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Epidemiology |

Association Between Vitamin D and Age-Related Macular Degeneration in the Third National Health and Nutrition Examination Survey, 1988 Through 1994 FREE

Niyati Parekh, PhD, RD(India); Richard J. Chappell, PhD; Amy E. Millen, PhD; Daniel M. Albert, MD; Julie A. Mares, PhD
[+] Author Affiliations

Author Affiliations: The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick (Dr Parekh); Department of Ophthalmology and Visual Sciences (Drs Parekh, Albert, and Mares) and Department of Statistics and Biostatistics (Dr Chappell), University of Wisconsin–Madison, Madison; and Department of Social and Preventive Medicine, University at Buffalo, Buffalo, NY (Dr Millen).


Section Editor: Leslie Hyman, PhD

More Author Information
Arch Ophthalmol. 2007;125(5):661-669. doi:10.1001/archopht.125.5.661.
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Published online

Objective  To evaluate the associations between levels of vitamin D (25-hydroxyvitamin D) in serum and prevalent age-related macular degeneration (AMD).

Methods and Design  Cross-sectional associations of serum vitamin D and early and advanced AMD, assessed from nonmydriatic fundus photographs, were evaluated in the third National Health and Nutrition Examination Survey, a multistage nationally representative probability sample of noninstitutionalized individuals (N = 7752; 11% with AMD).

Results  Levels of serum vitamin D were inversely associated with early AMD but not advanced AMD. The odds ratio (OR) and 95% confidence interval (CI) for early AMD among participants in the highest vs lowest quintile of serum vitamin D was 0.64 (95% CI, 0.5-0.8; P trend <.001). Exploratory analyses were conducted to evaluate associations with important food and supplemental sources of vitamin D. Milk intake was inversely associated with early AMD (OR, 0.75; 95% CI, 0.6-0.9). Fish intake was inversely associated with advanced AMD (OR, 0.41; 95% CI, 0.2-0.9). Consistent use vs nonuse of vitamin D from supplements was inversely associated with early AMD only in individuals who did not consume milk daily (early AMD: OR, 0.67; 95% CI, 0.5-0.9).

Conclusion  This study provides evidence that vitamin D may protect against AMD. Additional studies are needed to confirm these findings.

Age-related macular degeneration (AMD), a progressive degenerative condition of the retina, is the leading cause of legal blindness among older Americans. In the United States, 7 million individuals older than 40 years are diagnosed with early AMD and 1.75 million have advanced stages.1With increasing longevity, and with the projected doubling of the population aged 65 years and older by 2020, almost 3 million people will have AMD 1 unless risk for the condition is lowered with changes in diet, lifestyle, and medical treatments. High-dose antioxidants have been shown to slow progression from intermediate to late AMD,2 but long-term benefits and risks are unknown. Slowing the onset in earlier stages may further alleviate the economic burden of health care costs.

Several potential risk factors for the development and progression of AMD have been identified. The most consistent risk factors include age,3 cigarette smoking,4 hypertension,3 and family history of the disease.5 Other potential risk factors associated less consistently in previous studies include cardiovascular disease,6 sunlight exposure,3,7 and diets low in lutein and zeaxanthin8,9 or other dietary antioxidants9,10 or diets high in fats.1114 Recently, inflammation has received attention as a potential risk factor for this disease.1519 Immune components, including immunoglobulins, complement factors, and fibrinogen, have been observed to be entrapped within drusen.15,20 A major proportion of AMD cases have been identified in several independent cohorts to specific polymorphisms in the complement regulatory gene CFH (recently reviewed21,22) and implicate local inflammation and activation of the complement cascade, a mechanism in host immunologic defense in the development of drusen.23 The inflammatory nature of AMD pathogenesis is also supported by subsequently reported associations of AMD with other gene loci involved with the alternative complement pathway (Factor B) or in regions of genes suspected to be involved in cellular immunity (LOC 387715 and PLEKHA1) (as reviewed 22) and by enhanced AMD risk among persons with markers of chronic or acute inflammation and a history of smoking, which enhances inflammation.24 A number of studies suggest an anti-inflammatory role for vitamin D in vitro and in vivo.2528 There is also evidence that it reduces the proliferation of cells of the immune system.2528 Evidence suggests that an inverse relationship exists between vitamin D and several chronic conditions associated with inflammation.2932 Since histological studies confirm immune involvement in drusen biogenesis,18,33 it is possible that vitamin D may protect against AMD by virtue of its anti-inflammatory properties.

The primary purpose of this research was to examine the relationship between serum vitamin D level and prevalent AMD using the third National Health and Nutrition Examination Survey (NHANES III), 1988 through 1994. We hypothesized that participants in the highest quintile compared with the lowest quintile of serum vitamin D level would have decreased prevalent AMD. We also explored the relationships between the consumption of specific food and supplemental sources of vitamin D and the prevalence of AMD to ascertain whether they were consistent with the associations with serum vitamin D level.

STUDY POPULATION

The NHANES III, conducted by the Centers for Disease Control and Prevention, is a nationally representative stratified probability sample of the noninstitutionalized civilian population in the United States. Data were collected in 2 phases over a 6-year period between 1988 and 1994. Oversampling of non-Hispanic black individuals, Mexican American individuals, and adults aged 60 years and older was done to allow more accurate estimates for these individual subgroups. Details of sampling strategy have been described elsewhere.34

Of the targeted 14 464 participants aged 40 years and older who were eligible for the survey, 11 448 persons (79%) were interviewed. Participants with ungradeable or missing fundus photographs or missing AMD data (n = 3240); missing serum vitamin D data (n = 271); and missing serum cotinine levels (n = 185), a biomarker for smoking status; were excluded for statistical analyses. The final analyses included 7752 individuals (53% of targeted sample) and consisted of non-Hispanic white (n = 3889), non-Hispanic black (n = 1820) and Mexican American individuals (n = 1742) and people of other races and ethnicities (all Hispanics who were not Mexican American and all non-Hispanic individuals from racial groups other than white or black) (n = 301).

DEMOGRAPHIC, DIETARY, SUPPLEMENT USE, AND OTHER COVARIATE DATA

A medical examination that included blood and urine collection and fundus photography was performed.34 In the same visit, in-person interviews were conducted to obtain demographic, socioeconomic, health, supplement use, and dietary history data via both food frequency questionnaires and 24-hour dietary recalls. Race and ethnicity were self-reported by the participants.

Intake of vitamin D and other micronutrients was estimated from the 24-hour diet recall interview using food composition data from the National Coordinating Center database. Milk and fish intake was computed from responses to the food frequency questionnaire. The nonquantitative 60-item food frequency questionnaire queried intake of foods in the past 1-month period prior to the interview.35 Collection of other covariate data such as smoking and alcohol consumption were determined from the interviews and medical examinations.

COMPARISON OF PARTICIPANTS INCLUDED IN VS EXCLUDED FROM THE ANALYSES

On comparing characteristics of the participants who were included in (n = 7752) with those excluded from (n = 3696) these analyses, it was observed that those included differed from those excluded. Included participants were younger (aged 56 vs 65 years; P<.001), had a higher intake of dietary zinc (11 vs 10 mg/d; P<.001) and vitamin E (9 vs 8 mg/d; P<.001), had a lower prevalence of hypertension (47% vs 52%; P<.001), and smoked less (19% vs 23%; P<.001) compared with excluded participants.

SERUM DATA

Approximately 100 mL of whole blood was collected in evacuated containers during the medical examination held in mobile examination centers. Serum specimens were immediately frozen at −70°C and were subsequently used to estimate serum vitamin D levels within 2 weeks of collection as previously detailed.36 The NHANES III estimated serum 25-hydroxyvitamin D, the predominant form of circulating vitamin D in humans,37 using the Incstar 25(OH)D assay (now DiaSorin Inc, Stillwater, Minn) based on a radioimmunoassay method. The mean value obtained for serum vitamin D using this assay was 23.04 ng/mL (57.5 nmol/L) with a 2 SD range of 9.01 to 37.66 ng/mL (22.5-94 nmol/L).38 Serum cotinine levels were analyzed using the competitive enzyme immunoassay method. Serum C-reactive protein was quantified by latex enhanced nephelometry. Details of these procedures are described in the NHANES III manual of laboratory protocols.39

FUNDUS PHOTOGRAPHY AND GRADING

Nonmydriatic fundus photographs were taken in one eye during study visits as previously described.40 Characteristics of early AMD, large drusen and pigmentary abnormalities, and advanced AMD were identified by the University of Wisconsin Age-Related Maculopathy Grading Center.41,42 Soft drusen were defined as the presence of 1 or more drusen larger than 63 μm in diameter. Pigmentary abnormalities were defined as retinal pigment epithelial depigmentation or the presence of increased retinal pigment (presence of gray or black pigment clumps in or beneath the retina) and were graded as present or absent. Overall early AMD was defined as either the presence of soft drusen (grid area of >375 μm) or any type of drusen with pigmentary abnormalities in the absence of advanced AMD. Advanced AMD was defined as the presence of exudative macular degeneration (detachment of the neurosensory retina and/or retinal pigment epithelium, subretinal hemorrhage, retinal scarring) or geographic atrophy visualized as distinct areas with retinal pigment epithelial cells absent and areas with choroidal vessels more visible than in surrounding areas of the retina, after exclusion of mimicking retinal disorders.

STATISTICAL ANALYSES

Logistic regression analyses were performed and odds ratios (ORs) for AMD (early and advanced) were computed to examine the associations between prevalent AMD and quintile of serum vitamin D level. Odds ratios for AMD and 95% confidence intervals, adjusted for age only, were generated for overall early AMD, drusen, pigmentary abnormalities, and advanced AMD in quintiles 2 through 5 compared with quintile 1, the lowest level of serum vitamin D.

The distribution of possible risk factors for AMD were investigated by quintile of serum vitamin D level. Potential confounders tested in the model were age (continuous in years); body mass index (continuous; calculated as weight in kilograms divided by height in meters squared); cardiovascular disease (dichotomous; reported as personal history of stroke, heart attack, or angina); hypertension (dichotomous; defined as blood pressure >140/90 mm Hg or current antihypertensive medications); diabetes mellitus (dichotomous; excluding gestational diabetes); serum cotinine level (continuous in ng/mL); alcohol consumption (continuous in g/d); C-reactive protein level (continuous in mg/dL); fibrinogen level (continuous in g/L); and levels of dietary lutein and zeaxanthin, zinc, and vitamin E (continuous in mg/d). Confounders were defined as variables that changed the crude, age-adjusted ORs for AMD and serum vitamin D level by 10% or more when entered singly into the logistic regression model. The identified confounders of the relationship of AMD and serum vitamin D level were added to the final logistic regression models.

Blood vitamin D levels vary by race due to differing capacities to produce vitamin D.43 For this reason and because this sample was enriched with non-Hispanic black and Mexican American individuals who differ from non-Hispanic white individuals in age and response rates, we explored the associations of serum vitamin D level and early AMD by the 3 major race groups represented by this sample: non-Hispanic white, non-Hispanic black, and Mexican American. The NHANES III sample weights were applied in all the analyses to account for individual selection probabilities, nonresponse, and poststratification that resulted from the complex survey design. We used the jackknife replication method to obtain appropriate variance estimates in regression analyses to account for clustering, which resulted from the complex survey design in the NHANES III. All analyses were done using SAS version 9 (SAS Institute Inc, Cary, NC).

EXPLORATORY ANALYSES OF FOOD AND SUPPLEMENT SOURCES OF VITAMIN D

In separate logistic regression models, we explored the association between prevalent AMD and dietary intake of 2 concentrated food sources of vitamin D: milk and fish. Monthly servings of milk were categorized into logical consumption categories that were approximate tertiles (less than weekly, weekly to less than daily, and daily or more) and monthly servings of fish were categorized as less than bimonthly, bimonthly to weekly, and more than weekly. Individuals with missing milk and fish data were excluded from these analyses. Age-adjusted ORs were computed by frequency of intake of these foods. Correlations of milk and fish intake with serum vitamin D level were computed using Pearson correlation.

We next examined the relationship between use of vitamin D–containing supplements and AMD among consistent supplement users vs nonusers in the overall sample (n = 7752; 16% consistent supplement users) as well as among people with less than daily milk intake (n = 4531, 14% consistent supplement users). Age-adjusted ORs for AMD were computed for individuals with consistent vitamin D supplement use, defined as the consumption of greater than 200 IU (international units) per week from either vitamin D single supplements or multivitamins for at least 1 year, vs nonusers of vitamin D–containing supplements.

PARTICIPANT CHARACTERISTICS

Participant characteristics in the NHANES III were examined by quintile of serum vitamin D level (Table 1). Non-Hispanic black participants had lower serum vitamin D levels than the other racial subgroups. Individuals in the highest quintile of serum vitamin D level had higher intakes of dietary vitamin D, ω-3 fatty acids, zinc, vitamin E, and milk and lower intake of lutein and zeaxanthin. Individuals in the highest quintile of serum vitamin D level were less likely to have hypertension and diabetes. Prevalence of drusen was significantly lower among people in the highest quintile of serum vitamin D level.

Table Graphic Jump LocationTable 1. Weighted and Age-Adjusted Rates and Least Squared Means by Quintile of Serum Vitamin D Level in NHANES III Participants, 1988-1994 (n = 7752)*†
SERUM VITAMIN D

As summarized in Table 2, serum vitamin D level was inversely associated with early AMD after adjusting for age and serum cotinine level in the overall population and in non-Hispanic white participants. There was a significant decrease in odds of early AMD with increasing quintile medians for serum 25-hydroxyvitamin D level before and after adjusting for age and serum cotinine level in the overall population (P trend <.001) and among non-Hispanic white participants (P trend = .003). Relationships between serum 25-hydroxyvitamin D level and prevalent early AMD were in the same direction among non-Hispanic black and Mexican American individuals but were not statistically significant. In the crude and adjusted models for the overall population, there was also a statistically significant trend for decreasing odds of drusen with increasing quintile medians for serum 25-hydroxyvitamin D level. Relationships between serum 25-hydroxyvitamin D level and drusen were also in the same direction among specific ethnic groups but not statistically significant (data not shown). There were no associations observed between serum vitamin D level and risk for pigmentary abnormalities or advanced AMD. Further adjustment for sex and other covariates did not influence the ORs. Interactions for race, sex, and age were not significant (data not shown).

Table Graphic Jump LocationTable 2. Adjusted Odds Ratios and 95% Confidence Intervals for AMD in the NHANES III (1988-1994) by Quintiles of Serum Vitamin D Level in the Overall Population and by Race*†
MILK AND FISH CONSUMPTION

We explored the relationship between food sources rich in vitamin D and risk of AMD. Milk consumption was positively correlated with serum vitamin D level (Pearson correlation coefficient, 0.2; P<.001). As seen in Table 3reported intake of weekly to daily consumption of milk per month compared with less frequent consumption of milk was inversely associated with early AMD and drusen but not pigmentary abnormalities before and after adjusting for age and race.Odds ratios for early AMD associated with daily or greater consumption of milk were also less than 1 and statistically significant. Associations were in the same direction for advanced AMD but were not statistically significant.

Table Graphic Jump LocationTable 3. Odds Ratios and 95% Confidence Intervals for Early AMD and Advanced AMD Among Participants Aged 40 Years and Older in High vs Low Milk and Fish Intake Groups in the NHANES III, 1988-1994*†

Inverse associations were observed for drusen in individuals who consumed fish bimonthly to weekly compared with those who consumed fish less frequently. Odds ratios were in a similar direction for drusen in individuals who consumed fish weekly or more but were marginally significant. Fish consumption was not related to pigmentary abnormalities and overall early AMD. Weekly or greater consumption of fish was inversely associated with advanced AMD. However, reported fish intake was not significantly correlated with serum vitamin D level in this population (r = 0.02; P = .10). The frequency of consumption of this rich source of vitamin D was low. Approximately half of the population consumed fish weekly or more, often with the median intake of 4-monthly servings among these individuals.

SUPPLEMENT USE

Consistent use of vitamin D–containing supplements was not associated with early AMD in the overall population (data not shown). However, consistent users of vitamin D–containing supplements in a subgroup of people consuming less than one serving of milk daily had decreased prevalent early AMD (Table 4). Associations were similar for drusen and pigmentary abnormalities but were not statistically significant.

Table Graphic Jump LocationTable 4. Odds Ratios and 95% Confidence Intervals for Early AMD and Advanced AMD by Consistent Supplement Use Among People Consuming Milk Less Than Daily*†
SUNLIGHT

There are no estimates of sunlight exposure in the NHANES III to explore associations with this source of vitamin D alone. However, we explored relationships of serum vitamin D level to AMD after excluding persons who reported consuming milk at least daily and people who reported to consistently use vitamin D in supplements. This left a sample of people for whom endogenous vitamin D would represent the predominant source. In this sample, odds for early AMD were significantly lower among people in the highest vs lowest quintile for serum vitamin D level (Table 5). Associations were similar for soft drusen. There were too few cases of advanced AMD or pigmentary abnormalities to conduct exploratory analyses with these outcomes.

Table Graphic Jump LocationTable 5. Odds Ratios and 95% Confidence Intervals for Early AMD and Drusen in NHANES III (1988-1994) in People Who Neither Reported Daily Milk Drinking Nor Consistently Used Vitamin D–Containing Supplements (n = 3895) by Quintile of Serum Vitamin D Level*†

We observed evidence of an inverse association between vitamin D status and the prevalence of early AMD. Higher serum vitamin D levels were inversely associated with prevalent early AMD and with soft drusen specifically in the American population aged 40 years and older. These associations were consistent across all 3 major ethnic groups, although not statistically significant in non-Hispanic black and Mexican American individuals for whom sample sizes were considerably smaller. We observed no associations of serum vitamin D level with pigmentary abnormalities or with advanced AMD. This might reflect less reliable ORs for these less common and more advanced end points or might indicate that vitamin D level is more specifically related to the formation of drusen.

We speculate that vitamin D may reduce the risk of AMD by its anti-inflammatory properties. Several putative mechanisms support the anti-inflammatory role of vitamin D. Studies have reported that vitamin D decreases proliferation of T helper cells,44 T cytotoxic cells, and natural killer cells45 and enhances T suppressor cell activity.30 Vitamin D also decreases the production of proinflammatory agents such as IL-2,25,28 IL-6,46 IL-8,26 and IL-12.27 In addition, a recent study has shown that vitamin D intake reduces C-reactive protein, a marker of systemic inflammation.47

There is laboratory and epidemiologic evidence of inflammation underlying AMD pathology. A common polymorphism in complement factor H, a key regulator of the alternate complement pathway identified in a region of a gene responsible for binding heparin and C-reactive protein, was associated with higher risk for AMD in several previous studies.21,4851 Using histological methods, Anderson et al20 identified immuno-proteins entrapped within drusen, implying local inflammation, and Hageman et al33 proposed a mechanism by which local inflammation may contribute to drusen development. Associations between markers of inflammation (such as C-reactive protein) and AMD have been observed in some52,53 but not all54 previous epidemiological studies. Anti-inflammatory drug use was significantly related to AMD in one study55 but not other previous studies.56,57 Recently results of the Beaver Dam Eye Study19 indicated an association between histories of gout and emphysema, two diseases associated with inflammation, and intermediate and late stages of AMD.19

Alternatively, vitamin D might protect against AMD by virtue of its antiangiogenic properties. There is recent evidence of vitamin D being a potent inhibitor of angiogenesis by its effects on endothelial cells5860 and by interrupting signaling pathways that are key to angiogenesis, specifically in tumorigenesis. We speculate that by virtue of its antiangiogenic role, vitamin D may protect against “wet” advanced AMD, which involves growth of new blood vessels in the retina. Since we had few cases of wet advanced AMD, we were not able to examine the associations of serum vitamin D level and advanced AMD. However, further research on advanced AMD and disease progression is warranted due to the biological plausibility of this association.

Vitamin D is provided in some foods and is made endogenously on exposure to sunlight. The serum levels of 25-hydroxyvitamin D assessed in this study reflect vitamin D from all sources combined. Observations in this study are consistent with the idea of lower risk for early AMD only among people who are exposed to 3 main sources of vitamin D: milk, supplements, and sunlight. Milk consumption was associated with lower odds for AMD. Consistent supplement use was inversely associated with AMD among people who did not consume at least 1 daily serving of milk. However, supplement use was not associated with AMD in people who consume milk daily. Milk is a rich source of vitamin D since all fluid milk in the United States is fortified with vitamin D with 400 IU added to a quart or 946 mL of milk.61 We can speculate that supplement use may not be necessary to lower risk for AMD if vitamin D is obtained through diet. Finally, after excluding people whose usual daily intake of vitamin D is likely to be below 100 IU (Table 5), because of not drinking milk or taking supplements containing vitamin D regularly, serum vitamin D level in the highest vs lowest quintile was associated with 40% lower risk for early AMD. This observation is consistent with the idea that higher serum vitamin D derived from sunlight could be associated with lower risk for AMD.

Fish can be a rich source of vitamin D and may be protective against AMD. In this study population, fish intake was not correlated with serum vitamin D level, possibly due to a low frequency of fish consumption. Another reason we did not have observed associations with high fish intake and early AMD may be because we were not able to distinguish between fatty fish, a rich source of vitamin D, and other fish, which may contain lower levels of vitamin D. We report modest inverse associations of drusen with consumption of fish intake at least once a week. Consistent with the previous NHANES III62 and findings of 4 previous epidemiological studies,1214,63 we observed inverse associations of advanced AMD with higher fish consumption. The protective effects of fish on AMD may be explained in part by its high concentration of ω-3 fatty acids, which may modulate the release of proinflammatory cytokines.64

Our results support the idea that lower serum vitamin D levels may lead to progression of chronic diseases, specifically those associated with inflammation.2932,65 This may be important to the health of older Americans. Studies have reported a strikingly high incidence of insufficient vitamin D intake in the US population and recognize inadequate vitamin D status as a public health problem.66,67 Looker et al68 reported that in summer months, about 21% to 49% of NHANES III participants living at higher altitudes were vitamin D insufficient and had serum vitamin D levels of less than 25 ng/mL (62.5 nmol/L) with 1% to 3% adults being deficient. Consequently, because poor dietary choices and sun avoidance behavior persist, attention to the health effects of vitamin D insufficiency is warranted. Furthermore, vitamin D availability and metabolism declines with age,69 which enhances the concern in older adults.

Several potential limitations of the present investigation must be considered in drawing conclusions from the results. In particular, AMD was ascertained only in one eye, resulting in a possible underestimation of AMD cases; however, studies have shown that AMD development is typically symmetric.40 Further, AMD was identified using nonmydriatic fundus photography without dilating the pupils, which may have lead to potential misclassification of cases. In estimating milk and fish intake, the food frequency questionnaire used in this study was not validated and the measurement error was unknown. The serum 25-hydroxyvitamin D values would reflect sun exposure and food intake over recent weeks, rather than years, which would have enhanced random measurement error. Therefore, associations reported are likely to be biased toward the null. Next, the results of this study may be influenced by unknown or unmeasured risk or protective factors for AMD that are more common among persons with high compared with low serum levels of vitamin D. For example, family history of AMD, which was not ascertained in the current study, is known to influence AMD prevalence.5,70 Also, high blood vitamin D levels may be related to other unknown and unmeasured healthy lifestyles that protect against AMD. Finally, the cross-sectional study design limited the ability to assess whether vitamin D was antecedent to the development of AMD. The results of our study provide strong support for further investigation of this hypothesis.

The strategy of blood collection in the NHANES III may be a potential source of bias and may affect the interpretation of serum 25-hydroxyvitamin D levels. Blood sampling in the NHANES III was carried out in a mobile examination center to control examination conditions nationwide. Blood was collected in the northern states during summer and in the southern states during winter. However, we found that median serum vitamin D levels of the 2 seasonal subpopulations were not statistically different (data not shown). Additionally, there is no existing evidence that AMD prevalence varies with latitude. Due to the blood collection strategy in the NHANES III, we were unable to examine vitamin D level in relation to AMD in individuals who live in the northern United States, a group that is likely have the lowest vitamin D levels. Moreover, because the NHANES III consisted of individuals who were free living, we were unable to evaluate the relationship of vitamin D level and AMD in the institutionalized population, who may be at a high risk for AMD due to the presence of comorbidities such as atherosclerosis or hypertension, 2 postulated risk factors of AMD, in addition to the possibility of low sunlight exposure.

In conclusion, the present study conducted in a large, representative sample of the US population provides evidence for inverse associations between AMD and higher serum vitamin D levels and higher intake of milk. We also observed reduced prevalence of AMD among consistent vitamin D–supplement users who consumed milk less than daily. However, at this time there is insufficient epidemiologic evidence of the relationship between vitamin D level and AMD to make recommendations regarding optimum serum vitamin D levels or milk and fish intake to protect against AMD or its progression. The results of the present research warrant further investigation for confirmation of the vitamin D–AMD association in other population studies.

Correspondence: Julie A. Mares, PhD, Department of Ophthalmology and Visual Sciences, School of Medicine and Public Health, University of Wisconsin–Madison, Room 1063 WARF, 610 N Walnut St, Madison, WI 53726-2336 (jmarespe@wisc.edu).

Submitted for Publication: July 22, 2005; final revision received August 15, 2006; accepted September 7, 2006.

Financial Disclosure: None reported.

Funding/Support: This research was supported by grants EY13018 and 11722 from the National Institutes of Health, by Research to Prevent Blindness, Inc, and by the Retina Research Foundation.

Acknowledgment: We thank Drs Ronald and Barbara Klein and staff for grading the fundus photographs in the third National Health and Nutrition Examination Survey (NHANES III), which made this research possible. We thank the staff and participants of the NHANES III.

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Manolagas  SCProvvedini  DMMurray  EJTsoukas  CDDeftos  LJ The antiproliferative effect of calcitriol on human peripheral blood mononuclear cells. J Clin Endocrinol Metab 1986;63394- 400
PubMed Link to Article
Takahashi  KHoriuchi  HOhta  TKomoriya  KOhmori  HKamimura  T 1 alpha,25-dihydroxyvitamin D3 suppresses interleukin-1beta-induced interleukin-8 production in human whole blood: an involvement of erythrocytes in the inhibition. Immunopharmacol Immunotoxicol 2002;241- 15
PubMed Link to Article
D’Ambrosio  DCippitelli  MCocciolo  MG  et al.  Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3: involvement of NF-kappaB downregulation in transcriptional repression of the p40 gene. J Clin Invest 1998;101252- 262
PubMed Link to Article
Muller  KGram  JBollerslev  J  et al.  Down-regulation of monocyte functions by treatment of healthy adults with 1 alpha,25 dihydroxyvitamin D3. Int J Immunopharmacol 1991;13525- 530
PubMed Link to Article
Holick  MF Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr 2004;79362- 371
PubMed
Hayes  CENashold  FESpach  KMPedersen  LB The immunological functions of the vitamin D endocrine system. Cell Mol Biol (Noisy-le-grand) 2003;49277- 300
PubMed
Zhang  ABZheng  SSJia  CKWang  Y Role of 1,25-dihydroxyvitamin D3 in preventing acute rejection of allograft following rat orthotopic liver transplantation. Chin Med J (Engl) 2004;117408- 412
PubMed
Merlino  LACurtis  JMikuls  TRCerhan  JRCriswell  LASaag  KG Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women's Health Study. Arthritis Rheum 2004;5072- 77
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;20705- 732
PubMed Link to Article
Ezzati  TMMassey  JTWaksberg  JChu  AMaurer  KR Sample design: Third National Health and Nutrition Examination Survey. Vital Health Stat 2 1992; ((113)) 1- 35
PubMed
 NHANES III reference manuals and reports [CD-ROM]. United States Department of Health and Human Services; National Center for Health Statistics Hyattsville, Md Centers for Disease Control and Prevention 1996;
Gunter  EWLBKoncikowski  SM Laboratory Procedures Used for the Third National Health and Nutrition Examination Survey, 1988-1994: NHANES III Reference Manuals and Reports.  Hyattsville, Md Centers for Disease Control and Prevention 1996;
Holick  MF The use and interpretation of assays for vitamin D and its metabolites. J Nutr 1990;120 ((suppl 11)) 1464- 1469
PubMed
 25-hydroxyvitamin D 125I RIA kit instruction manual (68100E).  Stillwater, Minn DiaSorin Inc 2004;
Gunter  EWLewis  BLKoncikowski  SM Laboratory methods used for the third National Health and Nutrition Examination Survey (NHANES III), 1988-1994 [CD-ROM].  Hyattsville, Md Centers for Disease Control and Prevention 1996;
Klein  RKlein  BEJensen  SCMares-Perlman  JACruickshanks  KJPalta  M Age-related maculopathy in a multiracial United States population: the National Health and Nutrition Examination Survey III. Ophthalmology 1999;1061056- 1065
PubMed Link to Article
Klein  RMeuer  SMMoss  SEKlein  BENeider  MWReinke  J Detection of age-related macular degeneration using a nonmydriatic digital camera and a standard film fundus camera. Arch Ophthalmol 2004;1221642- 1646
PubMed Link to Article
Klein  RDavis  MDMagli  YLSegal  PKlein  BEHubbard  L The Wisconsin age-related maculopathy grading system. Ophthalmology 1991;981128- 1134
PubMed Link to Article
Dawson-Hughes  B Racial/ethnic considerations in making recommendations for vitamin D for adult and elderly men and women. Am J Clin Nutr 2004;80 ((suppl)) 1763S- 1766S
PubMed
Topilski  IFlaishon  LNaveh  YHarmelin  ALevo  YShachar  I The anti-inflammatory effects of 1,25-dihydroxyvitamin D3 on Th2 cells in vivo are due in part to the control of integrin-mediated T lymphocyte homing. Eur J Immunol 2004;341068- 1076
PubMed Link to Article
Thomasset  M Vitamin D and the immune system [in French]. Pathol Biol (Paris) 1994;42163- 172
PubMed
Lefebvre d’Hellencourt  CMontero-Menei  CNBernard  RCouez  D Vitamin D3 inhibits proinflammatory cytokines and nitric oxide production by the EOC13 microglial cell line. J Neurosci Res 2003;71575- 582
PubMed Link to Article
Timms  PMMannan  NHitman  GA  et al.  Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders? QJM 2002;95787- 796
PubMed Link to Article
Sepp  TKhan  JCThurlby  DA  et al.  Complement factor H variant Y402H is a major risk determinant for geographic atrophy and choroidal neovascularization in smokers and nonsmokers. Invest Ophthalmol Vis Sci 2006;47536- 540
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;1027227- 7232
PubMed Link to Article
Zareparsi  SBranham  KELi  M  et al.  Strong association of the Y402H variant in complement factor H at 1q32 with susceptibility to age-related macular degeneration. Am J Hum Genet 2005;77149- 153
PubMed Link to Article
Klein  RJZeiss  CChew  EY  et al.  Complement factor H polymorphism in age-related macular degeneration. Science 2005;308385- 389
PubMed Link to Article
Seddon  JMGeorge  SRosner  BRifai  N Progression of age-related macular degeneration: prospective assessment of C-reactive protein, interleukin 6, and other cardiovascular biomarkers. Arch Ophthalmol 2005;123774- 782
PubMed Link to Article
Seddon  JMGensler  GMilton  RCKlein  MLRifai  N Association between C-reactive protein and age-related macular degeneration. JAMA 2004;291704- 710
PubMed Link to Article
Klein  RKlein  BEMarino  EK  et al.  Early age-related maculopathy in the cardiovascular health study. Ophthalmology 2003;11025- 33
PubMed Link to Article
Clemons  TEMilton  RCKlein  RSeddon  JMFerris  FL  III Risk factors for the incidence of Advanced Age-Related Macular Degeneration in the Age-Related Eye Disease Study (AREDS) AREDS report no. 19. Ophthalmology 2005;112533- 539
PubMed Link to Article
Klein  RKlein  BEJensen  SC  et al.  Medication use and the 5-year incidence of early age-related maculopathy: the Beaver Dam Eye Study. Arch Ophthalmol 2001;1191354- 1359
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;1072224- 2232
PubMed Link to Article
Shokravi  MTMarcus  DMAlroy  JEgan  KSaornil  MAAlbert  DM Vitamin D inhibits angiogenesis in transgenic murine retinoblastoma. Invest Ophthalmol Vis Sci 1995;3683- 87
PubMed
Iseki  KTatsuta  MUehara  H  et al.  Inhibition of angiogenesis as a mechanism for inhibition by 1alpha-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 of colon carcinogenesis induced by azoxymethane in Wistar rats. Int J Cancer 1999;81730- 733
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;1432508- 2514
PubMed
Calvo  MSWhiting  SJBarton  CN Vitamin D fortification in the United States and Canada: current status and data needs. Am J Clin Nutr 2004;80 ((suppl)) 1710S- 1716S
PubMed
Heuberger  RAMares-Perlman  JAKlein  RKlein  BEMillen  AEPalta  M Relationship of dietary fat to age-related maculopathy in the Third National Health and Nutrition Examination Survey. Arch Ophthalmol 2001;1191833- 1838
PubMed Link to Article
Cho  EHung  SWillett  WC  et al.  Prospective study of dietary fat and the risk of age-related macular degeneration. Am J Clin Nutr 2001;73209- 218
PubMed
Trebble  TMArden  NKWootton  SA  et al.  Fish oil and antioxidants alter the composition and function of circulating mononuclear cells in Crohn disease. Am J Clin Nutr 2004;801137- 1144
PubMed
Schulte  CM Review article: bone disease in inflammatory bowel disease. Aliment Pharmacol Ther 2004;20 ((suppl 4)) 43- 49
PubMed Link to Article
Tangpricha  VColon  NAKaul  H  et al.  Prevalence of vitamin D deficiency in patients attending an outpatient cancer care clinic in Boston. Endocr Pract 2004;10292- 293
PubMed Link to Article
Moore  CMurphy  MMKeast  DRHolick  MF Vitamin D intake in the United States. J Am Diet Assoc 2004;104980- 983
PubMed Link to Article
Looker  ACDawson-Hughes  BCalvo  MSGunter  EWSahyoun  NR Serum 25-hydroxyvitamin D status of adolescents and adults in two seasonal subpopulations from NHANES III. Bone 2002;30771- 777
PubMed Link to Article
MacLaughlin  JHolick  MF Aging decreases the capacity of human skin to produce vitamin D3. J Clin Invest 1985;761536- 1538
PubMed Link to Article
Smith  WMitchell  P Family history and age-related maculopathy: the Blue Mountains Eye Study. Aust N Z J Ophthalmol 1998;26203- 206
PubMed Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1. Weighted and Age-Adjusted Rates and Least Squared Means by Quintile of Serum Vitamin D Level in NHANES III Participants, 1988-1994 (n = 7752)*†
Table Graphic Jump LocationTable 2. Adjusted Odds Ratios and 95% Confidence Intervals for AMD in the NHANES III (1988-1994) by Quintiles of Serum Vitamin D Level in the Overall Population and by Race*†
Table Graphic Jump LocationTable 3. Odds Ratios and 95% Confidence Intervals for Early AMD and Advanced AMD Among Participants Aged 40 Years and Older in High vs Low Milk and Fish Intake Groups in the NHANES III, 1988-1994*†
Table Graphic Jump LocationTable 4. Odds Ratios and 95% Confidence Intervals for Early AMD and Advanced AMD by Consistent Supplement Use Among People Consuming Milk Less Than Daily*†
Table Graphic Jump LocationTable 5. Odds Ratios and 95% Confidence Intervals for Early AMD and Drusen in NHANES III (1988-1994) in People Who Neither Reported Daily Milk Drinking Nor Consistently Used Vitamin D–Containing Supplements (n = 3895) by Quintile of Serum Vitamin D Level*†

References

Friedman  DSO’Colmain  BJMunoz  B  et al.  Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 2004;122564- 572
PubMed Link to Article
Age-Related Eye Disease Study Research Group, A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 2001;1191417- 1436
PubMed Link to Article
Klein  RPeto  TBird  AVannewkirk  MR The epidemiology of age-related macular degeneration. Am J Ophthalmol 2004;137486- 495
PubMed Link to Article
Mitchell  PWang  JJSmith  WLeeder  SR Smoking and the 5-year incidence of age-related maculopathy: the Blue Mountains Eye Study. Arch Ophthalmol 2002;1201357- 1363
PubMed Link to Article
Klein  MLMauldin  WMStoumbos  VD Heredity and age-related macular degeneration: observations in monozygotic twins. Arch Ophthalmol 1994;112932- 937
PubMed Link to Article
Vingerling  JRDielemans  IBots  MLHofman  AGrobbee  DEde Jong  PT Age-related macular degeneration is associated with atherosclerosis: the Rotterdam Study. Am J Epidemiol 1995;142404- 409
PubMed
Taylor  HRWest  SMunoz  BRosenthal  FSBressler  SBBressler  NM The long-term effects of visible light on the eye. Arch Ophthalmol 1992;11099- 104
PubMed Link to Article
Mares  J Carotenoids and eye disease: epidemiologic evidence. Krinsky  NIMayne  SedsCarotenoids in Health and Disease. New York, NY Marcel Dekker Inc2003;19
Mares-Perlman  JAMillen  AEFicek  TLHankinson  SE The body of evidence to support a protective role for lutein and zeaxanthin in delaying chronic disease. J Nutr 2002;132518S- 524S
PubMed
van Leeuwen  RBoekhoorn  SVingerling  JR  et al.  Dietary intake of antioxidants and risk of age-related macular degeneration. JAMA 2005;2943101- 3107
PubMed Link to Article
Mares-Perlman  JABrady  WEKlein  RVandenLangenberg  GMKlein  BEPalta  M Dietary fat and age-related maculopathy. Arch Ophthalmol 1995;113743- 748
PubMed Link to Article
Smith  WMitchell  PLeeder  SR Dietary fat and fish intake and age-related maculopathy. Arch Ophthalmol 2000;118401- 404
PubMed Link to Article
Seddon  JMCote  JRosner  B Progression of age-related macular degeneration: association with dietary fat, transunsaturated fat, nuts, and fish intake. Arch Ophthalmol 2003;1211728- 1737
PubMed Link to Article
Seddon  JMRosner  BSperduto  RD  et al.  Dietary fat and risk for advanced age-related macular degeneration. Arch Ophthalmol 2001;1191191- 1199
PubMed Link to Article
Johnson  LVOzaki  SStaples  MKErickson  PAAnderson  DH A potential role for immune complex pathogenesis in drusen formation. Exp Eye Res 2000;70441- 449
PubMed Link to Article
Smith  WMitchell  PLeeder  SRWang  JJ Plasma fibrinogen levels, other cardiovascular risk factors, and age-related maculopathy: the Blue Mountains Eye Study. Arch Ophthalmol 1998;116583- 587
PubMed Link to Article
Johnson  LVLeitner  WPStaples  MKAnderson  DH Complement activation and inflammatory processes in Drusen formation and age related macular degeneration. Exp Eye Res 2001;73887- 896
PubMed Link to Article
Wirostko  EWirostko  WJWirostko  BM Age-related macular degeneration is an inflammatory disease possibly treatable with minocycline. Acta Ophthalmol Scand 2004;82243- 244
PubMed Link to Article
Klein  RKlein  BETomany  SCCruickshanks  KJ Association of emphysema, gout, and inflammatory markers with long-term incidence of age-related maculopathy. Arch Ophthalmol 2003;121674- 678
PubMed Link to Article
Anderson  DHMullins  RFHageman  GSJohnson  LV A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol 2002;134411- 431
PubMed Link to Article
Haddad  SChen  CASantangelo  SLSeddon  JM The genetics of age-related macular degeneration: a review of progress to date. Surv Ophthalmol 2006;51316- 363
PubMed Link to Article
Gorin  MB A clinician's view of the molecular genetics of age-related maculopathy. Arch Ophthalmol 2007;12521- 29
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;1027227- 7232
PubMed Link to Article
Despriet  DDKlaver  CCWitteman  JC  et al.  Complement factor H polymorphism, complement activators, and risk of age-related macular degeneration. JAMA 2006;296301- 309
PubMed Link to Article
Manolagas  SCProvvedini  DMMurray  EJTsoukas  CDDeftos  LJ The antiproliferative effect of calcitriol on human peripheral blood mononuclear cells. J Clin Endocrinol Metab 1986;63394- 400
PubMed Link to Article
Takahashi  KHoriuchi  HOhta  TKomoriya  KOhmori  HKamimura  T 1 alpha,25-dihydroxyvitamin D3 suppresses interleukin-1beta-induced interleukin-8 production in human whole blood: an involvement of erythrocytes in the inhibition. Immunopharmacol Immunotoxicol 2002;241- 15
PubMed Link to Article
D’Ambrosio  DCippitelli  MCocciolo  MG  et al.  Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3: involvement of NF-kappaB downregulation in transcriptional repression of the p40 gene. J Clin Invest 1998;101252- 262
PubMed Link to Article
Muller  KGram  JBollerslev  J  et al.  Down-regulation of monocyte functions by treatment of healthy adults with 1 alpha,25 dihydroxyvitamin D3. Int J Immunopharmacol 1991;13525- 530
PubMed Link to Article
Holick  MF Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr 2004;79362- 371
PubMed
Hayes  CENashold  FESpach  KMPedersen  LB The immunological functions of the vitamin D endocrine system. Cell Mol Biol (Noisy-le-grand) 2003;49277- 300
PubMed
Zhang  ABZheng  SSJia  CKWang  Y Role of 1,25-dihydroxyvitamin D3 in preventing acute rejection of allograft following rat orthotopic liver transplantation. Chin Med J (Engl) 2004;117408- 412
PubMed
Merlino  LACurtis  JMikuls  TRCerhan  JRCriswell  LASaag  KG Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women's Health Study. Arthritis Rheum 2004;5072- 77
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;20705- 732
PubMed Link to Article
Ezzati  TMMassey  JTWaksberg  JChu  AMaurer  KR Sample design: Third National Health and Nutrition Examination Survey. Vital Health Stat 2 1992; ((113)) 1- 35
PubMed
 NHANES III reference manuals and reports [CD-ROM]. United States Department of Health and Human Services; National Center for Health Statistics Hyattsville, Md Centers for Disease Control and Prevention 1996;
Gunter  EWLBKoncikowski  SM Laboratory Procedures Used for the Third National Health and Nutrition Examination Survey, 1988-1994: NHANES III Reference Manuals and Reports.  Hyattsville, Md Centers for Disease Control and Prevention 1996;
Holick  MF The use and interpretation of assays for vitamin D and its metabolites. J Nutr 1990;120 ((suppl 11)) 1464- 1469
PubMed
 25-hydroxyvitamin D 125I RIA kit instruction manual (68100E).  Stillwater, Minn DiaSorin Inc 2004;
Gunter  EWLewis  BLKoncikowski  SM Laboratory methods used for the third National Health and Nutrition Examination Survey (NHANES III), 1988-1994 [CD-ROM].  Hyattsville, Md Centers for Disease Control and Prevention 1996;
Klein  RKlein  BEJensen  SCMares-Perlman  JACruickshanks  KJPalta  M Age-related maculopathy in a multiracial United States population: the National Health and Nutrition Examination Survey III. Ophthalmology 1999;1061056- 1065
PubMed Link to Article
Klein  RMeuer  SMMoss  SEKlein  BENeider  MWReinke  J Detection of age-related macular degeneration using a nonmydriatic digital camera and a standard film fundus camera. Arch Ophthalmol 2004;1221642- 1646
PubMed Link to Article
Klein  RDavis  MDMagli  YLSegal  PKlein  BEHubbard  L The Wisconsin age-related maculopathy grading system. Ophthalmology 1991;981128- 1134
PubMed Link to Article
Dawson-Hughes  B Racial/ethnic considerations in making recommendations for vitamin D for adult and elderly men and women. Am J Clin Nutr 2004;80 ((suppl)) 1763S- 1766S
PubMed
Topilski  IFlaishon  LNaveh  YHarmelin  ALevo  YShachar  I The anti-inflammatory effects of 1,25-dihydroxyvitamin D3 on Th2 cells in vivo are due in part to the control of integrin-mediated T lymphocyte homing. Eur J Immunol 2004;341068- 1076
PubMed Link to Article
Thomasset  M Vitamin D and the immune system [in French]. Pathol Biol (Paris) 1994;42163- 172
PubMed
Lefebvre d’Hellencourt  CMontero-Menei  CNBernard  RCouez  D Vitamin D3 inhibits proinflammatory cytokines and nitric oxide production by the EOC13 microglial cell line. J Neurosci Res 2003;71575- 582
PubMed Link to Article
Timms  PMMannan  NHitman  GA  et al.  Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders? QJM 2002;95787- 796
PubMed Link to Article
Sepp  TKhan  JCThurlby  DA  et al.  Complement factor H variant Y402H is a major risk determinant for geographic atrophy and choroidal neovascularization in smokers and nonsmokers. Invest Ophthalmol Vis Sci 2006;47536- 540
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;1027227- 7232
PubMed Link to Article
Zareparsi  SBranham  KELi  M  et al.  Strong association of the Y402H variant in complement factor H at 1q32 with susceptibility to age-related macular degeneration. Am J Hum Genet 2005;77149- 153
PubMed Link to Article
Klein  RJZeiss  CChew  EY  et al.  Complement factor H polymorphism in age-related macular degeneration. Science 2005;308385- 389
PubMed Link to Article
Seddon  JMGeorge  SRosner  BRifai  N Progression of age-related macular degeneration: prospective assessment of C-reactive protein, interleukin 6, and other cardiovascular biomarkers. Arch Ophthalmol 2005;123774- 782
PubMed Link to Article
Seddon  JMGensler  GMilton  RCKlein  MLRifai  N Association between C-reactive protein and age-related macular degeneration. JAMA 2004;291704- 710
PubMed Link to Article
Klein  RKlein  BEMarino  EK  et al.  Early age-related maculopathy in the cardiovascular health study. Ophthalmology 2003;11025- 33
PubMed Link to Article
Clemons  TEMilton  RCKlein  RSeddon  JMFerris  FL  III Risk factors for the incidence of Advanced Age-Related Macular Degeneration in the Age-Related Eye Disease Study (AREDS) AREDS report no. 19. Ophthalmology 2005;112533- 539
PubMed Link to Article
Klein  RKlein  BEJensen  SC  et al.  Medication use and the 5-year incidence of early age-related maculopathy: the Beaver Dam Eye Study. Arch Ophthalmol 2001;1191354- 1359
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;1072224- 2232
PubMed Link to Article
Shokravi  MTMarcus  DMAlroy  JEgan  KSaornil  MAAlbert  DM Vitamin D inhibits angiogenesis in transgenic murine retinoblastoma. Invest Ophthalmol Vis Sci 1995;3683- 87
PubMed
Iseki  KTatsuta  MUehara  H  et al.  Inhibition of angiogenesis as a mechanism for inhibition by 1alpha-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 of colon carcinogenesis induced by azoxymethane in Wistar rats. Int J Cancer 1999;81730- 733
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;1432508- 2514
PubMed
Calvo  MSWhiting  SJBarton  CN Vitamin D fortification in the United States and Canada: current status and data needs. Am J Clin Nutr 2004;80 ((suppl)) 1710S- 1716S
PubMed
Heuberger  RAMares-Perlman  JAKlein  RKlein  BEMillen  AEPalta  M Relationship of dietary fat to age-related maculopathy in the Third National Health and Nutrition Examination Survey. Arch Ophthalmol 2001;1191833- 1838
PubMed Link to Article
Cho  EHung  SWillett  WC  et al.  Prospective study of dietary fat and the risk of age-related macular degeneration. Am J Clin Nutr 2001;73209- 218
PubMed
Trebble  TMArden  NKWootton  SA  et al.  Fish oil and antioxidants alter the composition and function of circulating mononuclear cells in Crohn disease. Am J Clin Nutr 2004;801137- 1144
PubMed
Schulte  CM Review article: bone disease in inflammatory bowel disease. Aliment Pharmacol Ther 2004;20 ((suppl 4)) 43- 49
PubMed Link to Article
Tangpricha  VColon  NAKaul  H  et al.  Prevalence of vitamin D deficiency in patients attending an outpatient cancer care clinic in Boston. Endocr Pract 2004;10292- 293
PubMed Link to Article
Moore  CMurphy  MMKeast  DRHolick  MF Vitamin D intake in the United States. J Am Diet Assoc 2004;104980- 983
PubMed Link to Article
Looker  ACDawson-Hughes  BCalvo  MSGunter  EWSahyoun  NR Serum 25-hydroxyvitamin D status of adolescents and adults in two seasonal subpopulations from NHANES III. Bone 2002;30771- 777
PubMed Link to Article
MacLaughlin  JHolick  MF Aging decreases the capacity of human skin to produce vitamin D3. J Clin Invest 1985;761536- 1538
PubMed Link to Article
Smith  WMitchell  P Family history and age-related maculopathy: the Blue Mountains Eye Study. Aust N Z J Ophthalmol 1998;26203- 206
PubMed Link to Article

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