July 2014
Volume 55, Issue 7
Free
Clinical and Epidemiologic Research  |   July 2014
Myopia Is Associated With Lower Vitamin D Status in Young Adults
Author Affiliations & Notes
  • Seyhan Yazar
    Centre for Ophthalmology and Vision Science, University of Western Australia and the Lions Eye Institute, Perth, Western Australia, Australia
  • Alex W. Hewitt
    Centre for Ophthalmology and Vision Science, University of Western Australia and the Lions Eye Institute, Perth, Western Australia, Australia
    Centre for Eye Research Australia, Melbourne University, Melbourne, Victoria, Australia
  • Lucinda J. Black
    Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia
  • Charlotte M. McKnight
    Centre for Ophthalmology and Vision Science, University of Western Australia and the Lions Eye Institute, Perth, Western Australia, Australia
  • Jenny A. Mountain
    Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia
  • Justin C. Sherwin
    Royal Victorian Eye and Ear Hospital, Melbourne, Australia
  • Wendy H. Oddy
    Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia
  • Minas T. Coroneo
    Department of Ophthalmology, University of New South Wales, Sydney, Australia
  • Robyn M. Lucas
    Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia
    National Centre for Epidemiology and Population Health, the Australian National University, Canberra, Australia
  • David A. Mackey
    Centre for Ophthalmology and Vision Science, University of Western Australia and the Lions Eye Institute, Perth, Western Australia, Australia
  • Correspondence: Seyhan Yazar, Lions Eye Institute, 2 Verdun Street, Perth, Western Australia 6009, Australia; seyhanyazar@gmail.com
Investigative Ophthalmology & Visual Science July 2014, Vol.55, 4552-4559. doi:10.1167/iovs.14-14589
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      Seyhan Yazar, Alex W. Hewitt, Lucinda J. Black, Charlotte M. McKnight, Jenny A. Mountain, Justin C. Sherwin, Wendy H. Oddy, Minas T. Coroneo, Robyn M. Lucas, David A. Mackey; Myopia Is Associated With Lower Vitamin D Status in Young Adults. Invest. Ophthalmol. Vis. Sci. 2014;55(7):4552-4559. doi: 10.1167/iovs.14-14589.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose.: To investigate the association between serum vitamin D levels and myopia in young adults.

Methods.: A total of 946 individuals participating in the 20-year follow-up of the Western Australian Pregnancy Cohort (Raine) Study were included in this study. Ethnicity, parental myopia, and education status were ascertained by self-reported questionnaire. A comprehensive ophthalmic examination was performed, including postcycloplegic autorefraction and conjunctival UV autofluorescence photography. Serum 25-hydroxyvitamin D3 (25(OH)D3) concentrations were determined using mass spectrometry. The association between serum 25(OH)D3 concentrations and prevalent myopia was determined using multivariable logistic regression. Myopia was defined as mean spherical equivalent ≤ −0.5 diopters.

Results.: Of the 946 participants, 221 (23.4%) had myopia (n = 725 nonmyopic). Myopic subjects had lower serum 25(OH)D3 concentrations compared to nonmyopic participants (median 67.6 vs. 72.5 nmol, P = 0.003). In univariable analysis, lower serum 25(OH)D3 concentration was associated with higher risk of having myopia (odds ratio [OR] for <50 vs. ≥50 nmol/L: 2.63; confidence interval [95% CI] 1.71–4.05; P < 0.001). This association persisted after adjustment for potential confounders, including age, sex, ethnicity, parental myopia, education status, and ocular sun-exposure biomarker score (adjusted OR 2.07; 95% CI 1.29–3.32; P = 0.002).

Conclusions.: Myopic participants had significantly lower 25(OH)D3 concentrations. The prevalence of myopia was significantly higher in individuals with vitamin D deficiency compared to the individuals with sufficient levels. Longitudinal studies are warranted to investigate whether higher serum 25(OH)D3 concentration is protective against myopia or whether it is acting as a proxy for some other biologically effective consequence of sun exposure.

Introduction
Worldwide, including in Australia, the prevalence of myopia has been increasing. 1 Myopia prevalence varies across populations of different regions, ethnicities, and age groups. In some East Asian countries, myopia is an epidemic, with as many as 80% of children estimated to be myopic. 2 In two Australian schoolchildren cohorts who were aged 6 and 12 at the baseline examination, the incidence of myopia was reported to be 2.2% and 4.1% over a 5- to 6-year period. 3 Mild myopia is a relatively benign disorder, and blurred vision due to elongation of the eye can be corrected with spectacles, contact lenses, or laser refractive surgery. However, individuals with severe myopia are at increased risk of visual impairment and blindness due to associated conditions such as retinal detachment, retinal degeneration, and choroidal neovascularization. 4,5 Myopia is also associated with increased risk of age-related eye diseases including cataract and glaucoma. 6,7  
Several possible mechanisms have been proposed for the development of refractive error. One of the earliest of these hypothesized that vitamin D may have a role in the development of myopia. In the 1930s and 1940s, several researchers investigated the association of myopia with vitamin D status both experimentally and clinically. 8 Recently, Mutti and Marks 9 proposed that decreasing population-level vitamin D status (measured by the concentration in blood of 25-hydroxyvitamin D [25(OH)D]) may be associated with the rising prevalence of myopia. In a small cohort of 22 participants, after adjustment for age and dietary intake, myopes had lower 25(OH)D concentrations than nonmyopes. 9 More recently, low serum 25(OH)D levels were found to be associated with higher myopia prevalence in a large Korean population. 10  
Epidemiological studies have identified a range of potential environmental risk factors for the development of myopia. 11 The rapid increase in myopia prevalence in East Asian populations points to environmental or lifestyle factors sufficient to exert an effect in a short time period. Within these factors, decreasing time spent outdoors has been identified as a potential explanatory lifestyle behavior. In the last decade, a number of observational studies have investigated the hypothesis that greater time spent outdoors is protective against myopia. 1215 This is supported by findings from a recent meta-analysis of cross-sectional studies that demonstrated an inverse association between time spent outdoors and myopia prevalence. 16 These findings have been substantiated in prospective population-based studies and randomized controlled trials. 17,18  
In addition to the evidence of a well-grounded environmental contribution to risk, some variation in myopia and refractive error is accounted for by genetic factors. Interestingly, one of the candidate genes identified in family-based studies is the vitamin D receptor (VDR). Polymorphisms within this gene were associated with low-to-moderate myopia in Caucasians, 19 and a polymorphism in the VDR gene start codon (Fok1) was associated with high myopia in Indians. 20 However, these studies identified different risk alleles within the VDR, and the VDR (and related) gene polymorphisms for which there is evidence of functional effects are not those that show an association. These inconsistencies do cast some doubt on a causal role of polymorphisms in the VDR, and replication studies are needed. 
In many populations, the main source of vitamin D is endogenous synthesis following sun exposure of the skin. 21 Vitamin D deficiency is reportedly widespread, 22 and population 25(OH)D levels have been decreasing over time, 23 possibly due to behavioral changes to decrease sun exposure. Taken together, the environmental and genetic associations and the correlative temporal pattern provide compelling evidence that myopia risk is linked to vitamin D-related factors. 
Previous refractive error studies did not take account of individual ocular and nonocular sun exposure when exploring the relationship of myopia and vitamin D levels. The purpose of our current study was to examine the association between serum 25(OH)D3 concentrations and the prevalence of myopia, adjusting for potential confounders including a marker of ocular sun exposure, in a large cohort of young adults of mainly Northern European ancestry but with a subset of East Asian ancestry. 
Methods
Study Participants
The study comprised participants who were enrolled in the 20-year follow-up of the Western Australian Pregnancy Cohort (Raine) Study conducted between March 2010 and April 2012. 24 The Raine Study methodology has been described previously. 25 In brief, a total of 2900 pregnant women attending the public antenatal clinic at King Edward Memorial Hospital, or nearby private practices, were recruited into the Raine Study between May 1989 and November 1991. A total of 2868 of their offspring have since undergone serial assessment. The current study was conducted in accordance with the tenets of the Declaration of Helsinki. The protocol was approved by the Human Research Ethics Committee at the University of Western Australia. Informed consent was obtained from all participants at the initiation of the eye examination session at 20 years. 
Questionnaire
Each participant completed a questionnaire providing sociodemographic data and information on current education status (studying part- or full-time) and parental myopia, that is, whether one or both parents were myopic or short-sighted. Individuals were asked to report their time spent outdoors and had four possible responses to the question “In the summer, when not working at your job or at school, what part of the day do you spend outside?”: none, <¼ of the day, approximately half of the day, and >¾ of the day. “None” and “ <¼ of the day” groups were combined due to low numbers in the “none” category. 
Assessment of Myopia and Ocular Sun Exposure
As part of a comprehensive eye examination, 26 postcycloplegic autorefraction was measured using the Nidek ARK-510A (NIDEK Co. Ltd., Gamagori, Japan) autorefractor. The mean of three consecutive measurements was recorded for each eye. Myopia was defined as mean spherical equivalent (MSE, sum of spherical error and half of cylindrical error) of both eyes ≤ −0.5 diopters (D). This definition was adopted due to its wide use and validated reliability in young individuals. 27 The MSE of two eyes was calculated for each participant to determine the prevalence of myopia. We used a camera system developed by Ooi and colleagues 28 to derive a score for a biomarker of ocular sun exposure by measuring conjunctival UV autofluorescence (CUVAF). The area of fluorescence (mm2) for each photograph was determined using Adobe Photoshop CS4 Extend (Adobe Systems, Inc., San Jose, CA, USA). Total ocular sun exposure of individuals was determined as the summed area of the CUVAF in four photographs (left and right eyes, nasal and temporal conjunctiva) of each individual. The reliability of CUVAF as a biomarker of subacute sunlight exposure has been previously validated. 29  
Assessment of Serum 25(OH)D3 Concentrations
Participants provided a fasting blood sample for analysis of serum 25(OH)D concentration at the age 20 years follow-up. Venous blood samples were taken from an antecubital vein after an overnight fast, and samples were stored at −80°C until analyzed using liquid chromatography–tandem mass spectrometry (RDDT, Bundoora, VIC, Australia), according to published methodology. 30 The interassay coefficients of variation ranged from 5.8% to 9.2% at 28.2 and 180.8 nmol/L 25(OH)D3, respectively. 
Statistical Analysis
A comparison of participants completing the 20-year follow-up with those who were part of the original cohort but did not attend an eye examination was performed using the data from the year 1 follow-up to examine the sociodemographic characteristics between the two groups. These characteristics included sex, ethnicity, family structure (sole-parent versus couple families), income levels, and Socioeconomic Index for Areas (SEIFA) Index of Relative Advantage and Disadvantage (IRSAD) of parents/carers. For the latter, a higher score reflects higher relative socioeconomic advantage (www.abs.gov.au [in the public domain]). 
The fasting blood samples were collected year-round between March 2010 and April 2012. Therefore, the seasonal component was removed (deseasonalized) according to published methodology 31 by fitting a sinusoidal model to serum 25(OH)D3 concentrations incorporating the month the blood sample was taken. Serum 25(OH)D2 concentrations were detectable in just 10 participants and at levels below 7 nmol/L; therefore only deseasonalized serum 25(OH)D3 concentrations were included in the analysis. 
Mean spherical equivalent and total 25(OH)D3 concentrations were not normally distributed (evidence from Kolmogorov-Smirnov test, P < 0.001, and nonlinear quantile–quantile [Q-Q] plots); thus summary data are presented as medians and interquartile ranges (IQRs). The difference in serum 25(OH)D3 concentrations between myopic and nonmyopic participants was assessed using the Mann-Whitney U test. 
We defined vitamin D status as being sufficient when concentrations of serum 25(OH)D3 were ≥75 nmol/L, insufficient when they were 50 to 74.9 nmol/L, and deficient when they were <50 nmol/L. 32 Differences between categorical variables were assessed with χ2 tests. We used a χ2 test for trend to assess a possible dose–response relationship with myopia prevalence across categories of vitamin D status. A simple linear regression model was generated to describe the relationship between levels of 25(OH)D3 and MSE using the least squares method. We used simple logistic regression to estimate the odds ratios (OR) and confidence intervals (95% CI) of myopia prevalence in relation to each covariate, testing for trend by replacing categorical predictors with a single predictor, taking category rank scores. A P value < 0.05 was considered statistically significant. A multivariable logistic regression model was constructed to assess the association between myopia prevalence and 25(OH)D3 concentration (or vitamin D status) while adjusting for age, sex, and other covariates identified as being significant in univariable analysis. Separate multivariable models containing either total CUVAF or time spent outdoors were constructed due to the expected collinearity between these. 
Two subgroups were created based on self-reported ethnicity, Australians with Northern European ancestry and East Asians, and the above analyses repeated. 
Statistical analyses were performed using the statistical software R version 2.15.1 (R Foundation for Statistical Computing, http://www.r-project.org/ [in the public domain]). 
Results
Compared with individuals from the original cohort who did not participate in the 20-year follow-up, participants who attended eye examinations were more likely to have been born into couple families (84% vs. 61%) and families with a combined income of more than US $23,500 (59% vs. 38%) at a time when the average income of a full-time worker in Australia was approximately US $27,500. Similarly, the mean IRSAD score was higher for parents/carers of the participants from the 20-year follow-up (1039 ± 89) compared to parents/carers of their peers who were not examined (1001 ± 86, P < 0.001). There was no significant difference in sex and ethnicity between the two groups. 
Of 1344 participants who attended an eye examination, 198 (14.7%) participants did not have a 25(OH)D level measurement, and 200 (14.9%) participants had incomplete clinical examination or questionnaire data. Serum 25(OH)D3 concentration and potential confounders including age, sex, ethnicity, parental myopia, education, and ocular sun exposure were available for 946 participants (70.4%); just over half (n = 480; 50.7%) of these were female. Only 837 participants had data for time outdoors and potential confounders. The mean (± standard deviation) age was 20.0 ± 0.4 years (range, 18.3–22.1 years), and the majority (n = 798, 84.4%) of the participants had Northern European ancestry. Of the 946 participants, 837 (88.5%) reported their time spent outdoors during summer. Of these, 406 (48.5%) spent less than a quarter of an average summer day outside; 332 (39.7%) spent approximately half of their day outside; and 99 (11.8%) spent the majority of their day outside. Serum 25(OH)D3 concentration was lower in males (70.9 nmol/L; IQR = 56.1–84.8) compared to females (71.7 nmol/L [IQR = 58.6–85.2]; P = 0.015), and East Asian individuals had lower serum 25(OH)D3 concentrations compared to their peers with Northern European ancestry (55.3 nmol/L [IQR = 42.4–70.1] vs. 73.0 nmol/L [IQR = 59.6–87.9], P < 0.001). Serum 25(OH)D3 concentration increased with increasing CUVAF (Fig. 1A) and time spent outdoors estimate = 9.0 nmol/L increase per one category of time outdoors; standard error = 1.2, P trend < 0.001). 
Figure 1
 
Simple linear regression equations of 25(OH)D3 concentration (nmol/L) with (A) ocular sun exposure (conjunctival UV autofluorescence) and (B) refractive error in young adults (black, Northern Europeans; gray, East Asians).
Figure 1
 
Simple linear regression equations of 25(OH)D3 concentration (nmol/L) with (A) ocular sun exposure (conjunctival UV autofluorescence) and (B) refractive error in young adults (black, Northern Europeans; gray, East Asians).
Over one-fifth of participants (n = 221 [23.4%]) had myopia (MSE ≤ −0.5 D). Median MSE was −1.56 D (IQR = −3.19 to −0.88) and +0.44 D (IQR = +0.13 to +0.75) in the myopia and nonmyopia groups, respectively (P < 0.001). The demographic data for myopic and nonmyopic individuals are displayed in Table 1. Serum 25(OH)D3 concentrations were significantly lower in the myopic compared to the nonmyopic participants: median of 67.6 nmol (IQR = 52.3–79.6) and 72.5 nmol (IQR = 59.4–87.2), respectively (P = 0.003). Figure 1B shows the positive association between serum 25(OH)D3 concentrations and MSE. The prevalence of myopia decreased in association with higher 25(OH)D3 concentration (OR = 0.88, 95% CI 0.82–0.94, per 10 nmol/L increase) and across categories of increasing vitamin D status (χ2 for linear trend = 19.63, P < 0.001). Presence of myopia was also positively associated with currently studying and parental myopia and was inversely associated with higher CUVAF area, Northern European ethnicity, and greater time spent outdoors in univariable analyses (Table 2). 
Table 1
 
The Demographic Characteristics of the Study Cohort (n = 946)
Table 1
 
The Demographic Characteristics of the Study Cohort (n = 946)
Myopic Participants, n = 221 (%) Nonmyopic Participants, n = 725 (%) P Value
Sex, male 102 (53.8) 364 (49.7) 0.328
Ethnicity
 Northern European ancestry 170 (76.9) 628 (86.6) <0.001
 East Asian ancestry 29 (13.1) 31 (4.3)
 Other 22 (10.0) 66 (9.1)
Education (currently studying) 166 (75.1) 430 (59.3) <0.001
Parental myopia
 Neither parent 125 (56.6) 559 (77.1) <0.001
 One parent 65 (29.4) 126 (17.4)
 Both parents 31 (14.0) 40 (5.5)
Time spent outdoors during summer*
 Less than ¼ of day 115 (56.9) 291 (45.8) 0.020
 ½ day 69 (34.2) 263 (41.4)
 More than ¾ of day 18 (8.9) 81 (12.8)
Conjunctival UV autofluorescence†
 First quartile 72 (32.6) 165 (22.8) <0.001
 Second quartile 73 (33.0) 163 (22.5)
 Third quartile 40 (18.1) 196 (27.0)
 Fourth quartile 36 (16.3) 201 (27.7)
Vitamin D status‡
 Deficient 51 (31.7) 90 (12.4) <0.001
 Insufficient 100 (45.2) 309 (42.6)
 Optimal 70 (31.8) 326 (45.0)
Table 2
 
Univariable Logistic Regression Analysis of Associations With Myopia
Table 2
 
Univariable Logistic Regression Analysis of Associations With Myopia
Covariate All Participants, n = 946 Northern European Participants, n = 798 East Asian Participants, n = 60
OR (95% CI) P Value OR (95% CI) P Value OR (95% CI) P Value
Age, per year 1.25 (0.90–1.74) 0.180 1.26 (0.85–1.85) 0.235 2.75 (0.82–11.10) 0.119
Sex
 Female Reference Reference Reference
 Male 1.17 (0.87–1.59) 0.292 1.07 (0.76–1.51) 0.691 1.07 (0.76–1.51) 0.691
Ethnicity
 Non-Northern European Reference - - - -
 Northern European 0.51 (0.35–0.76) <0.001 - - - -
25(OH)D3 level Per 10 nmol/L increase 0.88 (0.82–0.94) <0.001 0.92 (0.85–0.99) 0.033 0.68 (0.48–0.90) 0.013
Vitamin D status*
 Sufficient Reference Reference Reference
 Insufficient 1.51 (1.07–2.13) <0.001 1.57 (1.09–2.28) 0.017 3.25 (0.64–24.58) 0.185
 Deficient 2.63 (1.71–4.05) 0.019 2.03 (1.19–3.42) 0.008 4.90 (0.95–37.84) 0.078
CUVAF Per mm2 0.99 (0.98–0.99) <0.001 0.98 (0.98–0.99) <0.001 0.99 (0.97–1.00) 0.150
CUVAF†
 First quartile Reference Reference Reference
 Second quartile 1.03 (0.69–1.52) 0.896 1.02 (0.65–1.59) 0.925 1.49 (0.39–6.04) 0.565
 Third quartile 0.47 (0.30–0.72) <0.001 0.55 (0.34–0.89) 0.016 0.46 (0.10–1.85) 0.289
 Fourth quartile 0.41 (0.26–0.64) <0.001 0.45 (0.27–0.75) 0.002 0.56 (0.10–2.74) 0.479
Time outdoors in summer‡
 Less than ¼ of day Reference Reference Reference
 ½ day 0.66 (0.47–0.93) 0.019 0.66 (0.45–0.98) 0.040 0.28 (0.07–0.92) 0.044
 More than ¾ of day 0.56 (0.31–0.96) 0.042 0.64 (0.34–1.13) 0.135 0.33 (0.01–3.80) 0.388
Parental myopia
 No parent affected Reference Reference Reference
 One parent affected 2.31 (1.61–3.29) <0.001 2.44 (1.64–3.61) <0.001 0.82 (0.21–2.95) 0.764
 Both parents affected 3.47 (2.08–5.75) <0.001 3.01 (1.68–5.30) <0.001 5.25 (1.13–38.08) 0.053
Education
 Not studying Reference Reference Reference
 Currently studying 2.07 (1.48–2.93) <0.001 1.84 (1.27–2.68) 0.001 1.67 (0.37–8.80) 0.513
Table 3 shows the results of the multivariable logistic regression models. In the model adjusted for age and sex only, the odds of being myopic decreased with increasing 25(OH)D3 concentration (OR: 0.88, 95% CI: 0.82–0.94 per 10 nmol/L increase, P < 0.001), and increased across categories of decreasing vitamin D status (OR: 2.67, 95% CI: 1.72–4.11 for vitamin D deficiency versus sufficiency). The significant association with 25(OH)D3 as a continuous variable was retained in the multivariable model adjusted for age, sex, ethnicity, parental myopia, education, and CUVAF (OR: 0.91, 95% CI: 0.85–0.98 per 10 nmol/L increase, P = 0.013). Across categories of vitamin D status, the odds of being myopic were significantly increased only in the comparison of vitamin D deficiency to vitamin D sufficiency in the fully adjusted model; but there was evidence of a significant trend (OR: 1.42, 95% CI: 1.12–1.79 per category increase, P for trend < 0.001). 
Table 3
 
Adjusted Multivariable Logistic Regression Analysis of the Association Between 25(OH)D3 Levels and Presence of Myopia
Table 3
 
Adjusted Multivariable Logistic Regression Analysis of the Association Between 25(OH)D3 Levels and Presence of Myopia
Age- and Sex-Adjusted Model Multivariable Model*
OR (95% CI) P Value Adjusted OR (95% CI) P Value
25(OH)D3, per 10 nmol/L
 All participants 0.88 (0.82–0.94) <0.001 0.91 (0.85–0.98) 0.013
 Northern European participants 0.92 (0.85–0.99) 0.037 0.94 (0.87–1.02) 0.138
 East Asian participants 0.66 (0.46–0.88) 0.009 0.58 (0.38–0.82) 0.005
Vitamin D status†
 All participants
  Deficient 2.67 (1.72–4.11) <0.001 2.07 (1.29–3.32) 0.002
  Insufficient 1.51 (1.07–2.13) 0.019 1.28 (0.89–1.84) 0.177
  Sufficient Reference Reference
 Northern European participants
  Deficient 2.01 (1.17–3.39) 0.010 1.77 (1.01–3.07) 0.043
  Insufficient 1.57 (1.09–2.28) 0.017 1.38 (0.94–2.03) 0.104
  Sufficient Reference Reference
 East Asian participants‡
  Deficient 6.24 (1.07–55.27) 0.060 - -
  Insufficient 3.59 (0.65–29.71) 0.173 - -
  Sufficient Reference Reference
In the subgroup analysis including only participants with Northern European background, the myopic group had a significantly lower median 25(OH)D3 concentration compared to the nonmyopic group (Fig. 2). The odds of having myopia decreased significantly with increasing 25(OH)D3 concentration in the age- and sex-adjusted model. This effect was no longer statistically significant after adjustment for the other factors in the fully adjusted model, although the strength of the association was very similar. Nevertheless, vitamin D deficiency was associated with an increased risk of myopia compared to vitamin D sufficiency in the fully adjusted model, with evidence of a trend across the categories (OR: 1.35, 95% CI: 1.04–1.75, P for trend = 0.024). 
Figure 2
 
Comparison of 25(OH)D3 Levels (nmol/L) between myopic and nonmyopic participants in individuals with Northern European and East Asian ancestries.
Figure 2
 
Comparison of 25(OH)D3 Levels (nmol/L) between myopic and nonmyopic participants in individuals with Northern European and East Asian ancestries.
Among the 60 participants with East Asian background, 48.3% (n = 29) were myopic. Serum 25(OH)D3 concentration was significantly lower in the myopic compared to nonmyopic East Asian participants (53.0 nmol/L [IQR: 11.2–94.8] vs. 61.0 nmol/L [IQR: 13.8–108.3], P = 0.035). Similarly, higher 25(OH)D3 concentration was associated with a decreased odds of having myopia in the age- and sex-adjusted model as well as the fully adjusted model (Table 3), but the trend across categories of vitamin D status was not statistically significant (P = 0.078), probably because of the small sample size. The point estimates suggest that the odds of being myopic were increased 6-fold in association with vitamin D deficiency compared to sufficiency. We were unable to undertake further adjustment in this subgroup because of the small sample size. 
In analyses of both the full sample and the Northern European subgroup, CUVAF, parental myopia, and education remained significant in the adjusted multivariable regression model for myopia that also included serum 25(OH)D3 concentration (all P ≤ 0.001). 
Separate models constructed to adjust for time spent outdoors provided results similar to those adjusting for CUVAF. For example, in the full sample, the odds of being myopic decreased with increasing 25(OH)D3 concentrations (adjusted OR: 0.89, 95% CI: 0.83–0.97 per 10 nmol/L increase, P = 0.008). Similarly, the adjusted odds of having myopia were 0.93 (95% CI: 0.85–1.01) and 0.56 (95% CI: 0.33–0.83) with every 10 nmol/L increase in 25(OH)D3 concentrations in Northern European (P = 0.091) and East Asian subsets (P = 0.011), respectively. The odds of being myopic were significantly increased in the comparison of vitamin D deficiency to vitamin D sufficiency in the fully adjusted model (OR: 2.14, 95% CI: 1.27–3.58, P = 0.008). In individuals with Northern European ancestry (n = 707), the odds of being myopic were not significantly different between those who were vitamin D deficient and sufficient (OR: 1.78; 95% CI: 0.96–3.27, P = 0.065). 
East Asian ethnicity was associated with both lower 25(OH)D3 levels and greater prevalence of myopia. We therefore examined these associations in more detail by comparing a model containing only ethnicity as a risk factor with a second model that included ethnicity and serum 25(OH)D3 concentrations. Addition of serum 25(OH)D3 concentration improved the model fit, and East Asian ethnicity remained significant with an Akaike information criterion (AIC) difference of 7.8 (P < 0.001) and the effect of ethnicity slightly reduced (β estimate of −0.664 to −0.518). 
Finally, a binary variable for serum 25(OH)D concentration was generated using a cut-off point of <75 vs. ≥75 nmol/L. We used this to explore the determinants of vitamin D insufficiency by setting this variable as the dependent parameter and using a model that included factors that were associated with vitamin D concentrations as independent variables. Presence of myopia was associated with an increased odds of being vitamin D insufficient in this model (adjusted OR: 1.63; 95% CI: 1.18–2.27; P = 0.003). 
Discussion
In this study of young adults at 20 years of age, lower serum 25(OH)D3 concentrations were associated with higher prevalence of myopia as previously identified in Caucasian teens 28 and Korean adolescents. 10 This association could be evidence of an underlying biochemical mechanism between serum 25(OH)D concentrations and myopia and explain previous findings that greater time spent outdoors is associated with reduced risk of myopia development. Alternatively, the 25(OH)D3 concentration could be simply a biomarker of sun exposure, with some other non-vitamin D element being a protective factor. Although it might be suggested that our results reflect reverse causality, whereby myopic young adults prefer to spend more time indoors and thus have lower self-reported time outdoors and lower 25(OH)D3 levels, this explanation is not supported by the findings from the study of Jones-Jordan et al. 33 In that prospective study, sports/outdoor activities were decreased in myopic subjects 3 years before onset, thus pointing to a causal relationship between outdoor exposure and myopia development. Hence, the results of the present study should not be interpreted in the sense of reflecting reverse causality. Our results are consistent with previous findings of environmental or demographic risk factors for myopia including Asian ethnicity, history of parental myopia, higher education, lower levels of CUVAF, and less time spent outdoors 34 (McKnight CM, manuscript submitted, 2014). 
Country of origin, genetic traits, and cultural behavior are important factors determining serum 25(OH)D3 concentrations. 35 A higher risk of vitamin D deficiency in individuals with Asian, Middle Eastern, and African origins is well described. 3640 Lower serum 25(OH)D levels in dark-skinned individuals are likely due to both behavioral factors 41 and decreased efficiency of vitamin D production in darker-skinned individuals. 42 Lower 25(OH)D3 concentrations among East Asian individuals have been reported previously. 43 Therefore, the markedly lower 25(OH)D3 concentrations in participants with East Asian compared to Northern European ancestry in our cohort was not unexpected. However, it was interesting to note that the East Asian group also had a higher prevalence of myopia. Further probing of this finding led us to identify that adjusting for 25(OH)D concentration accounted for part of the association between ethnicity and prevalence of myopia. Hence we suggest that lower vitamin D status is one factor that mediates the difference in myopia prevalence between various ethnicities. 
Many mechanisms have been postulated to explain the apparent protective effect of time spent outdoors for myopia development. Given that the association between near work and myopia is weak and inconsistent, substitution of outdoor activities for near work does not appear to be the important factor, nor does participating in sport per se. 13,44 In animal models, emmetropization is an active process by which optical defocus adjusts the rate of axial elongation during growth and development of the eye. Therefore, it was proposed that improved retinal image quality during distance viewing with a smaller pupil size and accommodative errors may inhibit ocular growth, thus decreasing the risk of development of myopia. However, evidence from animal models did not support this hypothesis. 45,46 Another hypothesis was that greater light intensities outside may alter the release of dopamine, known to inhibit ocular growth, in the retina, 13 and this has been tested in chick models. 47 In support of this hypothesis, high ambient lighting was found to retard development of myopia in chick and Rhesus monkey studies. 4850  
Matrix metalloproteinases (MMP) have been implicated in the scleral remodeling of experimental myopia 51 and in the development of simple myopia. 52 Recently an inverse correlation between blood MMP9 and 25(OH)D levels has been found in submariners. 53 A possible explanation for this might be that suboptimal serum 25(OH)D levels (from either sun avoidance 54 or Western diets that are typically low in vitamin D 55 ) may modulate blood and perhaps tissue levels of MMP with a downstream effect on scleral morphology and refraction. 
This study is unique in having a large sample size and an objective measure of ocular sun exposure that correlates well with time spent outdoors. The only method to determine vitamin D deficiency or sufficiency in an individual is to measure circulating 25(OH)D concentration. In this study, serum 25(OH)D concentrations were measured as the common pathway in vitamin D metabolism for both dietary and sun-induced vitamin D. Moreover, this study contains a wealth of supporting data reinforcing the identified association between myopia and vitamin D status. One caveat relating to this study that must be acknowledged is that the study used cross-sectional data collection from a birth cohort and refractive error was measured at only one point in time; therefore causality cannot be inferred. Furthermore, the highest incidence of myopia occurs in children aged 5 to 15 years. As no data on 25(OH)D concentrations were available from younger time points at the time of this analysis, we made the assumption that 25(OH)D levels in young adults are consistent with those in younger years during which myopia may have developed. Information on time spent outdoors and other potential risk factors including ethnicity, education, and parental myopia was extracted from self-reported questionnaires and is thus subject to recall bias. This, though, is likely to be nondifferential across the groups defined by having myopia or not, so would have resulted in a bias toward null findings; that is, our findings may be an underestimate of the true associations. It is also possible that the findings in participants were different from those in nonparticipants, given that more than 50% of the original cohort were lost to follow-up and a relatively high proportion (30%) of participants in the 20-year follow-up had incomplete data. Further investigations are necessary to validate the findings from this cohort and to assess effects of population differences. 
In conclusion, findings from this study suggest that there could be a biological association between the risk of myopia and reduced 25(OH)D3 concentrations within different populations. However it is important to bear in mind that the 25(OH)D3 could be acting as a proxy for ocular sun exposure, with the latter the important factor. Therefore, future studies prospectively investigating the effects of 25(OH)D3 concentrations and ocular sun exposure in the development of refractive error are warranted. 
Acknowledgments
We are grateful to the Raine Study participants. We thank the Raine Study and Lions Eye Institute research staff for cohort coordination and data collection. We thank Trevor Mori, PhD, for his assistance in serum 25(OH)D assays. 
The core management of the Raine Study is funded by University of Western Australia; Telethon Kids Institute; Raine Medical Research Foundation; University of Western Australia Faculty of Medicine, Dentistry and Health Sciences; Women's and Infant's Research Foundation; and Curtin University. The 20-year eye follow-up of the Raine Study was funded by National Health and Medical Research Council (NHMRC) Grant 1021105, Ophthalmic Research Institute of Australia (ORIA), Lions Eye Institute, the Australian Foundation for the Prevention of Blindness, and Alcon Research Institute. NHMRC Project 1022134 (2012–2014) funded LB and the serum 25(OH)D assays that were conducted by RDDT in Melbourne, Victoria, Australia. RML and WHO are funded by NHMRC Career Development Fellowships. The Centre for Eye Research Australia receives operational infrastructure support from the Victorian Government. 
Disclosure: S. Yazar, None; A.W. Hewitt, None; L.J. Black, None; C.M. McKnight, None; J.A. Mountain, None; J.C. Sherwin, None; W.H. Oddy, None; M.T. Coroneo, None; R.M. Lucas, None; D.A. Mackey, None 
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Figure 1
 
Simple linear regression equations of 25(OH)D3 concentration (nmol/L) with (A) ocular sun exposure (conjunctival UV autofluorescence) and (B) refractive error in young adults (black, Northern Europeans; gray, East Asians).
Figure 1
 
Simple linear regression equations of 25(OH)D3 concentration (nmol/L) with (A) ocular sun exposure (conjunctival UV autofluorescence) and (B) refractive error in young adults (black, Northern Europeans; gray, East Asians).
Figure 2
 
Comparison of 25(OH)D3 Levels (nmol/L) between myopic and nonmyopic participants in individuals with Northern European and East Asian ancestries.
Figure 2
 
Comparison of 25(OH)D3 Levels (nmol/L) between myopic and nonmyopic participants in individuals with Northern European and East Asian ancestries.
Table 1
 
The Demographic Characteristics of the Study Cohort (n = 946)
Table 1
 
The Demographic Characteristics of the Study Cohort (n = 946)
Myopic Participants, n = 221 (%) Nonmyopic Participants, n = 725 (%) P Value
Sex, male 102 (53.8) 364 (49.7) 0.328
Ethnicity
 Northern European ancestry 170 (76.9) 628 (86.6) <0.001
 East Asian ancestry 29 (13.1) 31 (4.3)
 Other 22 (10.0) 66 (9.1)
Education (currently studying) 166 (75.1) 430 (59.3) <0.001
Parental myopia
 Neither parent 125 (56.6) 559 (77.1) <0.001
 One parent 65 (29.4) 126 (17.4)
 Both parents 31 (14.0) 40 (5.5)
Time spent outdoors during summer*
 Less than ¼ of day 115 (56.9) 291 (45.8) 0.020
 ½ day 69 (34.2) 263 (41.4)
 More than ¾ of day 18 (8.9) 81 (12.8)
Conjunctival UV autofluorescence†
 First quartile 72 (32.6) 165 (22.8) <0.001
 Second quartile 73 (33.0) 163 (22.5)
 Third quartile 40 (18.1) 196 (27.0)
 Fourth quartile 36 (16.3) 201 (27.7)
Vitamin D status‡
 Deficient 51 (31.7) 90 (12.4) <0.001
 Insufficient 100 (45.2) 309 (42.6)
 Optimal 70 (31.8) 326 (45.0)
Table 2
 
Univariable Logistic Regression Analysis of Associations With Myopia
Table 2
 
Univariable Logistic Regression Analysis of Associations With Myopia
Covariate All Participants, n = 946 Northern European Participants, n = 798 East Asian Participants, n = 60
OR (95% CI) P Value OR (95% CI) P Value OR (95% CI) P Value
Age, per year 1.25 (0.90–1.74) 0.180 1.26 (0.85–1.85) 0.235 2.75 (0.82–11.10) 0.119
Sex
 Female Reference Reference Reference
 Male 1.17 (0.87–1.59) 0.292 1.07 (0.76–1.51) 0.691 1.07 (0.76–1.51) 0.691
Ethnicity
 Non-Northern European Reference - - - -
 Northern European 0.51 (0.35–0.76) <0.001 - - - -
25(OH)D3 level Per 10 nmol/L increase 0.88 (0.82–0.94) <0.001 0.92 (0.85–0.99) 0.033 0.68 (0.48–0.90) 0.013
Vitamin D status*
 Sufficient Reference Reference Reference
 Insufficient 1.51 (1.07–2.13) <0.001 1.57 (1.09–2.28) 0.017 3.25 (0.64–24.58) 0.185
 Deficient 2.63 (1.71–4.05) 0.019 2.03 (1.19–3.42) 0.008 4.90 (0.95–37.84) 0.078
CUVAF Per mm2 0.99 (0.98–0.99) <0.001 0.98 (0.98–0.99) <0.001 0.99 (0.97–1.00) 0.150
CUVAF†
 First quartile Reference Reference Reference
 Second quartile 1.03 (0.69–1.52) 0.896 1.02 (0.65–1.59) 0.925 1.49 (0.39–6.04) 0.565
 Third quartile 0.47 (0.30–0.72) <0.001 0.55 (0.34–0.89) 0.016 0.46 (0.10–1.85) 0.289
 Fourth quartile 0.41 (0.26–0.64) <0.001 0.45 (0.27–0.75) 0.002 0.56 (0.10–2.74) 0.479
Time outdoors in summer‡
 Less than ¼ of day Reference Reference Reference
 ½ day 0.66 (0.47–0.93) 0.019 0.66 (0.45–0.98) 0.040 0.28 (0.07–0.92) 0.044
 More than ¾ of day 0.56 (0.31–0.96) 0.042 0.64 (0.34–1.13) 0.135 0.33 (0.01–3.80) 0.388
Parental myopia
 No parent affected Reference Reference Reference
 One parent affected 2.31 (1.61–3.29) <0.001 2.44 (1.64–3.61) <0.001 0.82 (0.21–2.95) 0.764
 Both parents affected 3.47 (2.08–5.75) <0.001 3.01 (1.68–5.30) <0.001 5.25 (1.13–38.08) 0.053
Education
 Not studying Reference Reference Reference
 Currently studying 2.07 (1.48–2.93) <0.001 1.84 (1.27–2.68) 0.001 1.67 (0.37–8.80) 0.513
Table 3
 
Adjusted Multivariable Logistic Regression Analysis of the Association Between 25(OH)D3 Levels and Presence of Myopia
Table 3
 
Adjusted Multivariable Logistic Regression Analysis of the Association Between 25(OH)D3 Levels and Presence of Myopia
Age- and Sex-Adjusted Model Multivariable Model*
OR (95% CI) P Value Adjusted OR (95% CI) P Value
25(OH)D3, per 10 nmol/L
 All participants 0.88 (0.82–0.94) <0.001 0.91 (0.85–0.98) 0.013
 Northern European participants 0.92 (0.85–0.99) 0.037 0.94 (0.87–1.02) 0.138
 East Asian participants 0.66 (0.46–0.88) 0.009 0.58 (0.38–0.82) 0.005
Vitamin D status†
 All participants
  Deficient 2.67 (1.72–4.11) <0.001 2.07 (1.29–3.32) 0.002
  Insufficient 1.51 (1.07–2.13) 0.019 1.28 (0.89–1.84) 0.177
  Sufficient Reference Reference
 Northern European participants
  Deficient 2.01 (1.17–3.39) 0.010 1.77 (1.01–3.07) 0.043
  Insufficient 1.57 (1.09–2.28) 0.017 1.38 (0.94–2.03) 0.104
  Sufficient Reference Reference
 East Asian participants‡
  Deficient 6.24 (1.07–55.27) 0.060 - -
  Insufficient 3.59 (0.65–29.71) 0.173 - -
  Sufficient Reference Reference
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