Association of vitamin D with incident glaucoma: findings from the Women’s Health Initiative
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* Laura D Carbone
* Karen Johnson
* Joseph C Larson
* Fridtjof Thomas
* Jean Wactawski-Wende
* Kathryn Bollinger
* Zhao Chen
* Mitchell Watsky

## Abstract

The relationship between vitamin D and glaucoma is controversial. The objective of this study was to examine women from the Women’s Health Initiative (WHI) to determine if there is an association between vitamin D and incident glaucoma in postmenopausal women. We examined the association between dietary vitamin D intake, vitamin D supplements and serum 25 hydroxyvitamin D (25(OH)D) levels and the risk of developing glaucoma. 143,389 postmenopausal women from the WHI including a subset with serum 25(OH) D measurements were examined to determine the association of dietary, supplemental and serum levels of vitamin D to the development of glaucoma. Dietary intakes of vitamin D, use of vitamin D supplements and serum levels of 25(OH) D were predictors examined for the main outcome of incident glaucoma. In multivariable models adjusted for demographic, clinical variables and medication use, dietary vitamin D, vitamin D supplements, total vitamin D intake (diet plus supplements) and serum 25 (OH) D measurements were not significantly associated with incident glaucoma. In the CaD placebo-controlled intervention clinical trial, there was also no association in the active intervention arm with glaucoma. We conclude that dietary vitamin D intake, supplements and serum levels are not significantly related to the risk of developing glaucoma in postmenopausal women.

*   vitamin D
*   vitamin D deficiency
*   blindness

### Significance of this study

#### What is already known about this subject?

*   Vitamin D deficiency is a worldwide issue.

*   Glaucoma is prevalent in postmenopausal women.

*   Vitamin D supplementation is common.

*   The relationship between vitamin D and glaucoma is controversial.

#### What are the new findings?

*   In multivariable models adjusted for demographic, clinical variables and medication use, dietary vitamin D, vitamin D supplements, total vitamin D intake (diet plus supplements) and serum 25 (OH) D measurements were not significantly associated with incident glaucoma.

*   There was also no association between vitamin D supplementation and glaucoma in the active intervention arm CaD placebo-controlled clinical trial.

#### How might these results change the focus of research or clinical practice?

*   We conclude that dietary vitamin D intake, supplements and serum levels are not significantly related to the risk of developing glaucoma in postmenopausal women and that vitamin D supplementation should not be considered as a preventive strategy for glaucoma.

## Introduction

Worldwide, 67 million people suffer from glaucoma and currently over 8 million individuals are blind because of this disorder. With the continued aging of the population, the incidence of glaucoma is expected to rapidly increase.1 In addition to aging, risk factors associated with glaucoma include elevated intraocular pressure (IOP), high myopia and ethnic background.2 Vision loss secondary to glaucoma is considered irreversible. Therefore, identification of modifiable risk factors for the development of glaucoma is critically important for prevention of blindness due to this dise

Vitamin D is a hormone with pleiotropic actions.3 Vitamin D metabolites are present in the eye, including both the aqueous and vitreous humor and in tear fluid.4–6 Furthermore, both the vitamin D receptor and the enzymes that activate vitamin D are present and active in cells of both the anterior and posterior segments of the eye.4 7–11

Several studies suggest that vitamin D homeostasis plays a role in glaucoma. For example, there are differences in vitamin D receptor allelic frequency in normal versus glaucoma patients, and vitamin D polymorphisms have been linked to IOP regulation.12 13 A recent study using optical coherence tomography found decreased ganglion cell complex thickness in older adults with vitamin D deficiency.14 Therefore, vitamin D may influence the response of the optic nerve to damage under glaucomatous conditions. However, studies of the association of vitamin D levels with glaucoma are conflicting, with some15–18 but not all,19 suggesting that low vitamin D levels are associated with glaucoma. These studies were limited by a number of factors including the select populations examined (all Asians,15 16 relatively low numbers of participants17 and limited potential cofounders examined.17 Administration of 1, 25 dihydroxyvitamin D eye drops and one of its analogs markedly reduced IOP in non-human primates.20 However, a nested case-control study in humans revealed no association between serum (25(OH) D) levels and IOP, and administration of vitamin D3 to participants with low levels of 25(OH) D did not affect IOP,21 although this trial included a relatively low number of (87 total) participants, and none of African American descent.21 To our knowledge, there are no reports that have simultaneously examined the association of dietary vitamin D, vitamin D supplements and serum (25(OH) D) levels with incident glaucoma in a multiethnic population of postmenopausal women.

Therefore, the objectives of this study were to determine the relationship between dietary vitamin D, vitamin D supplements, total vitamin D intake (diet plus supplements) and, in a subset of women, serum levels of 25 (OH)D) with incident glaucoma in postmenopausal women in the Women’s Health Initiative (WHI).

## Methods

The study population included women in the WHI observational study (OS) and clinical trials (CT) (Hormone Therapy, Dietary Modification and Calcium and Vitamin D Trials). The WHI included postmenopausal women aged 50–79 years recruited between October 1, 1993 and December 31, 1998, at 40 clinical centers in the USA. Details of the original WHI, in which participants were followed for outcomes between 1993 and 2005, have been previously described.22 The institutional review board (IRB) at each participating center approved all protocols. This specific study was approved by the University of Tennessee Health Science Center IRB. Women provided written informed consent for their participation in the original WHI study. All protocols in this study adhered to the tenets of the Declaration of Helsinki.

For the purpose of these analyses, incident glaucoma was defined as self-report of glaucoma development during WHI with no history at the baseline visit. Follow-up for incident glaucoma was done through the end of 2005.

Height and weight at the baseline visit were measured in WHI as previously described23 and used to calculate body mass index (BMI). Questionnaires obtained at the baseline visit were used to collect information regarding age, race and ethnicity, smoking exposure (current, past, never), personal menopausal hormone use and oral corticosteroid use. Questionnaires from the baseline visit also collected history of treated diabetes and hypertension (defined as those who reported that they were told by a doctor that they had high blood pressure and/or that they were currently taking medicine for their hypertension at the baseline WHI visit) and information relative to socioeconomic status including income, education and medical insurance. Total solar irradiation was measured in Langley’s for each of the 40 clinical center regions.24–26 Enrollment in the OS or CT (and particular CT component) was recorded. Indicators were created for participation in each arm (treatment and control) of each clinical trial component. Vitamin D intake from foods was estimated from a self-administered food-frequency questionnaire (FFQ) specifically designed for WHI which assessed usual dietary intake over the previous 3 months.27 For the purposes of these analyses, we used information on use of calcium and vitamin D supplements, including multivitamins containing calcium and/or vitamin D ascertained by medication inventory of current medication use at baseline and year 3 from the OS and from baseline, years 1, 3, 6 and 9 from the CTs at years 1, 3, 6 and 9. Current medication use was ascertained by having the participants bring all the containers for medications taken for the 2 weeks prior to the study visit. Interviewers entered each medication into the database, which assigned drug codes using Medi-Span software (Wolters Kluwer Health; Conshohocken, Pennsylvania). Information on duration of use but not dose was recorded. The correlation coefficient for vitamin D intake was 0.70 between the FFQ and an 8-hour dietary intake assessment (this was done in a subset of WHI participants and consisted of four 24-hour recalls and a 4-hour food record).27 Dietary and use of calcium and vitamin D supplements were summed to derive total vitamin D intake. Data from the 36,282 participants from CaD placebo-controlled clinical trial were also examined (18,176 Active intervention arm and 18,106 Placebo).

### Statistical analyses

Baseline characteristics of all participants and those in the serum vitamin D subsample by incident glaucoma status are presented with means and SD for continuous variables, and frequencies and percentages for categorical variables. Differences between groups were assessed with a t-test for continuous variables and a χ² test for categorical variables.

The relationship between vitamin D intake (diet, supplements and diet plus supplements (total)) and incident glaucoma was assessed using proportional hazards models and two levels of adjustment. First, an unadjusted model with incident glaucoma as a function of categorical vitamin D intake was fit, with frequency, event totals, annualized rates and HRs from each category presented. The linear trend across median vitamin D categories was then assessed in a separate model, with the p value for trends tested. Fully adjusted models were done in the same fashion, with models adjusted for age, race/ethnicity, BMI, smoking, education, Langley sun exposure and hypertension and diabetes (latter as time dependent covariates). Both unadjusted and fully adjusted models are stratified within the model by WHI cohort (CT versus OS) as well as Calcium/ Vitamin D trial intervention assignment (active/placebo/not randomized).

Separate models were run to evaluate the relationship between vitamin D categories (diet, supplement, total, serum vitamin D levels) and glaucoma in African American and Caucasian participant subsets.

To adjust for being an unrepresentative sample of the full WHI set, serum Vitamin D models were inverse probability weighted to represent the full WHI population and were additionally adjusted for potential laboratory effects as not all vitamin D levels were measured in the same laboratory by the same methodology at the same time.

## Results

There were 161,808 women in the WHI cohort; of these, we excluded, in order, 7394 for a history of prevalent glaucoma, 659 who were missing follow-up information and 10,366 for missing information on covariates at baseline. For the main analyses, there were 143,389 women included, 14,865 with incident glaucoma and 128,524 who did not develop glaucoma during WHI follow-up, with 10,853 having measurements of serum 25 (OH)D. For the serum vitamin D analyses, there were 1175 women with incident glaucoma and 9678 who did not develop incident glaucoma during WHI follow-up (figure 1).

![Figure 1](/https://d3hme472k3gd2d.cloudfront.net/content/jim/69/4/843/F1.medium.gif)

[Figure 1](/content/69/4/843/F1)

Figure 1 
Study population. Derivation of WHI analytic entire cohorts. WHI, Women’s Health Initiative.

Baseline characteristics of the study population by self-report of incident glaucoma during WHI are shown in the whole cohort (table 1) and in the subset with serum vitamin D measurements (table 2). In the whole cohort, compared with those without glaucoma, those with glaucoma were older, had a higher BMI and were more likely to have hypertension or diabetes and to be in the WHI Clinical Trial Component (p<0.001). There were also differences in ethnicity, education, income, hormone use (personal as well as WHI Hormone Trial Assignment) and smoking status between those with and without glaucoma. There were no significant differences between the groups relative to medical insurance, use of corticosteroids or CaD intervention assignment in the CaD clinical trial (p>0.05)(table 1). Among those included in the association of serum measurements of vitamin D with incident glaucoma, those with glaucoma were older, had a higher BMI and were more likely to have treated diabetes (p<0.003). There were also differences in ethnicity, income and hormone use (incorporating personal use as well as WHI Hormone Trial Assignment), between those with and without glaucoma. There were no significant differences between the groups in education, insurance, solar irradiance category, smoking history, corticosteroid use or WHI study component or CaD intervention assignment (table 2).

View this table:
[Table 1](/content/69/4/843/T1)

Table 1 
Baseline characteristics of study population (n=143,389)

View this table:
[Table 2](/content/69/4/843/T2)

Table 2 
Characteristics of serum vitamin D study population at time of phlebotomy (n=10,853)

In unadjusted and both adjusted models, there was no significant association between dietary vitamin D, vitamin D supplement intake or total vitamin D intake with incident glaucoma (table 3). In addition, in the CaD clinical trial, the active intervention was not significantly associated with glaucoma compared with placebo (HR=0.98, 95% CI 0.91 to 1.04). Similarly, there was no association of serum vitamin D levels either as a continuous variable or by categories (25(OH) D<30 ng/mL compared with those >30 ng/mL)28 and by Institute of Medicine categories of low (<20 ng/mL), normal (20–50 ng/mL)) and high (>50 ng/mL) serum 25 (OH) D levels29 (table 3).

View this table:
[Table 3](/content/69/4/843/T3)

Table 3 
Vitamin D and incident glaucoma

There was a significant interaction of serum levels of 25(OH) D<30 ng/mL compared with those >30 ng/mL with race (p=0.04). Serum vitamin D levels>30 ng/mL were inversely associated with incident glaucoma in Whites but positively associated with incident glaucoma in African Americans although the findings were not statistically significant in either race. There were no significant associations of dietary vitamin D, vitamin D supplements or total vitamin D intake with incident glaucoma in either race (table 4).

View this table:
[Table 4](/content/69/4/843/T4)

Table 4 
Vitamin D and incident glaucoma by race

## Discussion

The major findings of our study are that there is no association between the development of glaucoma and dietary vitamin D, vitamin D supplements or serum 25 hydroxyvitamin D levels (including serum levels of vitamin D below optimal recommendations)30 in postmenopausal women. Further, the large CaD placebo-controlled clinical trial data also support no association between Vit D and incident glaucoma.

To our knowledge, ours is the first report to examine the relationship between dietary vitamin D and total vitamin D intake (diet plus supplements) with incident glaucoma. In support of our findings, a randomized clinical trial including 87 healthy participants with low serum vitamin D3 levels randomized to vitamin D3 20,000 IU twice per week versus placebo revealed no significant differences in IOP, one of the primary risk factors for glaucoma, at 6 months between the groups.21

In agreement with our findings of no significant association between serum 25 (OH) D levels and incident glaucoma in the cohort of postmenopausal women in WHI, a recent meta-analysis also reported no significant association.19 Limitations noted in this meta-analysis included significant heterogeneity among the study designs and considerable differences in sample sizes and in the vitamin D assays used.19 In contrast, however, two studies from Korea did report a significant correlation between low serum vitamin D levels and prevalent glaucoma.15 16 These reports differ from ours in that they examined prevalent and not incident glaucoma and were derived from primarily Asian populations. Notably, several studies suggest that specific race-based factors may contribute to the pathogenesis of glaucoma.31 32 Our findings in WHI, although not statistically significant, suggest that higher serum 25 (OH) D levels, might be protective against glaucoma in White women.

Our study has a number of important strengths. To our knowledge, this is the first study to examine the association of dietary vitamin D intake with incident glaucoma. Further, ours is the largest sample of multiethnic postmenopausal women in which the association of supplemental vitamin D and serum 25 (OH) D levels with incident glaucoma has been examined. Moreover, the large placebo-controlled clinical trial of calcium plus vitamin D in the WHI yielded similar results of no association. We were able to control for a number of important covariates associated with glaucoma including demographic characteristics, lifestyle factors, socioeconomic status, prevalent medical conditions and medication use (corticosteroids).

There are also a number of limitations to consider. To start, glaucoma was defined by self-report. However, agreement between self-report and medical records for glaucoma in previous studies has been reported to be substantial (κ=0.73).33 Second, we did not have the ability to distinguish specific types of glaucoma. In addition, serum 25 (OH) D levels were not measured in all women in WHI and the methodology for these measurements differed. Characteristics of women who donated blood at the baseline visit did not differ significantly from women who did not donate blood.34 Moreover, to at least partially account for these differences, scaling was used to standardize across laboratory/methodology effects. We defined optimal serum levels of vitamin as 30 ng/mL or greater,30 and by Institute of Medicine cut points;29 however, there is considerable disagreement as to the definition of “optimal levels”35 and this may also depend on the outcome being evaluated.36 Notably, however, our findings were consistent when we examined continuous measures for serum 25 (OH)D. Less than 2.5% of the population was Asian; therefore, we were unable to examine the association of vitamin D categories with incident glaucoma in this subgroup. Finally, the findings were from postmenopausal women enrolled in WHI, and the results may not be generalizable to other groups.

In conclusion, our findings suggest no association between vitamin D (as diet, supplements or serum levels) and the development of glaucoma in postmenopausal women. Optimizing vitamin D status is unlikely to impact the risk of glaucoma in postmenopausal women.

## Data availability statement

Data are available in a public, open access repository. Data underlying this publication can be found at the following site: [https://www.whi.org/researchers/data/Pages/Home.aspx](https://www.whi.org/researchers/data/Pages/Home.aspx). WHI data are also made available to Investigators through the following outlets: directly from the WHI Clinical Coordinating Center (on this site), The WHI Virtual Data Enclave (VDE), Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC), Database of Genotypes and Phenotypes (dbGaP).

## Ethics statements

### Patient consent for publication

Not required.

### Ethics approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

## Footnotes

*   Correction notice This article has been corrected since it first published. The provenance and peer review statement has been included.

*   Contributors LDC: study design, evaluation, primary manuscript author. KJ: study design, manuscript editing. JL: primary statistician, manuscript editing. FT: secondary statistician, manuscript editing. JW-W: study design, manuscript editing. KB: glaucoma specialist for the group, manuscript editing. ZC: study design, manuscript editing. MW: study design, evaluation, secondary manuscript author.

*   Funding The Women’s Health Initiative (WHI) program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C. Additional funding was supplied by NIH Grant #R01 EY021747 (MAW). JWW-WHI NHLBI support the WHI northeast regional center activities. KB is supported in part by NIH grant R01EY027406.

*   Competing interests None declared.

*   Provenance and peer review Not commissioned; externally peer reviewed.

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