2005 score, the statistically significant relationship between 25(OH)D and AMD was attenuated, although the OR was still less than 1.0. There was no statistically significant (P < .10) effect modification of the relationship between 25(OH)D status and early AMD in women younger than 75 years by BMI, physical activity, HEI 2005 score, hormone therapy, or self-reported family history of AMD. However, the relationship between early AMD and 25(OH)D was stronger among women with higher than lower intakes of lutein plus zeaxanthin (adjusted OR for early AMD among women in tertile 3 vs 1 for serum 25(OH)D: low intake, 0.94; 95% CI, 0.50, 1.76; high intake, 0.46; 95% CI, 0.22, 0.93; P for interaction = .04).

Table Graphic Jump LocationTable 4. Multivariatea Model Odds Ratios for Early AMD, Assessed From 2001-2004, of Participants Younger Than 75 Years in Quintiles 2-5 Compared With 1 for Serum 25(OH)D, Assessed in 1993-1998, Further Adjusted for Potential Dietary Confounders
SOURCES OF VITAMIN D AND EARLY AMD IN WOMEN YOUNGER THAN 75 YEARS

There was no observed protective effect of reported hours spent in direct sunlight at WHIOS baseline on early AMD, as hypothesized (Table 5). Although oral sources of vitamin D accounted for only a small variation in serum 25(OH)D concentrations (<10%), a 59% reduced odds of early AMD in quintile 5 compared with 1 for vitamin D from food and supplements combined (associated P for trend = .15) was observed. Decreased, but not statistically significant, odds of early AMD in high compared with low intake of vitamin D from foods was observed, with a significant P for trend of .04. The top food sources of vitamin D in this sample included milk, fish, fortified margarine, and fortified cereal. Exploratory analyses revealed no statistically significant effect modification of the relationship between early AMD and total vitamin D intake by sunlight exposure (data not shown).

Table Graphic Jump LocationTable 5. Multivariate Model Odds Ratios for Early AMD, Assessed From 2001-2004, of Participants Younger Than 75 Years Who Reported High vs Low Levels of Sunlight Exposure and High vs Low Intake of Vitamin D From Foods and Supplements, Assessed in 1993-1998

Analyses in the present sample of postmenopausal women confirm a protective association of vitamin D status to the prevalence of AMD, similar to that previously observed in the American population.14 In women younger than 75 years, having 25(OH)D concentrations higher than 38 nmol/L was significantly associated with a 48% decreased odds of early AMD. This association was consistent across subtypes of early AMD. Attenuation of the multivariate model after adjustment for BMI and physical activity is most likely explained by the strong correlation between these factors (predictors of vitamin D status) and 25(OH)D concentrations. Adjustment of the multivariate model for intake of lutein plus zeaxanthin, polyunsaturated fat, or CRP, a marker of systemic inflammation, did not explain the observed association, but the relationship was attenuated after adjustment for dietary pattern score. Some of the association between vitamin D status and early AMD may be explained by dietary patterns but may also have resulted in overadjustment of the multivariate model owing to multicolinearity between serum 25(OH)D and HEI 2005 score levels. A marginally statistically significant (P for trend = .05) direct association between 25(OH)D and early AMD was observed in women aged 75 years or older.

The observed significant age interaction is consistent with previous observations in CAREDS. Exposures (macular pigment density,35 lutein and zeaxanthin intake,17 and fat intake33) associated with decreased odds of early AMD in younger women were associated with increased odds in older women, suggesting selective mortality bias.36 We propose that, as people age, a greater proportion of those susceptible to early AMD than unsusceptible individuals with low 25(OH)D concentrations die of other chronic diseases prior to developing early AMD.36 Subsequently, a direct association between 25(OH)D and early AMD was observed in the oldest women. One way to avoid the influence of this bias is to examine associations in the youngest age group, as we have done in this investigation.

We observed a possible threshold effect with 50% decreased odds of early AMD in quintile 2 compared with 1 for 25(OH)D. The odds of early AMD did not further decrease after 25(OH)D concentrations rose higher than 38 nmol/L. This is higher than what is considered severely deficient, less than 25 nmol/L,37 but not high enough to be considered sufficient by some investigators who suggest that concentrations lower than 50 nmol/L16 or even 75 to 80 nmol/L are deficient.38 A previous cross-sectional analysis14 observed at least a 25% significant decreased odds of early AMD among persons with 25(OH)D concentrations of 54 nmol/L or higher. It is possible that measured serum 25(OH)D concentrations in this article slightly underestimated the true 25(OH)D concentrations due to degradation in storage, although this has been shown to minimally occur.22 If degradation occurred, it seems likely that it would have been fairly uniform across samples and not greatly affected the risk estimate.

We did not observe an association between early AMD and reported time spent outside in direct sunlight, although most circulating vitamin D in most individuals is derived from UVB-induced dermal production of vitamin D.39 Previous relationships between sunlight exposure and AMD have been investigated because chronic sunlight exposure is hypothesized to increase risk.40 Of the observational studies4153 investigating this relationship, only a few found direct associations between sunlight and AMD.43,45,50,53 Detrimental effects may be limited to blue light exposure,6,43 which is not measured in all studies. Two studies found that sunlight exposure was related to lower odds of developing AMD.46,48 In another cohort, AMD was directly associated with leisure time outdoors in summer,45,50,53 not associated with ambient UVB exposure, and (in some instances) inversely associated with UVB exposure after accounting for use of sunglasses and hats with brims.45,50,53 Perhaps some amount of UVB exposure, necessary for dermal vitamin D synthesis, may be protective for AMD when the eyes are also protected from blue light exposure. In the CAREDS, measurement error in assessment of sun exposure may have biased the results toward the null, or sunlight's protective effect via vitamin D synthesis and its detrimental effect from blue light ocular damage negate any findings between AMD and ambient sun exposure.

The inverse association between early AMD and 25(OH)D was supported by analyses of vitamin D intake. Significantly decreased odds of developing early AMD of similar magnitude to that observed with serum 25(OH)D was observed among persons in quintile 5 (estimated intake of 18 μg/d [720 IU/d]) compared with 1 for total vitamin D intake. This is greater than the Dietary Reference Intakes, which recommend 600 IU/d.54

Inflammation is thought to be involved in the pathogenesis of AMD. Vitamin D, because of its anti-inflammatory, immune-modulating properties,55 may suppress the cascade of destructive inflammation that occurs at the level of the retinal pigment epithelium–choroid interface in early stages of AMD.8 The vitamin D receptor is expressed on cells of the human immune system and 1,25-dihydroxyvitamin D has been shown to suppress proinflammatory cytokines in vitro, perhaps in part by altering T-cell function toward a T-helper 2 (anti-inflammatory) rather than a T-helper 1 (proinflammatory) response.15,55 A possible role of vitamin D in ocular functioning is supported by evidence that the vitamin D receptor is located in vertebrate retinal tissue56,57 and is expressed in human cultured retinal endothelial cells.58 Additionally, vitamin D may play a role in preventing AMD progression from early to neovascular AMD; however, we could not assess this in CAREDS. Vitamin D has been shown to inhibit angiogenesis in cultured endothelial cells59 and within the retinas of animal models of retinoblastoma60 and oxygen-induced ischemic retinopathy.61

Although we saw an inverse association between prevalent early AMD and 25(OH)D assessed 6 years earlier, we cannot firmly establish causality with this study design. Conclusions from this analysis can only be extrapolated to US postmenopausal women and white women, as CAREDS had limited minority representation and was not a nationally representative sample. Additionally, CAREDS is limited by a lack of measures for genetic risk factors which strongly predict risk of AMD.11

As previously described,17 selection bias is a potential concern in this study. As eligibility of participation in CAREDS was based on lutein plus zeaxanthin intake, to maximize dietary diversity, we investigated the associations between AMD and serum 25(OH)D stratified by lutein plus zeaxanthin intake (low and high). Regardless of intake, the relationship between AMD and vitamin D status was inverse, although stronger in those with higher lutein and zeaxanthin intake, suggesting that serum vitamin D status and lutein plus zeaxanthin intake may synergistically be important to eye health.

Thirty-six percent of participants who were eligible (n = 3143) for CAREDS declined to participate. Those persons younger than 75 years who participated were healthier with respect to dietary and lifestyle factors and had slightly greater self-reported AMD (3.4% vs 2.0%) at the Women's Health Initiative year 3 follow-up. For this reason, we suspect that nonparticipation would have biased our results toward the null. We cannot completely dismiss the possibility of selection bias in this study. This association needs to be observed in other longitudinal studies.

This is the second study to present an association between AMD status and 25(OH)D, and our data support the previous observation that vitamin D status may potentially protect against development of AMD. In CAREDS we were able to adjust for the major nongenetic risk factors for AMD as well as explore relationships between other surrogate measures for vitamin D status such as oral sources of vitamin D and sun exposure. In conclusion, vitamin D status may significantly affect a woman's odds of developing early AMD. More studies are needed to verify this association prospectively as well as to better understand the potential interaction between vitamin D status and genetic and lifestyle factors with respect to risk of early AMD.

Correspondence: Amy E. Millen, PhD, Department of Social and Preventive Medicine, University at Buffalo, Ferber Hall 240, Buffalo, NY 14214 (aemillen@buffal.edu).

Submitted for Publication: March 5, 2010; final revision received July 13, 2010; accepted July 23, 2010.

Author Contributions: Amy E. Millen had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Group Information: A list of the Women’s Health Initiative Investigators was published online December 13, 2010, in Arch Ophthalmol.

Financial Disclosure: Dr Gehrs reports currently serving as a consultant for Sequenome.

Funding/Support: This study was supported by grants EY13018, EY016886, and DK07665 from the National Institutes of Health and by Research to Prevent Blindness. It was part of the Carotenoids and Age-Related Eye Disease Study (CAREDS), an ancillary study of the Women's Health Initiative (WHI). The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, and the US Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221.

Additional Contributions: We thank the women who generously contributed their time to participate in the CAREDS.

Resnikoff  SPascolini  DEtya’ale  D  et al.  Global data on visual impairment in the year 2002. Bull World Health Organ 2004;82 (11) 844- 851
PubMed
Klein  RRowland  MLHarris  MI Racial/ethnic differences in age-related maculopathy: Third National Health and Nutrition Examination Survey. Ophthalmology 1995;102 (3) 371- 381
PubMed Link to Article
Klein  RKlein  BEJensen  SCMeuer  SM The five-year incidence and progression of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology 1997;104 (1) 7- 21
PubMed Link to Article
Klein  RKlein  BELinton  KL Prevalence of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology 1992;99 (6) 933- 943
PubMed Link to Article
Jager  RDMieler  WFMiller  JW Age-related macular degeneration. N Engl J Med 2008;358 (24) 2606- 2617
PubMed Link to Article
Shaban  HRichter  C A2E and blue light in the retina: the paradigm of age-related macular degeneration. Biol Chem 2002;383 (3-4) 537- 545
PubMed Link to Article
Beatty  SKoh  HPhil  MHenson  DBoulton  M The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv Ophthalmol 2000;45 (2) 115- 134
PubMed Link to Article
Hageman  GSLuthert  PJVictor Chong  NHJohnson  LVAnderson  DHMullins  RF An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch's membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res 2001;20 (6) 705- 732
PubMed Link to Article
Feigl  B Age-related maculopathy: linking aetiology and pathophysiological changes to the ischaemia hypothesis. Prog Retin Eye Res 2009;28 (1) 63- 86
PubMed Link to Article
Ting  AYLee  TKMacDonald  IM Genetics of age-related macular degeneration. Curr Opin Ophthalmol 2009;20 (5) 369- 376
PubMed Link to Article
Hageman  GSAnderson  DHJohnson  LV  et al.  A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A 2005;102 (20) 7227- 7232
PubMed Link to Article
Seddon  JMReynolds  RMaller  JFagerness  JADaly  MJRosner  B Prediction model for prevalence and incidence of advanced age-related macular degeneration based on genetic, demographic, and environmental variables. Invest Ophthalmol Vis Sci 2009;50 (5) 2044- 2053
PubMed Link to Article
Thornton  JEdwards  RMitchell  PHarrison  RABuchan  IKelly  SP Smoking and age-related macular degeneration: a review of association. Eye (Lond) 2005;19 (9) 935- 944
PubMed Link to Article
Parekh  NChappell  RJMillen  AEAlbert  DMMares  JA Association between vitamin D and age-related macular degeneration in the Third National Health and Nutrition Examination Survey, 1988 through 1994. Arch Ophthalmol 2007;125 (5) 661- 669
PubMed Link to Article
Mora  JRIwata  Mvon Andrian  UH Vitamin effects on the immune system: vitamins A and D take centre stage. Nat Rev Immunol 2008;8 (9) 685- 698
Link to Article
Holick  MF Vitamin D deficiency. N Engl J Med 2007;357 (3) 266- 281
PubMed Link to Article
Moeller  SMParekh  NTinker  L  et al. CAREDS Research Study Group, Associations between intermediate age-related macular degeneration and lutein and zeaxanthin in the Carotenoids in Age-related Eye Disease Study (CAREDS): ancillary study of the Women's Health Initiative. Arch Ophthalmol 2006;124 (8) 1151- 1162
PubMed Link to Article
Moeller  SMVoland  RTinker  L  et al. CAREDS Study Group; Women's Health Initiative, Associations between age-related nuclear cataract and lutein and zeaxanthin in the diet and serum in the Carotenoids in the Age-Related Eye Disease Study, an Ancillary Study of the Women's Health Initiative. Arch Ophthalmol 2008;126 (3) 354- 364
PubMed Link to Article
Anderson  GLManson  JWallace  R  et al.  Implementation of the Women's Health Initiative study design. Ann Epidemiol 2003;13 (9) ((suppl)) S5- S17
PubMed Link to Article
Antoniucci  DMBlack  DMSellmeyer  DE Serum 25-hydroxyvitamin D is unaffected by multiple freeze-thaw cycles. Clin Chem 2005;51 (1) 258- 261
PubMed Link to Article
Ockè  MCSchrijver  JObermann-de Boer  GLBloemberg  BPHaenen  GRKromhout  D Stability of blood (pro)vitamins during four years of storage at -20 degrees C: consequences for epidemiologic research. J Clin Epidemiol 1995;48 (8) 1077- 1085
PubMed Link to Article
Agborsangaya  CToriola  ATGrankvist  K  et al.  The effects of storage time and sampling season on the stability of serum 25-hydroxy vitamin D and androstenedione. Nutr Cancer 2010;62 (1) 51- 57
PubMed Link to Article
Hartweg  JGunter  MPerera  R  et al.  Stability of soluble adhesion molecules, selectins, and C-reactive protein at various temperatures: implications for epidemiological and large-scale clinical studies. Clin Chem 2007;53 (10) 1858- 1860
PubMed Link to Article
 SAS/STAT(R) 9.2 User's Guide, 2nd ed: PROC LOESS Statement; 2009: Editioneau of the Census; 2001. SAS Web site. http://support.sas.com/documentation/cdl/en/statug/63033/HTML/default/statug_loess_sect006.htm. Accessed January 26, 2010
Age-Related Eye Disease Study Research Group, The Age-Related Eye Disease Study system for classifying age-related macular degeneration from stereoscopic color fundus photographs: the Age-Related Eye Disease Study Report Number 6. Am J Ophthalmol 2001;132 (5) 668- 681
PubMed Link to Article
Patterson  REKristal  ARTinker  LFCarter  RABolton  MPAgurs-Collins  T Measurement characteristics of the Women's Health Initiative food frequency questionnaire. Ann Epidemiol 1999;9 (3) 178- 187
PubMed Link to Article
Patterson  REKristal  ARLevy  L McLerran  DWhite  E Validity of methods used to assess vitamin and mineral supplement use. Am J Epidemiol 1998;148 (7) 643- 649
PubMed Link to Article
Patterson  RELevy  LTinker  LFKristal  AR Evaluation of a simplified vitamin supplement inventory developed for the Women's Health Initiative. Public Health Nutr 1999;2 (3) 273- 276
PubMed Link to Article
Mares  JAVoland  RAdler  R  et al. CAREDS Group, Healthy diets and the subsequent prevalence of nuclear cataract in women. Arch Ophthalmol 2010;128 (6) 738- 749
PubMed Link to Article
Duncan  DDMuñoz  BWest  SKSalisbury Eye Evaluation Project Team, Assessment of ocular exposure to visible light for population studies. Dev Ophthalmol 2002;3576- 92
PubMed
Klein  RPeto  TBird  AVannewkirk  MR The epidemiology of age-related macular degeneration. Am J Ophthalmol 2004;137 (3) 486- 495
PubMed Link to Article
Millen  AEWactawski-Wende  JPettinger  M  et al.  Predictors of serum 25-hydroxyvitamin D concentrations among postmenopausal women: the Women's Health Initiative Calcium plus Vitamin D clinical trial. Am J Clin Nutr 2010;91 (5) 1324- 1335
PubMed Link to Article
Parekh  NVoland  RPMoeller  SM  et al. CAREDS Research Study Group, Association between dietary fat intake and age-related macular degeneration in the Carotenoids in Age-Related Eye Disease Study (CAREDS): an ancillary study of the Women's Health Initiative. Arch Ophthalmol 2009;127 (11) 1483- 1493
PubMed Link to Article
Mares  JAVoland  RPSondel  SA  et al.  Healthy lifestyles related to subsequent prevalence of age-related macular degeneration [published online December 13, 2010]. Arch Ophthalmol
PubMed
LaRowe  TLMares  JASnodderly  DMKlein  MLWooten  BRChappell  RCAREDS Macular Pigment Study Group, Macular pigment density and age-related maculopathy in the Carotenoids in Age-Related Eye Disease Study: an ancillary study of the women's health initiative. Ophthalmology 2008;115 (5) 876- 883, e1
PubMed Link to Article
Kaplan  GAHaan  MNCohen  RD Risk factors and the study of prevention in the elderly: methodological issues. Wallace  RBWoolson  RFEpidemiologic Study of the Elderly. New York, NY Oxford University Press1992;20- 36
Holick  MF High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc 2006;81 (3) 353- 373
PubMed Link to Article
Bischoff-Ferrari  HAGiovannucci  EWillett  WCDietrich  TDawson-Hughes  B Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes [printed correction appears in Am J Clin Nutr. 2006;84(5):1253]. Am J Clin Nutr 2006;84 (1) 18- 28
PubMed
Holick  MF Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr 2004;80 (6) ((suppl)) 1678S- 1688S
PubMed
West  ESSchein  OD Sunlight and age-related macular degeneration. Int Ophthalmol Clin 2005;45 (1) 41- 47
PubMed Link to Article
Hyman  LGLilienfeld  AMFerris  FL  IIIFine  SL Senile macular degeneration: a case-control study. Am J Epidemiol 1983;118 (2) 213- 227
PubMed
West  SKRosenthal  FSBressler  NM  et al.  Exposure to sunlight and other risk factors for age-related macular degeneration. Arch Ophthalmol 1989;107 (6) 875- 879
PubMed Link to Article
Taylor  HRMuñoz  BWest  SBressler  NMBressler  SBRosenthal  FS Visible light and risk of age-related macular degeneration. Trans Am Ophthalmol Soc 1990;88163- 178
PubMed
The Eye Disease Case-Control Study Group, Risk factors for neovascular age-related macular degeneration. Arch Ophthalmol 1992;110 (12) 1701- 1708
PubMed Link to Article
Cruickshanks  KJKlein  RKlein  BE Sunlight and age-related macular degeneration: the Beaver Dam Eye Study. Arch Ophthalmol 1993;111 (4) 514- 518
PubMed Link to Article
Darzins  PMitchell  PHeller  RF Sun exposure and age-related macular degeneration: an Australian case-control study. Ophthalmology 1997;104 (5) 770- 776
PubMed Link to Article
Age-Related Eye Disease Study Research Group, Risk factors associated with age-related macular degeneration: a case-control study in the age-related eye disease study: age-Related Eye Disease Study Report Number 3. Ophthalmology 2000;107 (12) 2224- 2232
PubMed Link to Article
Delcourt  CCarrière  IPonton-Sanchez  AFourrey  SLacroux  APapoz  LPOLA Study Group, Light exposure and the risk of age-related macular degeneration: the Pathologies Oculaires Liées à l’Age (POLA) study. Arch Ophthalmol 2001;119 (10) 1463- 1468
PubMed Link to Article
McCarty  CAMukesh  BNFu  CLMitchell  PWang  JJTaylor  HR Risk factors for age-related maculopathy: the Visual Impairment Project. Arch Ophthalmol 2001;119 (10) 1455- 1462
PubMed Link to Article
Tomany  SCCruickshanks  KJKlein  RKlein  BEKnudtson  MD Sunlight and the 10-year incidence of age-related maculopathy: the Beaver Dam Eye Study. Arch Ophthalmol 2004;122 (5) 750- 757
PubMed Link to Article
Khan  JCShahid  HThurlby  DA  et al. Genetic Factors in AMD Study, Age related macular degeneration and sun exposure, iris colour, and skin sensitivity to sunlight. Br J Ophthalmol 2006;90 (1) 29- 32
PubMed Link to Article
Fletcher  AEBentham  GCAgnew  M  et al.  Sunlight exposure, antioxidants, and age-related macular degeneration. Arch Ophthalmol 2008;126 (10) 1396- 1403
PubMed Link to Article
Cruickshanks  KJKlein  RKlein  BENondahl  DM Sunlight and the 5-year incidence of early age-related maculopathy: the beaver dam eye study. Arch Ophthalmol 2001;119 (2) 246- 250
PubMed
Institute of Medicine, Dietary Reference Intakes for Calcium and Vitamin D.  Washington, DC The National Academy Press2011;
Mullin  GEDobs  A Vitamin d and its role in cancer and immunity: a prescription for sunlight. Nutr Clin Pract 2007;22 (3) 305- 322
PubMed Link to Article
Craig  TASommer  SSussman  CRGrande  JPKumar  R Expression and regulation of the vitamin D receptor in the zebrafish, Danio rerio. J Bone Miner Res 2008;23 (9) 1486- 1496
PubMed Link to Article
Bidmon  HJStumpf  WE 1,25-Dihydroxyvitamin D3 binding sites in the eye and associated tissues of the green lizard Anolis carolinensis. Histochem J 1995;27 (7) 516- 523
PubMed
Choi  DAppukuttan  BBinek  SJ  et al.  Prediction of cis-regulatory elements controlling genes differentially expressed by retinal and choroidal vascular endothelial cells. J Ocul Biol Dis Infor 2008;1 (1) 37- 45
PubMed Link to Article
Bernardi  RJJohnson  CSModzelewski  RATrump  DL Antiproliferative effects of 1alpha,25-dihydroxyvitamin D(3) and vitamin D analogs on tumor-derived endothelial cells. Endocrinology 2002;143 (7) 2508- 2514
PubMed
Shokravi  MTMarcus  DMAlroy  JEgan  KSaornil  MAAlbert  DM Vitamin D inhibits angiogenesis in transgenic murine retinoblastoma. Invest Ophthalmol Vis Sci 1995;36 (1) 83- 87
PubMed
Albert  DMScheef  EAWang  S  et al.  Calcitriol is a potent inhibitor of retinal neovascularization. Invest Ophthalmol Vis Sci 2007;48 (5) 2327- 2334
PubMed Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1. Characteristics of Participants in Low and High Quintiles for 25(OH)D, Assessed at Baseline, Adjusted for Month of Blood Drawa
Table Graphic Jump LocationTable 2. Energy, Nutrient Intake, and Serum Nutrient Concentrations, Assessed at Baseline in Participants in the Low and High Quintiles of 25(OH)D, Adjusted for Month of Blood Drawa
Table Graphic Jump LocationTable 3. Odds Ratios for AMD, Assessed From 2001-2004 Among Participants in Quintiles 2 Through 5 Compared With 1 for 25(OH)D, Assessed in 1993-1998
Table Graphic Jump LocationTable 4. Multivariatea Model Odds Ratios for Early AMD, Assessed From 2001-2004, of Participants Younger Than 75 Years in Quintiles 2-5 Compared With 1 for Serum 25(OH)D, Assessed in 1993-1998, Further Adjusted for Potential Dietary Confounders
Table Graphic Jump LocationTable 5. Multivariate Model Odds Ratios for Early AMD, Assessed From 2001-2004, of Participants Younger Than 75 Years Who Reported High vs Low Levels of Sunlight Exposure and High vs Low Intake of Vitamin D From Foods and Supplements, Assessed in 1993-1998

References

Resnikoff  SPascolini  DEtya’ale  D  et al.  Global data on visual impairment in the year 2002. Bull World Health Organ 2004;82 (11) 844- 851
PubMed
Klein  RRowland  MLHarris  MI Racial/ethnic differences in age-related maculopathy: Third National Health and Nutrition Examination Survey. Ophthalmology 1995;102 (3) 371- 381
PubMed Link to Article
Klein  RKlein  BEJensen  SCMeuer  SM The five-year incidence and progression of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology 1997;104 (1) 7- 21
PubMed Link to Article
Klein  RKlein  BELinton  KL Prevalence of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology 1992;99 (6) 933- 943
PubMed Link to Article
Jager  RDMieler  WFMiller  JW Age-related macular degeneration. N Engl J Med 2008;358 (24) 2606- 2617
PubMed Link to Article
Shaban  HRichter  C A2E and blue light in the retina: the paradigm of age-related macular degeneration. Biol Chem 2002;383 (3-4) 537- 545
PubMed Link to Article
Beatty  SKoh  HPhil  MHenson  DBoulton  M The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv Ophthalmol 2000;45 (2) 115- 134
PubMed Link to Article
Hageman  GSLuthert  PJVictor Chong  NHJohnson  LVAnderson  DHMullins  RF An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch's membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res 2001;20 (6) 705- 732
PubMed Link to Article
Feigl  B Age-related maculopathy: linking aetiology and pathophysiological changes to the ischaemia hypothesis. Prog Retin Eye Res 2009;28 (1) 63- 86
PubMed Link to Article
Ting  AYLee  TKMacDonald  IM Genetics of age-related macular degeneration. Curr Opin Ophthalmol 2009;20 (5) 369- 376
PubMed Link to Article
Hageman  GSAnderson  DHJohnson  LV  et al.  A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A 2005;102 (20) 7227- 7232
PubMed Link to Article
Seddon  JMReynolds  RMaller  JFagerness  JADaly  MJRosner  B Prediction model for prevalence and incidence of advanced age-related macular degeneration based on genetic, demographic, and environmental variables. Invest Ophthalmol Vis Sci 2009;50 (5) 2044- 2053
PubMed Link to Article
Thornton  JEdwards  RMitchell  PHarrison  RABuchan  IKelly  SP Smoking and age-related macular degeneration: a review of association. Eye (Lond) 2005;19 (9) 935- 944
PubMed Link to Article
Parekh  NChappell  RJMillen  AEAlbert  DMMares  JA Association between vitamin D and age-related macular degeneration in the Third National Health and Nutrition Examination Survey, 1988 through 1994. Arch Ophthalmol 2007;125 (5) 661- 669
PubMed Link to Article
Mora  JRIwata  Mvon Andrian  UH Vitamin effects on the immune system: vitamins A and D take centre stage. Nat Rev Immunol 2008;8 (9) 685- 698
Link to Article
Holick  MF Vitamin D deficiency. N Engl J Med 2007;357 (3) 266- 281
PubMed Link to Article
Moeller  SMParekh  NTinker  L  et al. CAREDS Research Study Group, Associations between intermediate age-related macular degeneration and lutein and zeaxanthin in the Carotenoids in Age-related Eye Disease Study (CAREDS): ancillary study of the Women's Health Initiative. Arch Ophthalmol 2006;124 (8) 1151- 1162
PubMed Link to Article
Moeller  SMVoland  RTinker  L  et al. CAREDS Study Group; Women's Health Initiative, Associations between age-related nuclear cataract and lutein and zeaxanthin in the diet and serum in the Carotenoids in the Age-Related Eye Disease Study, an Ancillary Study of the Women's Health Initiative. Arch Ophthalmol 2008;126 (3) 354- 364
PubMed Link to Article
Anderson  GLManson  JWallace  R  et al.  Implementation of the Women's Health Initiative study design. Ann Epidemiol 2003;13 (9) ((suppl)) S5- S17
PubMed Link to Article
Antoniucci  DMBlack  DMSellmeyer  DE Serum 25-hydroxyvitamin D is unaffected by multiple freeze-thaw cycles. Clin Chem 2005;51 (1) 258- 261
PubMed Link to Article
Ockè  MCSchrijver  JObermann-de Boer  GLBloemberg  BPHaenen  GRKromhout  D Stability of blood (pro)vitamins during four years of storage at -20 degrees C: consequences for epidemiologic research. J Clin Epidemiol 1995;48 (8) 1077- 1085
PubMed Link to Article
Agborsangaya  CToriola  ATGrankvist  K  et al.  The effects of storage time and sampling season on the stability of serum 25-hydroxy vitamin D and androstenedione. Nutr Cancer 2010;62 (1) 51- 57
PubMed Link to Article
Hartweg  JGunter  MPerera  R  et al.  Stability of soluble adhesion molecules, selectins, and C-reactive protein at various temperatures: implications for epidemiological and large-scale clinical studies. Clin Chem 2007;53 (10) 1858- 1860
PubMed Link to Article
 SAS/STAT(R) 9.2 User's Guide, 2nd ed: PROC LOESS Statement; 2009: Editioneau of the Census; 2001. SAS Web site. http://support.sas.com/documentation/cdl/en/statug/63033/HTML/default/statug_loess_sect006.htm. Accessed January 26, 2010
Age-Related Eye Disease Study Research Group, The Age-Related Eye Disease Study system for classifying age-related macular degeneration from stereoscopic color fundus photographs: the Age-Related Eye Disease Study Report Number 6. Am J Ophthalmol 2001;132 (5) 668- 681
PubMed Link to Article
Patterson  REKristal  ARTinker  LFCarter  RABolton  MPAgurs-Collins  T Measurement characteristics of the Women's Health Initiative food frequency questionnaire. Ann Epidemiol 1999;9 (3) 178- 187
PubMed Link to Article
Patterson  REKristal  ARLevy  L McLerran  DWhite  E Validity of methods used to assess vitamin and mineral supplement use. Am J Epidemiol 1998;148 (7) 643- 649
PubMed Link to Article
Patterson  RELevy  LTinker  LFKristal  AR Evaluation of a simplified vitamin supplement inventory developed for the Women's Health Initiative. Public Health Nutr 1999;2 (3) 273- 276
PubMed Link to Article
Mares  JAVoland  RAdler  R  et al. CAREDS Group, Healthy diets and the subsequent prevalence of nuclear cataract in women. Arch Ophthalmol 2010;128 (6) 738- 749
PubMed Link to Article
Duncan  DDMuñoz  BWest  SKSalisbury Eye Evaluation Project Team, Assessment of ocular exposure to visible light for population studies. Dev Ophthalmol 2002;3576- 92
PubMed
Klein  RPeto  TBird  AVannewkirk  MR The epidemiology of age-related macular degeneration. Am J Ophthalmol 2004;137 (3) 486- 495
PubMed Link to Article
Millen  AEWactawski-Wende  JPettinger  M  et al.  Predictors of serum 25-hydroxyvitamin D concentrations among postmenopausal women: the Women's Health Initiative Calcium plus Vitamin D clinical trial. Am J Clin Nutr 2010;91 (5) 1324- 1335
PubMed Link to Article
Parekh  NVoland  RPMoeller  SM  et al. CAREDS Research Study Group, Association between dietary fat intake and age-related macular degeneration in the Carotenoids in Age-Related Eye Disease Study (CAREDS): an ancillary study of the Women's Health Initiative. Arch Ophthalmol 2009;127 (11) 1483- 1493
PubMed Link to Article
Mares  JAVoland  RPSondel  SA  et al.  Healthy lifestyles related to subsequent prevalence of age-related macular degeneration [published online December 13, 2010]. Arch Ophthalmol
PubMed
LaRowe  TLMares  JASnodderly  DMKlein  MLWooten  BRChappell  RCAREDS Macular Pigment Study Group, Macular pigment density and age-related maculopathy in the Carotenoids in Age-Related Eye Disease Study: an ancillary study of the women's health initiative. Ophthalmology 2008;115 (5) 876- 883, e1
PubMed Link to Article
Kaplan  GAHaan  MNCohen  RD Risk factors and the study of prevention in the elderly: methodological issues. Wallace  RBWoolson  RFEpidemiologic Study of the Elderly. New York, NY Oxford University Press1992;20- 36
Holick  MF High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc 2006;81 (3) 353- 373
PubMed Link to Article
Bischoff-Ferrari  HAGiovannucci  EWillett  WCDietrich  TDawson-Hughes  B Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes [printed correction appears in Am J Clin Nutr. 2006;84(5):1253]. Am J Clin Nutr 2006;84 (1) 18- 28
PubMed
Holick  MF Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr 2004;80 (6) ((suppl)) 1678S- 1688S
PubMed
West  ESSchein  OD Sunlight and age-related macular degeneration. Int Ophthalmol Clin 2005;45 (1) 41- 47
PubMed Link to Article
Hyman  LGLilienfeld  AMFerris  FL  IIIFine  SL Senile macular degeneration: a case-control study. Am J Epidemiol 1983;118 (2) 213- 227
PubMed
West  SKRosenthal  FSBressler  NM  et al.  Exposure to sunlight and other risk factors for age-related macular degeneration. Arch Ophthalmol 1989;107 (6) 875- 879
PubMed Link to Article
Taylor  HRMuñoz  BWest  SBressler  NMBressler  SBRosenthal  FS Visible light and risk of age-related macular degeneration. Trans Am Ophthalmol Soc 1990;88163- 178
PubMed
The Eye Disease Case-Control Study Group, Risk factors for neovascular age-related macular degeneration. Arch Ophthalmol 1992;110 (12) 1701- 1708
PubMed Link to Article
Cruickshanks  KJKlein  RKlein  BE Sunlight and age-related macular degeneration: the Beaver Dam Eye Study. Arch Ophthalmol 1993;111 (4) 514- 518
PubMed Link to Article
Darzins  PMitchell  PHeller  RF Sun exposure and age-related macular degeneration: an Australian case-control study. Ophthalmology 1997;104 (5) 770- 776
PubMed Link to Article
Age-Related Eye Disease Study Research Group, Risk factors associated with age-related macular degeneration: a case-control study in the age-related eye disease study: age-Related Eye Disease Study Report Number 3. Ophthalmology 2000;107 (12) 2224- 2232
PubMed Link to Article
Delcourt  CCarrière  IPonton-Sanchez  AFourrey  SLacroux  APapoz  LPOLA Study Group, Light exposure and the risk of age-related macular degeneration: the Pathologies Oculaires Liées à l’Age (POLA) study. Arch Ophthalmol 2001;119 (10) 1463- 1468
PubMed Link to Article
McCarty  CAMukesh  BNFu  CLMitchell  PWang  JJTaylor  HR Risk factors for age-related maculopathy: the Visual Impairment Project. Arch Ophthalmol 2001;119 (10) 1455- 1462
PubMed Link to Article
Tomany  SCCruickshanks  KJKlein  RKlein  BEKnudtson  MD Sunlight and the 10-year incidence of age-related maculopathy: the Beaver Dam Eye Study. Arch Ophthalmol 2004;122 (5) 750- 757
PubMed Link to Article
Khan  JCShahid  HThurlby  DA  et al. Genetic Factors in AMD Study, Age related macular degeneration and sun exposure, iris colour, and skin sensitivity to sunlight. Br J Ophthalmol 2006;90 (1) 29- 32
PubMed Link to Article
Fletcher  AEBentham  GCAgnew  M  et al.  Sunlight exposure, antioxidants, and age-related macular degeneration. Arch Ophthalmol 2008;126 (10) 1396- 1403
PubMed Link to Article
Cruickshanks  KJKlein  RKlein  BENondahl  DM Sunlight and the 5-year incidence of early age-related maculopathy: the beaver dam eye study. Arch Ophthalmol 2001;119 (2) 246- 250
PubMed
Institute of Medicine, Dietary Reference Intakes for Calcium and Vitamin D.  Washington, DC The National Academy Press2011;
Mullin  GEDobs  A Vitamin d and its role in cancer and immunity: a prescription for sunlight. Nutr Clin Pract 2007;22 (3) 305- 322
PubMed Link to Article
Craig  TASommer  SSussman  CRGrande  JPKumar  R Expression and regulation of the vitamin D receptor in the zebrafish, Danio rerio. J Bone Miner Res 2008;23 (9) 1486- 1496
PubMed Link to Article
Bidmon  HJStumpf  WE 1,25-Dihydroxyvitamin D3 binding sites in the eye and associated tissues of the green lizard Anolis carolinensis. Histochem J 1995;27 (7) 516- 523
PubMed
Choi  DAppukuttan  BBinek  SJ  et al.  Prediction of cis-regulatory elements controlling genes differentially expressed by retinal and choroidal vascular endothelial cells. J Ocul Biol Dis Infor 2008;1 (1) 37- 45
PubMed Link to Article
Bernardi  RJJohnson  CSModzelewski  RATrump  DL Antiproliferative effects of 1alpha,25-dihydroxyvitamin D(3) and vitamin D analogs on tumor-derived endothelial cells. Endocrinology 2002;143 (7) 2508- 2514
PubMed
Shokravi  MTMarcus  DMAlroy  JEgan  KSaornil  MAAlbert  DM Vitamin D inhibits angiogenesis in transgenic murine retinoblastoma. Invest Ophthalmol Vis Sci 1995;36 (1) 83- 87
PubMed
Albert  DMScheef  EAWang  S  et al.  Calcitriol is a potent inhibitor of retinal neovascularization. Invest Ophthalmol Vis Sci 2007;48 (5) 2327- 2334
PubMed Link to Article

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 27

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles