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Low serum vitamin D is associated with axial length and risk of myopia in young children

  • Erasmus MC and Wageningen University

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The aim of the study was to investigate the relationship between serum 25(OH)D levels and axial length (AL) and myopia in 6-year-old children. A total of 2666 children aged 6 years participating in the birth-cohort study Generation R underwent a stepwise eye examination. First, presenting visual acuity (VA) and AL were performed. Second, automated cycloplegic refraction was measured if LogMAR VA > 0.1. Serum 25-hydroxyvitamin D [25(OH)D] was determined from blood using liquid chromatography/tandem mass spectrometry. Vitamin D related SNPs were determined with a SNP array; outdoor exposure was assessed by questionnaire. The relationships between 25(OH)D and AL or myopia were investigated using linear and logistic regression analysis. Average 25(OH)D concentration was 68.8 nmol/L (SD ± 27.5; range 4–211); average AL 22.35 mm (SD ± 0.7; range 19.2–25.3); and prevalence of myopia 2.3 % (n = 62). After adjustment for covariates, 25(OH)D concentration (per 25 nmol/L) was inversely associated with AL (β −0.043; P < 0.01), and after additional adjusting for time spent outdoors (β −0.038; P < 0.01). Associations were not different between European and non-European children (β −0.037 and β −0.039 respectively). Risk of myopia (per 25 nmol/L) was OR 0.65 (95 % CI 0.46–0.92). None of the 25(OH)D related SNPs showed an association with AL or myopia. Lower 25(OH)D concentration in serum was associated with longer AL and a higher risk of myopia in these young children. This effect appeared independent of outdoor exposure and may suggest a more direct role for 25(OH)D in myopia pathogenesis. Electronic supplementary material The online version of this article (doi:10.1007/s10654-016-0128-8) contains supplementary material, which is available to authorized users.
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Low serum vitamin D is associated with axial length and risk
of myopia in young children
J. Willem L. Tideman
Jan Roelof Polling
Trudy Voortman
Vincent W. V. Jaddoe
´G. Uitterlinden
Albert Hofman
Johannes R. Vingerling
Oscar H. Franco
Caroline C. W. Klaver
Received: 17 November 2015 / Accepted: 8 February 2016 / Published online: 8 March 2016
ÓThe Author(s) 2016. This article is published with open access at
Abstract The aim of the study was to investigate the
relationship between serum 25(OH)D levels and axial length
(AL) and myopia in 6-year-old children. A total of 2666
children aged 6 years participating in the birth-cohort study
Generation R underwent a stepwise eye examination. First,
presenting visual acuity (VA) and AL were performed.
Second, automated cycloplegic refraction was measured if
LogMAR VA [0.1. Serum 25-hydroxyvitamin D
[25(OH)D] was determined from blood using liquid chro-
matography/tandem mass spectrometry. Vitamin D related
SNPs were determined with a SNP array; outdoor exposure
was assessed by questionnaire. The relationships between
25(OH)D and AL or myopia were investigated using linear
and logistic regression analysis. Average 25(OH)D con-
centration was 68.8 nmol/L (SD ±27.5; range 4–211);
average AL 22.35 mm (SD ±0.7; range 19.2–25.3); and
prevalence of myopia 2.3 % (n =62). After adjustment for
covariates, 25(OH)D concentration (per 25 nmol/L) was
inversely associated with AL (b-0.043; P\0.01), and
after additional adjusting for time spent outdoors (b-0.038;
P\0.01). Associations were not different between Euro-
pean and non-European children (b-0.037 and b-0.039
respectively). Risk of myopia (per 25 nmol/L) was OR 0.65
(95 % CI 0.46–0.92). None of the 25(OH)D related SNPs
showed an association with AL or myopia. Lower 25(OH)D
concentration in serum was associated with longer AL and a
higher risk of myopia in these young children. This effect
appeared independent of outdoor exposure and may suggest
a more direct role for 25(OH)D in myopia pathogenesis.
Keywords Myopia Vitamin D Axial length Children
AL Axial length
25(OH)D 25-Hydroxyvitamin D
VA Visual acuity
VDR Vitamin D receptor gene
SE Spherical equivalent
OR Odds ratio
In the last decades, the prevalence of myopia has increased
dramatically in Asia as well as in the Western world [13].
Prevalence estimates are now around 2 % in 6-year-old
children with European ethnicity, and 12 % in children of
Asian descent [4,5]. These figures rise to 50 % in young
European adults [6] and up to 96 % in students from South
Electronic supplementary material The online version of this
article (doi:10.1007/s10654-016-0128-8) contains supplementary
material, which is available to authorized users.
&Caroline C. W. Klaver
J. Willem L. Tideman
Department of Ophthalmology, Erasmus Medical Center,
NA2808, PO Box 5201, 3008 AE Rotterdam, The
Department of Epidemiology, Erasmus Medical Center,
Rotterdam, The Netherlands
Department of Paediatrics, Erasmus Medical Center,
Rotterdam, The Netherlands
Department of Internal Medicine, Erasmus Medical Center,
Rotterdam, The Netherlands
Department of Orthoptics and Optometry, Faculty of Health,
University of Applied Sciences, Utrecht, The Netherlands
Eur J Epidemiol (2016) 31:491–499
DOI 10.1007/s10654-016-0128-8
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Korea [7]. Although myopic refractive error can be cor-
rected optically by glasses, contact lenses, or refractive
surgery, the longer axial length ([26 mm) increases the
life-time risk of severe visual impairment and blindness
due to retinal complications [8]. The basis of myopia is a
developmental mismatch between the optical components
of the eye [9,10], of which excessive elongation of axial
length (AL) in early youth is the most important [11].
The need to reveal the etiology of myopia and develop
preventive measures is urgent from a public health per-
spective. Associations with genetic risk variants [12,13]
and environmental factors such as time spent outdoors [14
16] and education [4,12] have been well established [17,
18]. Recent studies reported an association with serum
25-hydroxy vitamin D [25(OH)D] concentration and
myopia in adolescents [19,20]. Whether this reflects the
association between outdoor exposure and myopia, or
whether vitamin D itself plays a role in the pathophysiol-
ogy is unclear. Studies investigating the potential relation
with vitamin D receptor (VDR) polymorphisms found no
consistent relationships [21,22].
Serum 25(OH)D is derived from multiple sources.
Cholecalciferol (vitamin D3) is formed in the skin after
sunlight exposure, and also absorbed by the gut after
dietary intake of e.g., fatty fish. Ergocalciferol (vitamin
D2) results from intake of foods containing yeasts and
fungi [23,24] Both precursors are hydroxylated in the liver
into 25(OH)D. Its active metabolite 1,25(OH)
D is formed
after transformation in the kidney [25] and is distributed to
other sites of the body thereafter. In non-supplemented
individuals, sunlight exposure is thought to be the main
determinant of 25(OH)D [24,2628]. The main function of
D is regulation of calcium and phosphate meta-
bolism in bone tissue and plasma, but it also has metabolic
functions in insulin metabolism [29,30]. In neuronal dis-
ease such as cognitive decline and Parkinson disease [31,
32], it can be involved in immune responses [33] and in
DNA transcription and methylation [34,35]. Whether
D has a direct effect on eye growth is currently
The aim of this study was to investigate the association
between 25(OH)D levels, AL, and the risk of myopia in
children at age 6 years in a large population-based study.
Additionally, influence of time spent outdoors on these
relationships, and vitamin D related genotypes was studied.
Population and methods
Study population
This study was embedded in the Generation R Study, a
population-based prospective cohort study of pregnant
women and their children in Rotterdam, The Netherlands.
The complete methodology has been described elsewhere
[36,37]. A total of 4154 children underwent an ophthal-
mologic examination by trained nurses at the research
center at age 6 years and underwent blood withdrawal for
serum measurements. The study protocol was approved by
the Medical Ethical Committee of the Erasmus Medical
Center, Rotterdam (MEC 217.595/2002/20), and written
informed consent was obtained from all participants.
Research was conducted according to the declaration of
Assessment of AL and myopia
The examination included a stepwise ophthalmological
examination. Step 1 consisted of monocular visual acuity
with LogMAR based LEA-charts at 3 meter distance by
means of the ETDRS method, and ocular biometry
including AL (mm) was measured by Zeiss IOL-master
500 (Carl Zeiss MEDITEC IOL-master, Jena, Germany)
per eye; five measurements were averaged to a mean AL
[38]. Step 2 was carried out in children with a LogMAR
visual acuity of [0.1 in at least one eye and in children
wearing prescription glasses, and included performance of
automated cycloplegic refraction [Topcon auto refractor
KR8900 (Topcon, Japan)] and a complete ophthalmologic
work up by an ophthalmologist. Two drops (three in case of
dark irises) of cyclopentolate (1 %) were administered at
least 30 min before refractive error measurement. Pupil
diameter was C6 mm at time of the measurement. Spher-
ical equivalent (SE) was calculated as the sum of the full
spherical value and half of the cylindrical value in accor-
dance with standard practice, and myopia was defined as
SE B-0.5D in at least one eye. Children with LogMAR
visual acuity B0.1, no glasses or ophthalmic history were
classified as non-myopic [39,40].
Assessment of 25(OH)D
At a median age of 6.0 y (95 % range 5.6–7.9), nonfasting
blood samples were drawn by antecubital venipuncture and
stored at -80 °C until analysis. Serum samples were col-
lected in all children on the examination day at the research
center. The measurements of 25(OH)D (nmol/L) in the
samples (110lmL serum per sample) were DEQAS certi-
fied and were conducted at the Endocrine Laboratory of the
VU University Medical Center, Amsterdam, The Nether-
lands between July 2013 and January 2014 [41]. Serum
25(OH)D was measured with the use of isotope dilution
online solid phase extraction liquid chromatography–tan-
dem mass spectrometry, the ‘gold standard’ (LC–MS/MS)
[42] using a deuterated internal standard [IS: 25(OH)D3-
d6] (Synthetica AS, Oslo, Norway). This method is highly
492 J. W. L. Tideman et al.
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sensitive and has been widely used in 25(OH)D studies [43,
44]. The limit of quantitation was 4.0 nmol/L; intra-assay
CV was \6 %, and interassay CV was \8 % for concen-
trations between 25 and 180 nmol/L.
Each mother completed a questionnaire regarding the daily
life activities of their child. Time spent playing outdoors
and time spent watching television was obtained using
questions such as ‘‘how much time does your child spend
outdoors/watching television in the morning/afternoon/
evening’’. Questions were asked for weekdays and week-
end days separately, and answers were multiple choice
(never, 0–,–1, 1–2, 2–3, 3–4 h). Total time spent in a
week was summed and divided by seven to make an
average h/day.
Genotyping of SNPs in vitamin D pathway
Samples were genotyped using Illumina Infinium II
HumanHap610 Quad Arrays following standard manufac-
turer’s protocols. Intensity files were analyzed using the
Beadstudio Genotyping Module software v.3.2.32, and
genotype calling based on default cluster files. Any sample
displaying call rates below 97.5 %, excess of autosomal
heterozygosity (F \mean -4SD) and mismatch between
called and phenotypic gender were excluded. Genotypes
were imputed for all polymorphic SNPs from phased
haplotypes in autosomal chromosomes using the 1000
Genomes GIANTv3 panel. SNPs located in genes involved
in the Vitamin D metabolic pathway were studied for
association with AL and presence of myopia; i.e., genes
determining serum 25(OH)D levels (GC, DHCR7,
CYP2R1), a gene involved in activation of serum 25(OH)D
(CYP27B1), the vitamin D receptor gene (VDR), and the
gene involved in deactivation of 1,25-(OH)
D in mito-
chondria (CYP24A1). A total of 33 SNPs [21,45,46] were
tested, and analyses were adjusted for multiple testing
using Bonferroni adjusted Pvalue 0.05/33, P=0.0015.
Measurement of covariates
Height and weight of children were measured by trained
nurses, and BMI (weight/height
) was calculated. Age was
determined at the time of the visit. Income was obtained
using the questionnaire and was clustered in low income
(lowest tertile) and higher income. If income at the time of
the visit was not available, income at birth was used.
Ethnicity was obtained in the questionnaire, according to
standardized criteria employed by ‘Statistics Netherlands’,
the official national statistics agency [47], concerning the
country of birth of parents and child: (1) if both parents
were born in the Netherlands, the ethnicity is Dutch; (2) if
one of the parents was born in another country than the
Netherlands, that country was considered country of birth;
(3) if both parents were born in the same country other than
the Netherlands, that country was represented; (4) if the
parents were born in different countries outside the
Netherlands, then the country of the mother was repre-
sented; and (5) if that child and both parents were born in
different countries outside the Netherlands, the country of
birth of the child was represented. Ethnicity was grouped
into European and non-European. To adjust for seasonality,
four seasons were formed on basis of the month in which
the children participated in the study (Winter: December–
February, Spring: March–May, Summer: June–August,
Autumn: September–November).
Statistical analysis
Separate analyses were performed for AL and myopia.
Differences in covariates between myopia and children
without myopia were tested using logistic regression
analysis adjusting for potentially confounding effects of
age and gender. The relation between 25(OH)D and AL
was investigated using multivariable linear regression
analysis; the relation with myopia (SE B-0.5D) was
analyzed using multivariable logistic regression analysis,
Covariates were only added to the model if they were
significantly related with the outcome as well as with
25(OH)D. Three models were tested: model 1 only adjus-
ted for age and gender; model 2 for age, gender, BMI,
ethnicity, television watching, family income, and season
visiting the research center; model 3 additionally adjusted
for time spent playing outdoors. Effect estimates were
determined per 25 nmol/L 25(OH)D. Beta’s are presented
with SE; Odds Ratios (ORs) with 95 % confidence inter-
vals (95 % CI). Statistical analyses were performed using
SPSS version 21.0 for Windows software (SPSS Inc).
A flow diagram presenting the selection of children for the
current analysis is shown in Supplement Figure 1. A total
of 2666 children were available for analysis of serum
Vitamin D and myopia; 2636 children were available for
analysis of serum 25(OH)D and AL. Demographic char-
acteristics are presented in Table 1. Children with myopia
were on average somewhat older. Adjusted for age and
height, girls had smaller AL than boys but not a lower
frequency of myopia. Myopic children had a higher BMI,
watched more television, and spent less time outdoors.
Low serum vitamin D is associated with axial length and risk of myopia in young children 493
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Myopia occurred more frequently in children of non-
European ethnicity.
Serum 25(OH)D
The average serum 25(OH)D in the total study population
was lower than the optimal level of 75 nmol/L [23]. Only
37.2 % (1023) of the children reached this optimal level;
these were mostly (41.1 %) children who had been exam-
ined in summer time (Table 2). Figure 1shows an inverse
relation between serum 25(OH)D and AL for the entire
population (P\0.001). Most myopes had high AL and
low serum 25(OH)D levels; only 18 % (11/62) of myopic
children reached serum levels which corresponded to the
optimal level.
Table 3shows associations between serum 25(OH)D
and AL and myopia. Lower serum levels were associated
with higher AL and higher risks of myopia. The estimates
remained statistically significant after adjustment for
covariates. The effect between serum 25(OH)D and AL
remained [beta -0.033 (SE 0.012; P0.02)] after exclusion
of myopic children. The association was similar in children
of European and non-European descent, but the association
with AL in the relatively small non-European group failed
to reach statistical significance.
Search for possible explanations
We hypothesized that our findings could be explained by
outdoor exposure. Figure 2shows the positive relation
between time spent outdoors and serum 25(OH)D (Pear-
son, P=\0.001). Independent of serum 25(OH)D, time
spent outdoors (hr/day) was a risk factor for AL [beta
-0.034 (SE 0.012; P0.003)]. It was not a significant risk
factor for myopia (OR 0.81; 95 % CI 0.61–1.07), possibly
due to the small number of myopes. The association
between serum 25(OH)D and AL and myopia remained
significant after adjustment for time spent outdoors
(model 3). We explored possible interactions as well, but
there was no significant interaction effect between
25(OH)D, ethnicity or income. Additionally, the associa-
tion was tested separately in the small subgroup with
missing data on time spent outdoors. The effect was
similar to the effect in the group with data.
Table 1 Demographic
characteristics of study
participants in Generation R
(N =2666)
No myopia
Age (years) 6.12 (0.44) 6.12 (0.44) 6.28 (0.65) 0.001
Sex, female (%) 49.1 (1308) 49.1 (1278) 48.4 (30) 0.99
BMI (kg/m
) 16.09 (1.71) 16.07 (1.69) 16.86 (2.14) 0.005
Low family income (%) 28.0 (747) 27.5 (715) 51.6 (32) \0.001
Axial length (mm) 22.35 (0.7) 22.33 (0.7) 23.14 (0.86) \0.001
Ethnicity (%)
European 75.5 (2013) 76.3 (1986) 43.5 (27) \0.001
Non-European 24.5 (653) 23.7 (618) 56.5 (35)
Activities daily life
Time spent outdoors (h/day) 1.59 (1.14) 1.60 (1.14) 1.16 (0.96) 0.003
Watching television (h/day) 1.34 (0.99) 1.33 (0.97) 1.83 (1.48) 0.001
Values are means (SD), or percentages (absolute numbers)
Pvalues are corrected for age, gender, height in logistic regression
Table 2 Average serum
25(OH)D (nmol/L) per season
in myopic and non-myopic
Serum 25(OH)D concentration (nmol/L) N All No myopia Myopia
All seasons 2666 68.8 (27.5) 69.2 (27.4) 50.2 (24.1)
Spring 751 60.8 (21.7) 61.3 (21.6) 42.5 (17.5)
Summer 693 84.2 (28.4) 84.4 (28.4) 69.2(22.6)
Autumn 686 72.9 (26.8) 73.1 (26.8) 63.3 (24.7)
Winter 536 54.7 (23.0) 55.3 (22.9) 36.8 (19.7)
Values are means (SD)
Pvalues are corrected for age, gender, height. Pvalues \0.05 are shown in bold
494 J. W. L. Tideman et al.
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To investigate a possible genetic association between
Vitamin D and eye growth, we studied genes incorporated
in the Vitamin D pathway. We considered single nucleotide
polymorphisms (SNPs) in genes that determine serum
25(OH)D levels, in genes involved in activation of serum
25(OH)D, in the vitamin D receptor gene (VDR), and in
the gene involved in deactivation of 1,25-(OH)
mitochondria (CYP24A1) (supplemental Table 1). One
SNP (rs2245153) in the CYP24A1 gene showed a signifi-
cant association with AL (beta 0.039; P0.04) and myopia
(OR 1.55; 95 % CI 1.04–2.31), 2 SNPs in CYP24A1
(rs4809959 beta 0.032; P0.04 and rs3787557 beta 0.046;
P0.04) and one in the VDR (rs11568820 beta -0.042;
P0.03) only showed a significant association with axial
length. Pvalues were all insignificant after adjustment for
multiple testing.
In this cohort study of young children, we found a sig-
nificant association between serum 25(OH)D levels, AL
and myopia. In this study children with lower serum
levels of 25(OH)D had longer AL, and those with higher
25(OH)D had a lower risk of myopia (OR 0.65; 95 % CI
0.46–0.92 per 25 nmol/L). The association remained sig-
nificant after adjusting for outdoor exposure, indicating
that these two closely related determinants may have
some overlapping as well as separate effects on the
development of myopia. Genetic variants in the vitamin D
pathway genes appeared not to be related: although SNPs
in the VDR and CYP24A1 genes showed some associa-
tion with AL and myopia, this did not remain after
adjustment for multiple testing.
Fig. 1 Distribution of axial length as a function of serum level of
25(OH)D in the Generation R cohort
Table 3 Multivariate regression analysis of the association between 25(OH)D and axial length and myopia in children at age 6 years
Model 1: Age and sex adjusted
Model 2: Multivariate model excluding
outdoor exposure
Model 3: Multivariate model including
outdoor exposure
Association PAssociation PAssociation P
N=2636 N =2636 N =2636
Axial length (mm), beta (SE) of association with 25(OH)D, per 25 nmol/L
All participants -0.054 (0.012) \0.001 -0.043 (0.014) 0.002 -0.038(0.014) 0.007
European ethnicity -0.051 (0.014) \0.001 -0.043 (0.016) 0.006 -0.037 (0.016) 0.02
Non-European ethnicity -0.034 (0.027) 0.20 -0.043 (0.030) 0.16 -0.039 (0.031) 0.20
Model 1: Age and sex adjusted
Model 2: Multivariate model excluding
outdoor exposure
Model 3: Multivariate model including
outdoor exposure
Association PAssociation PAssociation P
N=2666 N =2666 N =2666
Myopia, OR (95 % CI) of association with 25(OH)D, per 25 nmol/L
All participants 0.47 (0.35–0.62) \0.001 0.63 (0.45–0.89) 0.008 0.65 (0.46–0.92) 0.01
European ethnicity 0.61 (0.39–0.95) 0.02 0.69 (0.42–1.11) 0.13 0.71 (0.44–1.16) 0.17
Non-European ethnicity 0.56 (0.37–0.85) 0.006 0.59 (0.37–0.95) 0.03 0.61 (0.38–0.98) 0.04
The multivariate model for axial length includes adjustment for model 1 and BMI, season of blood withdrawal, ethnicity, television watching,
family income. The multivariate model for myopia includes adjustment for model 1 and BMI, ethnicity, television watching, education mother.
Outdoor exposure indicates time spent outdoors
Low serum vitamin D is associated with axial length and risk of myopia in young children 495
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Our study had strengths and weaknesses. Assets were
the particularly large study sample, the inclusion of the
combination of measurements of AL and myopia, and the
correction for many potential confounders. The young age
of our study population was a benefit as well as a potential
drawback. It allowed for measurements of the determinant
very close to the onset of myopia, leaving less room for
confounding bias. On the other hand, it hampered the study
of large effects as most children did not develop excessive
eye growth yet. There were other drawbacks. We per-
formed cycloplegia only in children with a diminished
visual acuity. Reports show that our cut off value of Log-
MAR VA of [0.1 had a 97.8 % sensitivity to diagnose
myopia [39,40]. We therefore think that our approach did
not substantially affect the number of myopes in our study,
nor biased the observed associations. Finally, as the cor-
relation between serum 25(OH)D level and time playing
outdoors was relatively low in our study, our questionnaire
may not have fully assessed all time spent outdoors. Not all
participants filled in the questionnaire completely and data
on time spent outdoors was partially missing. However,
association in the sample of children without data on time
spent outdoors was similar to the association in those with
complete data.
A novel finding of our study was that the increase in AL
in children with low 25(OH)D was already present in the
physiological range of refractive error, before the onset of
myopia. This implies that Vitamin D has a continuous
effect on AL, and not only determines the development of
myopia. We confirmed that the risk of myopia decreased
with increasing 25(OH)D levels (OR 0.65) with each
25 nmol/L. The association between 25(OH)D and axial
length was also significant in the European children; but
failed to reach significance in the Non-European group due
to low statistical power. Correction for time spent outdoors
demonstrated some attenuation of the association, but did
not explain it entirely. Whether this is due to residual
confounding of time spent outdoors or whether Vitamin D
is truly causally related with AL and myopia remains an
open question. The evidence for a role of time spent out-
doors in myopia is available from cross sectional studies,
intervention and randomized clinical trials as well as from
animal studies [15,16,48,51]. Vitamin D production is
triggered by UV-exposure, not by light exposure per se.
Animal studies have shown that artificial light, free of UV,
can inhibit development of myopia development [48]. This
may suggests that outdoor exposure and Vitamin D are
independent risk factors for axial elongation and myopia.
However, true causality cannot be concluded from a cross
sectional study; longitudinal and functional studies are
needed to provide more profound evidence.
A few previous studies have investigated the role of
serum 25(OH)D in myopia. A South-Korean and an Aus-
tralian study found a positive association in adolescents
and young adults [19,49]. The ALSPAC study found an
association with development of refractive error only for
, not for 25(OH)D
in 15 years old children. A
potential drawback of this study was the measurement of
refraction without any cycloplegia [50]. Mutti et al. [21]
found an association between SNPs in the VDR gene and
myopia in a smaller study. We could not validate this
association, as none of the Vitamin D related SNPs were
significant after adjusting for multiple testing.
Various hypotheses underscribe a function of 25(OH)D
in eye growth. One theory focusses on Vitamin D in rela-
tion to dopamine. The current view is that light exposure
initiates the release of dopamine in retinal amacrine cells
[5153]. The released dopamine appears to influence the
function of gap junctions and the size of receptive fields
[54], an important determinant of eye growth. Vitamin D is
known to influence dopamine metabolism in neurological
disorders, such as Morbus Parkinson and restless legs
syndrome [55]. In particular in Parkinson, Vitamin D
protects against cell death in the substantia nigra of the
dopamine secreting neuron [32,56]. Increased dopamine
metabolism [57] was found in the rat brain under influence
of vitamin D. In the developing rat brain, Vitamin D was
found to upregulate glial derived neurotrophic factor
(GDNF) which increases dopamine neurons [58]. Taken
together, Vitamin D appears to strengthen the function of
dopamine or dopamine secreting cells in neuronal tissues.
Fig. 2 Distribution of serum level of 25(OH)D as a function of time
spent outdoors
496 J. W. L. Tideman et al.
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Whether this also accounts for dopamine secreted by
amacrine cells in the retina remains an intriguing question.
Another mechanism may be the regulation of DNA
transcription in genes containing vitamin D response ele-
ments (VDRE, supplemental figure 2). In this case, the
active intracellular 1,25(OH)
D binds to VDR binding
protein, enters the nucleus, and forms a complex with
retinoid X receptor in order to bind to VDRE and initiate
transcription. VDREs are located in many genes [59]. It has
been shown that retinal cells can metabolize 1,25(OH)
and this active form of vitamin D may interfere with
transcription of genes that promote the myopia signaling
cascade [60].
In conclusion, we found that serum levels of 25(OH)D
were inversely related to AL, and that low levels increased
the risk of myopia. Our data suggest that this relationship
may be independent from time spent outdoors. The
potential role for 25(OH)D in myopia pathogenesis should
be further explored by intervention research and functional
Acknowledgments The Generation R Study is conducted by the
Erasmus Medical Center in close collaboration with the School of
Law and Faculty of Social Sciences of the Erasmus University Rot-
terdam, the Municipal Health Service Rotterdam area, Rotterdam, the
Rotterdam Homecare Foundation, Rotterdam and the Stichting
Trombosedienst & Artsenlaboratorium Rijnmond (STAR-MDC),
Rotterdam. We gratefully acknowledge the contribution of children
and parents, general practitioners, hospitals, midwives and pharma-
cies in Rotterdam. The generation and management of GWAS
genotype data for the Generation R Study were done at the Genetic
Laboratory of the Department of Internal Medicine, Erasmus MC,
The Netherlands. We thank Mila Jhamai, Manoushka Ganesh, Pascal
Arp, Marijn Verkerk, Lizbeth Herrera and Marjolein Peters for their
help in creating, managing and QC of the GWAS database. Also, we
thank Karol Estrada and Carolina Medina-Gomez for their support in
creation and analysis of imputed data.
Funding The Generation R Study is made possible by financial
support from the Erasmus Medical Center, Rotterdam, the Erasmus
University Rotterdam; the Netherlands Organisation of Scientific
Research (NWO); Netherlands Organization for the Health Research
and Development (ZonMw); the Ministry of Education, Culture and
Science; the Ministry for Health, Welfare and Sports; the European
Commission (DG XII); The author was supported by the following
foundations: MaculaFonds, Novartis Fonds, ODAS, LSBS, Oogfonds
and ANVVB that contributed through UitZicht (Grant 2013-24). The
funding organizations had no role in the design or conduct of this
research. They provided unrestricted grants TV and OHF work in
ErasmusAGE, a center for aging research across the life course fun-
ded by Nestle
´Nutrition (Nestec Ltd.), Metagenics Inc., and AXA.
´Nutrition (Nestec Ltd.), Metagenics Inc., and AXA had no role
in design or conduct of the study; collection, management, analysis,
or interpretation of the data; or preparation, review or approval of the
Authors’ contribution Willem Tideman designed and conducted
the research, analyzed the data, wrote the paper and approved the final
manuscript as submitted. He had primary responsibility for final
content. Jan Roelof Polling designed, conducted the research, ana-
lyzed the data and critically revised all versions of the manuscript. He
approved the final manuscript as submitted. Trudy Voortman pro-
vided comments and consultation regarding the analyses and manu-
script and critically revised all versions of the manuscript. She
approved the final manuscript as submitted. Vincent Jaddoe initiated
and designed the original Generation R study, was responsible for the
infrastructure in which the study is conducted, contributed to the
original data collection and critically revised the manuscript. He
approved the final manuscript as submitted. Andre
´Uitterlinden con-
tributed to the analysis, provided comments and consultation
regarding the analyses and manuscript. He approved the final manu-
script as submitted. Albert Hofman initiated and designed the original
Generation R study, was responsible for the infrastructure in which
the study is conducted, contributed to the original data collection and
critically revised the manuscript. He approved the final manuscript as
submitted. Johannes Vingerling provided comments and consultation
regarding the analyses and manuscript and critically revised all ver-
sions of the manuscript. He approved the final manuscript as sub-
mitted. Oscar Franco contributed to the analysis, provided comments
and consultation regarding the analyses and manuscript. He approved
the final manuscript as submitted. Caroline Klaver designed and
conducted the research and wrote the paper and approved the final
manuscript as submitted. She had primary responsibility for final
Compliance with ethical standards
Conflict of interest The authors have indicated they have no
potential conflicts of interest to disclose.
Financial disclosure The authors have no financial relationships
relevant to this article to disclose.
Open Access This article is distributed under the terms of the
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... As demonstrated in Table 1, the association between vitamin D and myopia is controversial in cross-sectional studies. Many studies suggest that the serum 25(OH)D3 level shows an inverse association with myopia and may have a protective effect on myopia [39,[41][42][43][44]47,50,51,53,55]. However, several case-control studies from Australia [52], Denmark [46], and the US [54] found that the risks of myopia are not related to their neonatal vitamin D levels. ...
... One study reported the association of VDR polymorphisms, rs2853559, with myopia [58]. However, the results of other studies suggested that the true contribution of the vitamin D pathway to myopia could be negligible [42,45,59]. Our meta-analysis suggested that polymorphisms in the VDR gene are not associated with myopia [57]. ...
Full-text available
The contributory roles of vitamin D in ocular and visual health have long been discussed, with numerous studies pointing to the adverse effects of vitamin D deficiency. In this paper, we provide a systematic review of recent findings on the association between vitamin D and different ocular diseases, including myopia, age-related macular degeneration (AMD), glaucoma, diabetic retinopathy (DR), dry eye syndrome (DES), thyroid eye disease (TED), uveitis, retinoblastoma (RB), cataract, and others, from epidemiological, clinical and basic studies, and briefly discuss vitamin D metabolism in the eye. We searched two research databases for articles examining the association between vitamin D deficiency and different ocular diseases. One hundred and sixty-two studies were found. There is evidence on the association between vitamin D and myopia, AMD, DR, and DES. Overall, 17 out of 27 studies reported an association between vitamin D and AMD, while 48 out of 54 studies reported that vitamin D was associated with DR, and 25 out of 27 studies reported an association between vitamin D and DES. However, the available evidence for the association with other ocular diseases, such as glaucoma, TED, and RB, remains limited.
... Studies have indicated a negative correlation between serum 25(OH)D levels and myopia (19). In a prospective population-based cohort study (20) A recent Mendelian randomization study demonstrated no association between DHCR7, CYP2R1, GC, and CYP24A1 genedetermined 25(OH)D levels and myopia severity (22). There are inconsistencies in these clinical research findings. ...
Full-text available
Purpose We performed this study to determine the relationship between serum vitamin D levels and refractive status in adolescents aged 12–19 years. Methods Cross-sectional study using the National Health and Nutrition Examination Survey (NHANES) database from 2001 to 2006. We used weighted multivariate linear regression models to assess the association between serum vitamin levels and adolescent refractive status and then built a smooth curve fitting to investigate their internal non-linear relationships. Finally, subgroup analysis was performed according to gender, and the threshold effect of serum vitamin D levels on spherical equivalent degree was analyzed using a two-piecewise linear regression model. Result A total of 5,901 adolescents aged 12 to 19 years were included in this study. After adjusting for all confounding factors, the multiple linear regression model showed no significant correlation between adolescent spherical equivalent degree and serum vitamin D [0.0019 (−0.0018, 0.0046)]. However, smooth curve fitting analysis showed an inverted U-shaped curve relationship between spherical equivalent degree and serum vitamin D levels in adolescents (turning point: 58.1 nmol/L). In analyses by gender subgroup, this inverted U-shaped relationship was found to be more pronounced in female adolescents (turning point: 61.6 nmol/L). Conclusion Our results suggest that the correlation between refractive status and serum vitamin D in adolescents differs by gender. When serum vitamin D concentrations were <61.6 nmol/L in female adolescents and <53.2 nmol/L in male adolescents, the spherical equivalent degree showed a positive correlation with serum vitamin D levels. However, there was no significant correlation when adolescent vitamin levels exceeded this threshold.
... Some studies have revealed that outdoor sports could increase the duration of light exposure, increase the release of retinal dopamine, and effec-tively inhibit the growth of the eye axis, thereby preventing the occurrence of myopia. [30][31][32][33] Many studies investigating outdoor time in relation to myopia found that the longer children's outdoor activities, the lower the incidence of myopia. 34,35 The Sydney Myopia Study found a lesser odds of myopia with more than 2 hours of outdoor time every day. ...
Full-text available
Objective: To explore the relationship between sports and the prevalence of myopia in young sports-related groups in Tianjin, China. Methods: In this cross-sectional study, a cluster sampling method was used to survey professional athletes in Tianjin, students at Tianjin University of Sport, and Tianjin Vocational College of Sports. All participants completed epidemiological questionnaires and ophthalmic examinations. Multivariable logistic regression models were used to explore the potential risk factors of myopia. Results: This study recruited 1401 participants. The prevalence of myopia was 50.18%. The prevalence of low, moderate, and high myopia were 52.63%, 37.41%, and 9.96%, respectively. There were no sex-related differences in the prevalence of myopia. The odds of having myopia was 1.788 times higher in the indoor sports group than the outdoor sports group (the adjusted odds ratio [OR], 95% confidence interval [CI], 1.391-2.297). Training time of more than 4 h/d (4-6 h/d: OR, 0.539; 95% CI, 0.310-0.938; >6 h/d: OR, 0.466; 95% CI, 0.257-0.844) resulted in a lower risk of myopia. Participants who often used the electronic screen (OR, 1.406; 95% CI, 1.028-1.923) and/or had a family history of myopia (OR, 2.022; 95% CI, 1.480-2.763) were more likely to suffer from myopia. Conclusions: Outdoor sports do not necessarily guarantee to insulate against myopia. Youngsters engaged in outdoor sports had a lower prevalence of myopia than those participating in indoor sports. Electronic screen use, training time, and family history of myopia were also associated with the prevalence of myopia in young sports-related groups.
... It has been proposed that the substantial myopia shift during the pandemic was due to increased digital screen time [25], although more reading hours could also be a potential myopigenic factor [14]. The reduced outdoor time, associated with reduced retinal dopamine secretion [29] and vitamin D formation [30], could be another possible explanation for the increased myopia prevalence [31,32]. The results of the current study support the idea that increased axial myopia during COVID might be linked to the high prevalence of astigmatism. ...
Full-text available
During the COVID-19 pandemic, the Hong Kong Government enforced a “school from home” policy between February and September 2020. This cross-sectional epidemiological study was conducted to investigate the prevalence of astigmatism and visual habits after the home confinement period. Vision screenings were conducted at three local government-funded primary schools in Hong Kong from October 2020 to December 2020. A total of 418 ethnically Chinese primary school children completed the eye examination and returned questionnaires concerning demographic information and visual habits. It was found that 46.5% (95% CI, 41.7–61.4%) of the children aged 8 to 11 years had astigmatism ≥ 0.75 D, which was predominately With-The-Rule astigmatism. The prevalence of astigmatism reported in these children is generally higher than that of studies conducted before COVID. Compared to their non-astigmatic peers, astigmatic children had a longer axial length (p < 0.001) and engaged in fewer outdoor activities (p = 0.04). Multiple linear regression analyses also revealed significant relationships between axial length and both cylindrical error and J0 astigmatism. Due to the high astigmatism prevalence, there is a pressing need for further studies on the long-term impact of the pandemic on children’s vision.
... Typically, myopia starts in childhood [79,80]. Data indicate that the prevalence of longer axial length and myopia is significantly higher in children, young adults and adults with vitamin D deficiency compared to those with sufficient levels [81][82][83][84][85][86]. However, the relationship between myopia and vitamin D has been contradicted in some studies [87][88][89][90][91]. ...
Full-text available
The global prevalence of eye diseases continues to grow, bringing with it a reduction in the activity levels and quality of life of patients, and partial or complete blindness if left untreated. As such, there is considerable interest in identifying more effective therapeutic options and preventive agents. One such agent is vitamin D, known to have a range of anti-cancer, anti-angiogenic, anti-inflammatory and anti-oxidative properties, and whose deficiency is linked to the pathogenesis of a range of cardiovascular, cancer, and inflammatory diseases. This review presents the current stage of knowledge concerning the link between vitamin D and its receptor and the occurrence of eye disease, as well as the influence of analogues of calcitriol, an active metabolite of vitamin D. Generally, patients affected by various ocular disorders have vitamin D deficiency. In addition, previous findings suggest that vitamin D modulates the course of eye diseases and may serve as a marker, and that its supplementation could mitigate some disorders. However, as these studies have some limitations, we recommend further randomized trials to clarify the link between vitamin D and its activity with eye disease.
... Sejumlah penelitian telah melaporkan, kadar serum vitamin D pada miopia lebih rendah dibandingkan dengan yang bukan miopia. Rendahnya konsentrasi 25hidroksivitamin D dalam serum dikaitkan dengan risiko miopia yang lebih tinggi pada anak kecil, dan efeknya tidak bergantung dengan waktu pemaparan cahaya matahari di luar ruangan (Tideman et al., 2016). ...
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Pendahuluan; Miopia, sebagai masalah kesehatan dan kualitas hidup global, bukan hanya berkenaan dengan gangguan penglihatan dan dampak akibat kesalahan refraksi pada kehidupan sehari-hari, tetapi juga karena morbiditas yang terkait dengan ametropia ini. Miopia adalah faktor risiko untuk terjadinya masalah penglihatan hingga kebutaan permanen. Miopia remaja biasanya dimulai pada tahun-tahun sekolah dan individu yang terkena dampak biasanya menghadapi ketergantungan seumur hidup pada koreksi optik dan beban keuangan terkait kondisi myopia yang dialaminya. Tujuan: literature review ini bertujuan untuk memaparkan pembaruan informasi terkini dan panduan tentang pengelolaan miopia. Metode: Penelitian ini adalah studi literature review dan sumber Pustaka yang digunakan melibatkan 33 pustaka yang terdiri dari 3 jurnal nasional dan 30 jurnal internasional. Hasil: Beberapa studi menunjukkan myopia dapat dicegah dan di kontrol dengan menghabiskan lebih banyak waktu diluar ruangan. Hal ini berguna untuk untuk mengurangi atau memperlambat perkembangan miopia termasuk aplikasi tetes mata atropin dosis rendah setiap hari, dalam konsentrasi berkisar antara 0,01% dan 0,05%. Kesimpulan: Miopia merupakan kelainan refraksi di mana berkas cahaya yang masuk ke mata sejajar sumbu optik dibiaskan ke dalam depan retina ketika akomodasi okular berelaksasi. Aktivitas di luar ruangan serta penggunaan tetes mata atropin dapat mencegah dan mengontrol terjadinya miopia
... In contrast, certain international studies have reported that low vitamin D levels were inversely proportional to the risk of myopia in children. 10,[16][17][18][19] Myopia is prevalent in the Asian population. 1 At present, recommended methods for preventing myopia that are supported by strong evidence are time spent outdoors, bifocal lenses, and a drop of atropine. 19 Studies on outdoor activities are a bit controversial as some have indicated no association, 19 while others reported that outdoor time was protective against myopia. ...
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Objective: To study the role of vitamin D deficiency as a risk factor for myopia in children aged 5-15 years. Method: The cross-sectional observational study was conducted from January to September 2019 at the Ophthalmology and Paediatric departments of Shifa Foundation Community Health Centre, Islamabad, Pakista. It comprised patients with suspected / symptomatic vitamin D deficiency who were enrolled from the paediatric outpatient department and referred to the ophthalmology clinics for eye exam. Apart from taking detailed ocular history, slit lamp examination, Snellen's distance visual acuity, auto-refraction to calculate spherical equivalent, and amplitude scan for measuring the axial length were performed. An average of 3 measurements was taken for both refraction and axial length calculation. Myopia was labelled if mean spherical equivalent was ≤0.25 dioptres. Vitamin D deficiency was defined as serum 25-hydroxyvitamin D level < 20ng/ml. Data was analysed using SPSS 23. Results: There were 72 subjects with a mean age of 10.11±2.69 years; 37(51.4%) boys and 35(48.6%) girls. Myopia was seen in 40(55.6%) patients, while 32(44.4%) were emmetropic. The overall mean vitamin D level was 20.25±12.18 ng/ml. There was no significant association between myopia and vitamin D deficiency (p=0.115). Significant associations were found between myopia and relatively older age (p=0.005), higher height (p=0.001), more weight (p=0.001) and higher body mass index value (p=0.008). Conclusion: Low vitamin D levels were not significantly associated with myopia in children aged 5-15 years, but significant associations were found between myopia and relatively older age, and various anthropometric measures
Purpose: To determine the role of calcipotriol, a vitamin D3 analogue, in myopia development and altering the expression of scleral α1 chain of type I collagen (Col1α1) in mice. We also aimed to identify if the signaling pathway mediating the above changes is different from the one involved in transforming growth factor β2 (TGF-β2)-mediated increases of COL1A1 in cultured human scleral fibroblasts (HSFs). Methods: C57BL/6J mice were either intraperitoneally injected with calcipotriol and subjected to form deprivation (FD) or exposed to normal refractive development for 4 weeks. Scleral vitamin D receptor (Vdr) expression was knocked down using a Sub-Tenon's capsule injection of an adeno-associated virus-packaged short hairpin RNA (AAV8-shRNA). Refraction and biometric measurements evaluated myopia development. A combination of knockdown and induction strategies determined the relative contributions of the vitamin D3 and the TGF-β2 signaling pathways in modulating COL1A1 expression in HSFs. Results: Calcipotriol injections suppressed FD-induced myopia (FDM), but it had no significant effect on normal refractive development. AAV8-shRNA injection reduced Vdr mRNA expression by 42% and shifted the refraction toward myopia (-3.15 ± 0.99D, means ± SEM) in normal eyes. In HSFs, VDR knockdown reduced calcipotriol-induced rises in COL1A1 expression, but it did not alter TGF-β2-induced increases in COL1A1 expression. Additionally, TGF-β2 augmented calcipotriol-induced rises in COL1A1 expression. TGF-β receptor (TGFBRI/II) knockdown blunted TGF-β2-induced increases in COL1A1 expression, whereas calcipotriol-induced increases in VDR and COL1A1 expression levels were unaltered. Conclusions: Scleral vitamin D3 inhibits myopia development in mice, potentially by activating a VDR-dependent signaling pathway and increasing scleral COL1A1 expression levels.
Цель исследования: определить уровень содержания витамина D3 у пациентов с катарактой в сочетании с миопией средней и высокой степени.Материалы и методы: проведено стандартное офтальмологическое обследование и изучение уровня содержания витамина D3 у 118 пациентов с катарактой. Основную группу составили 80 пациентов с катарактой в сочетании с миопией средней и высокой степени, из них 35 – со средней степенью и 45 – с высокой степенью миопии. Группу контроля составили 38 пациентов с катарактой. Уровень 25(ОН)D в сыворотке крови определяли методом иммунохемилюминесцентного анализа.Результаты: у пациентов с катарактой в сочетании с миопией средней и высокой степени в 94% случаев отмечаются офтальмологические изменения в виде выраженных нарушений связочного аппарата, увеличения ПЗО глаза, изменения толщины и плотности хрусталика. У пациентов с катарактой в сочетании с миопией высокой степени эти нарушения определяются чаще, чем при миопии средней степени. У пациентов с катарактой, катарактой в сочетании с миопией средней и высокой степени определяется снижение уровня витамина D3 в сыворотке крови. Выявлена разница в содержании витамина 25(ОН)D у пациентов обследованных групп в зависимости от пола, при этом в группе пациентов с катарактой и миопией выявлен наиболее низкий уровень 25(ОН)D у женщин по сравнению с мужчинами. У пациентов с миопией средней степени показатель уровня витамина D3 выше, чем при миопии высокой степени. У пациентов с миопией средней и высокой степени чаще выявляется дефицит витамина D3, показатели витамина D3 ниже у женщин, чем у мужчин. Заключение: определение у пациентов с катарактой в сочетании с миопией средней и высокой степени нарушений связочного аппарата и уровня витамина D3 являетсявысокочувствительным и диагностически точным тестом. Чувствительность и диагностическая точность теста определения уровня витамина D3 для пациентов c миопией составляет соответственно 93%; 75%. Определение нарушений связочного аппарата для группы пациентов с миопией имело чувствительность 93%, специфичность 81% и диагностическую точность исследования 90%. Introduction: nowadays, vitamin D3 deficiency is becoming pandemic in many countries in the world. In the development of moderate and high myopia heredity, metabolic, local functional and dystrophic disorders are important. There are no data on the study of vitamin D3 in patients with cataracts in combination with moderate and high myopia in the scientific literature, so we are going to study the level of vitamin D3 in patients with cataract.Purpose: to study ophthalmic features and vitamin D3 content in patients with cataracts combined with moderate and high myopia.Materials and methods: a standard ophthalmological examination and study of the level of vitamin D3 – level 25-hydroxyvitamin D in 118 patients with cataracts were carried out. The main group consisted of 80 patients with cataracts in combination with moderate and high myopia. 35 of them with moderate and 45 with high myopia. The control group consisted of 38 patients with cataracts. The level of 25 (OH) D in the blood serum was determined by the method of immunochemiluminescence analysis.The results of the study: in patients with cataracts in combination with moderate and high myopia, in 94% of cases, ophthalmic changes are noted in the form of pronounced disorders of the ligamentous apparatus: an increase in the PZO of the eye, changes in the thickness and density of the lens. In patients with cataracts in combination with high myopia, these disorders are determined more often than in moderate myopia. In patients with cataracts, cataracts in combination with moderate and high myopia, a decrease in the level of vitamin D3 in the blood serum is determined. There was a difference in the content of vitamin 25 (OH) D in patients of the examined groups depending on gender, while in the group of patients with cataracts and myopia, the lowest level of 25 (OH) D was found in women compared to men. Patients with moderate myopia have a higher vitamin D3 level than those with high myopia. In patients with moderate and high myopia, vitamin D3 deficiency is more often detected, vitamin D3 indicators are lower in women than in men.Conclusion: determination in patients with cataracts in combination with moderate to high myopia. disorders of the ligamentous apparatus and the status of vitamin D3 is a highly sensitive and diagnostically accurate test. The sensitivity and diagnostic accuracy of the vitamin D3 test for myopic patients is 93%, respectively; 75%. Determination of disorders of the ligamentous apparatus for a group of patients with myopia had sensitivity 93%, specificity 81% and diagnostic accuracy of the study 90%.
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To estimate the prevalence of refractive error in adults across Europe. Refractive data (mean spherical equivalent) collected between 1990 and 2013 from fifteen population-based cohort and cross-sectional studies of the European Eye Epidemiology (E3) Consortium were combined in a random effects meta-analysis stratified by 5-year age intervals and gender. Participants were excluded if they were identified as having had cataract surgery, retinal detachment, refractive surgery or other factors that might influence refraction. Estimates of refractive error prevalence were obtained including the following classifications: myopia ≤−0.75 diopters (D), high myopia ≤−6D, hyperopia ≥1D and astigmatism ≥1D. Meta-analysis of refractive error was performed for 61,946 individuals from fifteen studies with median age ranging from 44 to 81 and minimal ethnic variation (98 % European ancestry). The age-standardised prevalences (using the 2010 European Standard Population, limited to those ≥25 and <90 years old) were: myopia 30.6 % [95 % confidence interval (CI) 30.4–30.9], high myopia 2.7 % (95 % CI 2.69–2.73), hyperopia 25.2 % (95 % CI 25.0–25.4) and astigmatism 23.9 % (95 % CI 23.7–24.1). Age-specific estimates revealed a high prevalence of myopia in younger participants [47.2 % (CI 41.8–52.5) in 25–29 years-olds]. Refractive error affects just over a half of European adults. The greatest burden of refractive error is due to myopia, with high prevalence rates in young adults. Using the 2010 European population estimates, we estimate there are 227.2 million people with myopia across Europe. Electronic supplementary material The online version of this article (doi:10.1007/s10654-015-0010-0) contains supplementary material, which is available to authorized users.
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Despite accumulating data showing the various neurological actions of vitamin D (VD), its effects on brain neurochemistry are still far from fully understood. To further investigate the neurochemical influence of VD, we assessed neurotransmitter systems in the brain of rats following 6-week calcitriol (1,25-dihydroxyvitamin D) administration (50 ng/kg/day or 100 ng/kg/day). Both the two doses of calcitriol enhanced VDR protein level without affecting serum calcium and phosphate status. Rats treated with calcitriol, especially with the higher dose, exhibited elevated γ-aminobutyric acid (GABA) status. Correspondingly, the mRNA expression of glutamate decarboxylase (GAD) 67 was increased. 100 ng/kg of calcitriol administration also increased glutamate and glutamine levels in the prefrontal cortex, but did not alter glutamine synthetase (GS) expression. Additionally, calcitriol treatment promoted tyrosine hydroxylase (TH) and tryptophan hydroxylase 2 (TPH2) expression without changing dopamine and serotonin status. However, the concentrations of the metabolites of dopamine and serotonin were increased and the drug use also resulted in a significant rise of monoamine oxidase A (MAOA) expression, which might be responsible to maintain the homeostasis of dopaminergic and serotonergic neurotransmission. Collectively, the present study firstly showed the effects of calcitriol in the major neurotransmitter systems, providing new evidence for the role of VD in brain function.
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Purpose: More time outdoors is associated with a lesser risk of myopia but the underlying mechanism is unclear. We tested the hypothesis that 25-hydroxyvitamin D (vitamin D) mediates the protective effects of time outdoors against myopia. Methods: We analyzed data for children participating in the Avon Longitudinal Study of Parents and Children (ALSPAC) population-based birth cohort: Non-cycloplegic autorefraction at age 7 to 15 years; maternal report of time outdoors at age 8 years and serum vitamin D2 and D3 at age 10 years. A survival analysis hazard ratio (HR) for incident myopia was calculated for children spending a high vs. low time outdoors, before and after controlling for vitamin D level (N=3,677). Results: Total vitamin D and D3, but not D2, levels were higher in children who spent more time outdoors [mean (95% CI) vitamin D in nmol/l: Total, 60.0 (59.4 to 60.6) vs. 56.9 (55.0 to 58.8), P=0.001; D3, 55.4 (54.9 to 56.0) vs. 53.0 (51.3 to 54.9), P=0.014; D2, 5.7 (5.5 to 5.8) vs. 5.4 (5.1 to 5.8), P=0.23]. In models including both time outdoors and sunlight-exposure-related vitamin D, there was no independent association between vitamin D and incident myopia [Total, HR=0.83 (0.66 to 1.04), P=0.11; D3, HR=0.89 (0.72 to 1.10), P=0.30], whilst time outdoors retained the same strong negative association with incident myopia as in unadjusted models [HR=0.69 (0.55 to 0.86), P=0.001]. Conclusions: Total vitamin D and vitamin D3 were biomarkers for time spent outdoors, however there was no evidence they were independently associated with future myopia. Copyright © 2014 by Association for Research in Vision and Ophthalmology.
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Background and aim Restless legs syndrome (RLS) is a distressing sleep disorder that occurs worldwide. Although there have been recent developments in understanding the pathophysiology of RLS, the exact mechanism of the disease has not been well elucidated. An increased prevalence of neurologic and psychiatric diseases involving dopaminergic dysfunction in vitamin D–deficient patients led us to hypothesize that vitamin D deficiency might result in dopaminergic dysfunction and consequently, the development of RLS (in which dopaminergic dysfunction plays a pivotal role). Thus, the aim of this study was to evaluate the relationship between vitamin D deficiency and RLS. Methods One hundred and fifty-five consecutive patients, 18–65 years of age, who were admitted to the Department of Internal Medicine with musculoskeletal symptoms and who subsequently underwent neurological and electromyography (EMG) examination by the same senior neurologist, were included in this study. The patients were divided into two groups according to serum 25-hydroxyvitamin D (25(OH)D) (a vitamin D metabolite used as a measure of vitamin D status) level: 36 patients with serum 25(OH)D levels ≥20 ng/mL comprised the normal vitamin D group, and 119 patients with serum 25(OH)D levels <20 ng/mL comprised the vitamin D deficiency group. The two groups were compared for the presence of RLS and associated factors. Results The two groups were similar in terms of mean age, sex, mean body mass index (BMI), and serum levels of calcium, phosphate, alkaline phosphatase (ALP), and ferritin. The presence of RLS was significantly higher in the vitamin D deficiency group (χ2=12.87, P<0.001). Regression analysis showed vitamin D deficiency and serum 25(OH)D level to be significantly associated with the presence of RLS (odds ratio [OR] 5.085, P<0.001 and OR 1.047, P=0.006, respectively). Conclusion The present study demonstrated a possible association between vitamin D deficiency and RLS. Given the dopaminergic effects of vitamin D, 25(OH)D depletion may lead to dopaminergic dysfunction and may have a place in the etiology of RLS. Prospective vitamin D treatment studies are needed to confirm this relationship and to evaluate the efficacy of vitamin D as a treatment for RLS patients.
Vitamin D deficiency is now recognized as a pandemic. The major cause of vitamin D deficiency is the lack of appreciation that sun exposure in moderation is the major source of vitamin D for most humans. Very few foods naturally contain vitamin D, and foods that are fortified with vitamin D are often inadequate to satisfy either a child's or an adult's vitamin D requirement. Vitamin D deficiency causes rickets in children and will precipitate and exacerbate osteopenia, osteoporosis, and fractures in adults. Vitamin D deficiency has been associated with increased risk of common cancers, autoimmune diseases, hypertension, and infectious diseases. A circulating level of 25-hydroxyvitamin D of >75 nmol/L, or 30 ng/mL, is required to maximize vitamin D's beneficial effects for health. In the absence of adequate sun exposure, at least 800–1000 IU vitamin D3/d may be needed to achieve this in children and adults. Vitamin D2 may be equally effective for maintaining circulating concentrations of 25-hydroxyvitamin D when given in physiologic concentrations.
Background: There is concern about a reemergence of vitamin D deficiency in children in developed countries. Objectives: The aims of this study were to describe vitamin D status in the Generation R study, a large multiethnic cohort of 6-y-old children in The Netherlands, and to examine sociodemographic, lifestyle, and dietary determinants of vitamin D deficiency. Methods: We measured serum 25-hydroxyvitamin D [25(OH)D] concentrations in 4167 children aged 6 y and defined deficiency following recommended cutoffs. We examined the associations between subject characteristics and vitamin D deficiency with the use of multivariable logistic regression analyses. Results: Serum 25(OH)D concentrations ranged from 4 to 211 nmol/L (median 64 nmol/L), with 6.2% of the children having severely deficient (<25 nmol/L), 23.6% deficient (25 to <50 nmol/L), 36.5% sufficient (50 to <75 nmol/L), and 33.7% optimal (≥75 nmol/L) 25(OH)D concentrations. The prevalence of vitamin D deficiency [25(OH)D <50 nmol/L] was higher in winter (51.3%) than in summer (10.3%); and higher in African, Asian, Turkish, and Moroccan children (54.5%) than in those with a Dutch or other Western ethnic background (17.6%). In multivariable models, several factors were associated with vitamin D deficiency, including household income (OR 1.74; 95% CI: 1.34, 2.27 for low vs. high income), child age (OR 1.39; 95% CI: 1.20, 1.62 per year), child television watching (OR 1.32; 95% CI: 1.06, 1.64 for ≥2 vs. <2 h/d), and playing outside (OR 0.71; 95% CI: 0.57, 0.89 for ≥1 vs. <1 h/d). In a subgroup with dietary data (n = 1915), vitamin D deficiency was associated with a lower diet quality, but not with vitamin D intake or supplement use in early childhood. Conclusions: Suboptimal vitamin D status is common among 6-y-old children in The Netherlands, especially among non-Western children and in winter and spring. Important modifiable factors associated with vitamin D deficiency were overall diet quality, sedentary behavior, and playing outside.
The Generation R Study is a population-based prospective cohort study from fetal life until adulthood. The study is designed to identify early environmental and genetic causes and causal pathways leading to normal and abnormal growth, development and health from fetal life, childhood and young adulthood. In total, 9,778 mothers were enrolled in the study. Data collection in children and their parents include questionnaires, interviews, detailed physical and ultrasound examinations, behavioural observations, Magnetic Resonance Imaging and biological samples. Efforts have been conducted for collecting biological samples including blood, hair, faeces, nasal swabs, saliva and urine samples and generating genomics data on DNA, RNA and microbiome. In this paper, we give an update of the collection, processing and storage of these biological samples and available measures. Together with detailed phenotype measurements, these biological samples provide a unique resource for epidemiological studies focused on environmental exposures, genetic and genomic determinants and their interactions in relation to growth, health and development from fetal life onwards.
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.
Current therapies for Parkinson's disease (PD) offer symptomatic relief but do not provide a cure or slow the disease process. Treatments that could halt progression of the disease or help restore function to damaged neurons would be of substantial benefit. Calcitriol, the active metabolite of vitamin D, has been shown to have significant effects on the brain. These effects include upregulating trophic factor levels, and reducing the severity of some central nervous system lesions. While previous studies have shown that calcitriol can be neuroprotective in 6-hydroxydopamine (6-OHDA) rodent models of PD, the present experiments were designed to examine the ability of calcitriol to promote restoration of extracellular dopamine (DA) levels and tissue content of DA in animals previously lesioned with 6-OHDA. Male Fischer-344 rats were given a single injection of 12 µg 6-OHDA into the right striatum. Four weeks later the animals were administered vehicle or calcitriol (0.3 or 1.0 µg/kg, s.c.) once a day for eight consecutive days. Three weeks after the calcitriol treatments in vivo microdialysis experiments were conducted to measure potassium and amphetamine evoked overflow of DA from both the left and right striata. In control animals treated with 6-OHDA and vehicle there were significant reductions in both potassium and amphetamine evoked overflow of DA on the lesioned side of the brain compared to the contralateral side. In animals treated with 6-OHDA followed by calcitriol there was significantly greater potassium and amphetamine evoked overflow of DA from the lesioned striatum compared to that from the control animals. The calcitriol treatments also led to increases in postmortem tissue levels of DA in the striatum and substantia nigra. These results suggest that calcitriol may help promote recovery of dopaminergic functioning in injured nigrostriatal neurons.