parkinson 's disease ( pd ) is the second most common neurodegenerative disorder after alzheimer 's disease in the elderly .
clinically , pd is characterized by tremor , rigidity , slowness of movement , and postural imbalance .
although its etiology is not fully understood , pd is suggested to involve interactions between a susceptible genetic background and environmental factors .
vitamin d , which is now considered a hormone rather than a vitamin , is suggested to be an environmentally modifiable factor in the pathogenesis of pd recently .
a long - term cohort study from finland suggested that low serum vitamin d is a predictive factor for high risk of pd .
the vitamin d receptor ( vdr ) is the key mediator of vitamin d 's functions . upon binding to 1 , 25-dihydroxy vitamin d3 , the biologically active form of vitamin d
, vdr is activated and interacts with vitamin d responsive elements in the promoters of vitamin d target genes to regulate their expression .
interestingly , vdr is most highly expressed in dopaminergic neurons of the substantia nigra and an earlier animal study with knockout of vdr gene resulted in rats with muscular and motor impairments . all these suggested a role of vdr in the pathogenesis of pd .
previous results showed that variations in the vdr gene influence receptor activation by altering the affinity of the receptor for vitamin d. recently , butler et al . suggested that the vdr gene is a candidate gene for promoting pd and then a number of restriction fragment length polymorphisms ( rflp ) in this gene
have been studied . among the accumulating studies on the association between vdr gene and pd in recent years , polymorphisms of apai ( rs7975232 ) , bsmi ( rs1544410 ) , foki
( rs10735810 ) , and taqi ( rs731236 ) have been most extensively investigated , but results to date are inconsistent .
the discrepancies in findings may be attributed to small sample sizes , clinical heterogeneity , statistical power or a combination of these factors . to overcome the limitations of individual studies
, we performed a meta - analysis to investigate the effects of these polymorphisms on pd .
relevant publications were identified by conducting a literature search in pubmed , embase , ebsco , china national knowledge infrastructure , weipu database , and wanfang database up to january 2015 , with the following terms and combinations : vdr , calcitriol receptors , polymorphism , single nucleotide polymorphism , variant , pd .
the references of the identified studies and reviews were additionally screened to determine other potential eligible studies .
the inclusion criteria were as follows : ( 1 ) case  control studies ; ( 2 ) studies analyzing the association of apai , bsmi , foki , and taqi gene polymorphisms and pd risk ; ( 3 ) those reporting sufficient genotype data to calculate the odds ratio ( or ) and corresponding 95% confidence interval ( ci ) and ; ( 4 ) cases in the control group are publication - based or hospital - based which are matched for gender and age .
studies were excluded for the following reasons : ( 1 ) case reports or reviews ; ( 2 ) family - based studies ; ( 3 ) insufficient genotype data for calculation and ; ( 4 ) genotype distribution of controls not in hardy - weinberg equilibrium ( hwe ) , indicating the chance of bias during control selection or genotyping errors .
in addition , we checked the polymerase chain reaction primer sequence in genebank ( http://www.ncbi.nlm.nih.gov/genebank/index.html ) to confirm whether the selected genes were the target genes .
the quality of studies was independently assessed by the two reviewers using the newcastle - ottawa scale ( nos ) based on three aspects : selection , comparability , and exposure of cases and controls .
nos scores ranged from 0 to 9 , and studies with a score equal to or higher than six were regarded as high quality .
two investigators reviewed the publications independently and extracted the relevant information from each eligible study based on criteria in a standard data form , including name of first author , year of publication , ethnicity of the study population , number of cases and controls , matching criteria , source of controls , allele and genotype frequency , genotyping method , and evidence of hwe in controls .
cochrane review manager version 5.3 ( cochrane library , oxford , uk ) was used to calculate available data from each study .
the pooled or and 95% ci were calculated to measure the genetic association between vdr polymorphisms and risk of pd in four genetic models , including additive genetic model ( m vs. w ) , codominant model ( mm vs. ww and mw vs. ww ) , dominant model ( mm + mw vs. ww ) and recessive model ( mm vs. mw + ww ) . here ,
 m  represent  wild - type  and  mutant type ,  respectively . the significance of or was determined with the z - test , in which p < 0.05 was considered statistically significant .
the degree of heterogeneity between studies was detected using the q - test and i - statistics .
i values of 25% , 50% , and 75% were assigned as low , moderate , and high estimates , respectively .
the fixed - effects model was adopted at pq > 0.05 or i < 50% .
sensitivity analysis was conducted by omitting each study to assess the stability of the results .
publication bias was assessed using begger 's funnel plots and egger 's linear regression test by stata 12.0 software ( stata coporation , tx , usa ) .
relevant publications were identified by conducting a literature search in pubmed , embase , ebsco , china national knowledge infrastructure , weipu database , and wanfang database up to january 2015 , with the following terms and combinations : vdr , calcitriol receptors , polymorphism , single nucleotide polymorphism , variant , pd .
the references of the identified studies and reviews were additionally screened to determine other potential eligible studies .
the inclusion criteria were as follows : ( 1 ) case  control studies ; ( 2 ) studies analyzing the association of apai , bsmi , foki , and taqi gene polymorphisms and pd risk ; ( 3 ) those reporting sufficient genotype data to calculate the odds ratio ( or ) and corresponding 95% confidence interval ( ci ) and ; ( 4 ) cases in the control group are publication - based or hospital - based which are matched for gender and age .
studies were excluded for the following reasons : ( 1 ) case reports or reviews ; ( 2 ) family - based studies ; ( 3 ) insufficient genotype data for calculation and ; ( 4 ) genotype distribution of controls not in hardy - weinberg equilibrium ( hwe ) , indicating the chance of bias during control selection or genotyping errors .
in addition , we checked the polymerase chain reaction primer sequence in genebank ( http://www.ncbi.nlm.nih.gov/genebank/index.html ) to confirm whether the selected genes were the target genes .
the quality of studies was independently assessed by the two reviewers using the newcastle - ottawa scale ( nos ) based on three aspects : selection , comparability , and exposure of cases and controls .
nos scores ranged from 0 to 9 , and studies with a score equal to or higher than six were regarded as high quality .
two investigators reviewed the publications independently and extracted the relevant information from each eligible study based on criteria in a standard data form , including name of first author , year of publication , ethnicity of the study population , number of cases and controls , matching criteria , source of controls , allele and genotype frequency , genotyping method , and evidence of hwe in controls .
cochrane review manager version 5.3 ( cochrane library , oxford , uk ) was used to calculate available data from each study .
the pooled or and 95% ci were calculated to measure the genetic association between vdr polymorphisms and risk of pd in four genetic models , including additive genetic model ( m vs. w ) , codominant model ( mm vs. ww and mw vs. ww ) , dominant model ( mm + mw vs. ww ) and recessive model ( mm vs. mw + ww ) . here ,
 m  represent  wild - type  and  mutant type ,  respectively . the significance of or was determined with the z - test , in which p < 0.05 was considered statistically significant .
the degree of heterogeneity between studies was detected using the q - test and i - statistics .
i values of 25% , 50% , and 75% were assigned as low , moderate , and high estimates , respectively .
the fixed - effects model was adopted at pq > 0.05 or i < 50% .
sensitivity analysis was conducted by omitting each study to assess the stability of the results .
publication bias was assessed using begger 's funnel plots and egger 's linear regression test by stata 12.0 software ( stata coporation , tx , usa ) .
in total , 60 studies relevant to search keywords were identified , from which 30 repeated publications , 10 reviews and 8 irrelevant polymorphism studies were excluded , leaving 12 studies . after a full - text review ,
three of these studies were excluded , as they were not case - control analyses , and two were excluded owing to insufficient genotype data [ figure 1 ] . ultimately , seven case - control studies involving 2034 pd patients and 2432 healthy individuals met our inclusion criteria .
, four focused on apai , four on bsmi , two on foki , and four on taqi gene polymorphisms .
all genotype distributions in the controls in this meta - analysis did not deviate from hwe [ table 1 ] .
characteristics of the eligible studies snp : single nucleotide polymorphism ; pb : population - based ; hb : hospital - based ; hwe : hardy - weinberg equilibrium ; nos : newcastle - ottawa scale ; pcr - rflp : polymerase chain reaction - restriction fragment length polymorphism .
the results of the assessment of correlations between vdr polymorphisms and pd are shown in tables 2 and 3 .
meta - analysis was performed for a combined asian and caucasian population and by each individual ethnic category . in overall population ,
no evidence of significant association between apai ( g / t ) , bsmi ( g / a ) or taqi ( t / c ) polymorphisms and pd was observed under all genetic models [ table 2 ] . for foki ( c / t ) polymorphism
, we found it was significantly associated with pd risk under the additive , codominant model and dominant model ( c vs. t : or = 1.41 , 95% ci : 1.141.75 , p = 0.001 ; cc vs. tt : or = 2.45 , 95% ci : 1.523.93 , p = 0.0002 ; ct vs. tt : or = 2.21 , 95% ci : 1.383.52 , p = 0.0009 , cc vs. ct+tt : or = 2.32 , 95% ci : 1.493.61 , p = 0.0002 ) .
meta - analysis of the association between vdr gene polymorphism and pd or : odds ratio ; ci : confidence interval ; vdr : vitamin d receptor ; pd : parkinson s disease ; snp : single nucleotide polymorphism . subgroup analysis of the association between the vdr gene polymorphism and pd or : odds ratio ; ci : confidence interval ; vdr : vitamin d receptor ; pd : parkinson s disease ; snp : single nucleotide polymorphism .
consistently , ethnicity - specific analysis revealed no association between apai , bsmi or taqi polymorphisms and pd risk while a significant association between foki ( c / t ) polymorphisms and pd was observed in both asian and caucasian population [ table 3 ] .
a sensitivity analysis was additionally conducted in which one study at a time was removed .
the results showed no significant alterations in pooled or and 95% ci values , indicating that our analysis is statistically robust .
no between - study heterogeneity was found in analyses of the apai , bsmi or taqi polymorphisms in the combined population .
visual inspection of funnel plots did not find any evidence of funnel plot asymmetry [ figure 2 ] .
statistical result of egger 's test till did not show publication bias among studies [ table 2 ] .
funnel plots for vitamin d receptor gene polymorphisms and parkinson 's disease ( [ a ] t vs. g of apai ; [ b ] a vs. g of bsmi ; [ c ] c vs. t of foki ; [ d ] c vs. t of taqi ) .
in total , 60 studies relevant to search keywords were identified , from which 30 repeated publications , 10 reviews and 8 irrelevant polymorphism studies were excluded , leaving 12 studies . after a full - text review ,
three of these studies were excluded , as they were not case - control analyses , and two were excluded owing to insufficient genotype data [ figure 1 ] . ultimately , seven case - control studies involving 2034 pd patients and 2432 healthy individuals met our inclusion criteria .
, four focused on apai , four on bsmi , two on foki , and four on taqi gene polymorphisms .
all genotype distributions in the controls in this meta - analysis did not deviate from hwe [ table 1 ] .
characteristics of the eligible studies snp : single nucleotide polymorphism ; pb : population - based ; hb : hospital - based ; hwe : hardy - weinberg equilibrium ; nos : newcastle - ottawa scale ; pcr - rflp : polymerase chain reaction - restriction fragment length polymorphism .
the results of the assessment of correlations between vdr polymorphisms and pd are shown in tables 2 and 3 .
meta - analysis was performed for a combined asian and caucasian population and by each individual ethnic category . in overall population ,
no evidence of significant association between apai ( g / t ) , bsmi ( g / a ) or taqi ( t / c ) polymorphisms and pd was observed under all genetic models [ table 2 ] . for foki ( c / t ) polymorphism
, we found it was significantly associated with pd risk under the additive , codominant model and dominant model ( c vs. t : or = 1.41 , 95% ci : 1.141.75 , p = 0.001 ; cc vs. tt : or = 2.45 , 95% ci : 1.523.93 , p = 0.0002 ; ct vs. tt : or = 2.21 , 95% ci : 1.383.52 , p = 0.0009 , cc vs. ct+tt : or = 2.32 , 95% ci : 1.493.61 , p = 0.0002 ) .
meta - analysis of the association between vdr gene polymorphism and pd or : odds ratio ; ci : confidence interval ; vdr : vitamin d receptor ; pd : parkinson s disease ; snp : single nucleotide polymorphism .
subgroup analysis of the association between the vdr gene polymorphism and pd or : odds ratio ; ci : confidence interval ; vdr : vitamin d receptor ; pd : parkinson s disease ; snp : single nucleotide polymorphism .
consistently , ethnicity - specific analysis revealed no association between apai , bsmi or taqi polymorphisms and pd risk while a significant association between foki ( c / t ) polymorphisms and pd was observed in both asian and caucasian population [ table 3 ] .
a sensitivity analysis was additionally conducted in which one study at a time was removed .
the results showed no significant alterations in pooled or and 95% ci values , indicating that our analysis is statistically robust .
no between - study heterogeneity was found in analyses of the apai , bsmi or taqi polymorphisms in the combined population .
visual inspection of funnel plots did not find any evidence of funnel plot asymmetry [ figure 2 ] .
statistical result of egger 's test till did not show publication bias among studies [ table 2 ] .
funnel plots for vitamin d receptor gene polymorphisms and parkinson 's disease ( [ a ] t vs. g of apai ; [ b ] a vs. g of bsmi ; [ c ] c vs. t of foki ; [ d ] c vs. t of taqi ) .
although the multifactorial nature of pd is well - recognized , genetic factors are considered the significant determinants .
numerous genes have been studied in connection with pd , and the vdr gene has been one of the research hotspots recently . it is suggested that genetic polymorphisms in the vdr gene alter the affinity of the receptor for vitamin d , which may be an environmentally modifiable factor in the pathogenesis of pd .
given the potential association between vdr and pd , vdr polymorphisms affecting its expression have been analyzed to determine their potential effects on pd .
the human vdr gene contains eight exons and seven introns spanning > 75 kb dna on chromosome 12q12 . to date , over 60 polymorphisms have been identified for vdr genes .
these subtle dna sequence variations , which often occur in the population , have a modest but real biological effect . among these , apai , bsmi , foki , and taqi
polymorphisms have been most intensively investigated in relation to pd as well as other neurodegenerative diseases .
however , controversial results have been obtained . to establish the association of vdr apai , bsmi , foki , and taqi polymorphisms with risk of pd
, we performed a meta - analysis of seven studies ( including 2034 pd cases and 2432 controls ) .
we failed to detect any association between apal , bsml , taql polymorphisms and pd susceptibility in all four genetic models .
a previous study suggested strong linkage disequilibrium for bsmi , apai , and taqi rflps , which may explain the high degree of consistency between these three polymorphisms and their link to pd susceptibility .
these three polymorphisms are located at the 3end of the vdr gene neighboring the 3utr region , which do not result in changes in the predicted amino acid sequence of the vdr .
however , one thing we should pay attention to is that the serum vitamin d level , which most of the included studies did not measure , may influence the effect size of a vdr polymorphism . in a study analyzing association between vdr polymorphisms and incidence of type i diabetes mellitus , the or of the risk allele increasing with higher vitamin d levels in the studied population .
a recent report that the positive association between vdr genetic variants and multiple sclerosis was found in studies conducted in regions at lower latitudes but rather than higher latitudes .
therefore , it is important to include measurement of serum vitamin d levels in future studies to better characterize the genetic effects of vdr polymorphisms in pd .
our data suggest that foki ( c / t ) polymorphism is significantly associated with pd and the c allele may increase the risk of pd .
the foki polymorphism is located in exon 2 at the 5 coding region of the gene .
previous studies by gross et al . suggested that vdr encoded by the c allele is three amino acids shorter than that encoded by the t allele .
however , since there are only two studies on the foki ( c / t ) gene polymorphism have been documented , one in an asian and the other in a caucasian population . although the results from both investigations were consistent , data should be carefully interpreted because of the relatively small sample sizes .
additional studies with larger sample sizes are necessary to verify the role of foki polymorphisms in pd .
first , the number of cases and controls involved in the meta - analysis were limited , which could increase the probability of false positives or false negatives .
second , although publication bias among studies were not detected , and the quality of our studies was good ( nos6 ) , the possibility of bias could not be eliminated because of the relatively small sample size .
third , factors such as gene - gene or gene - environment interactions may influence the gene - disease factor .
however , the lack of individual data from the included studies limited further evaluation of these potential interactions .
data from our meta - analysis suggest that the apai , bsmi , and taqi gene polymorphisms are not significantly associated with pd while the foki ( c / t ) polymorphism may increase pd risk .
given the limitations mentioned above , further studies with more specific common information and larger sample sizes are warranted .
furthermore , additional investigations are required to determine the biological mechanisms underlying the observed associations and their potential relationship with pd .
 background : the vitamin d receptor ( vdr ) gene has been identified as a candidate gene for susceptibility to parkinson 's disease ( pd ) , but results from genetic association studies to date are inconsistent . here 
 , we conducted a meta - analysis of published case - control studies to evaluate the association of the extensively studied vdr apai ( g / t ) , bsmi ( g / a ) , foki ( c / t ) , and taqi ( t / c ) gene polymorphisms with risk of pd.methods:electronic search at pubmed , embase , ebsco , china national knowledge infrastructure , weipu database , and wanfang database was conducted to identify all relevant studies . 
 odds ratio ( or ) with 95% confidence interval ( ci ) values was applied to evaluate the strength of the association.results:a total of seven studies with 2034 pd cases and 2432 controls were included in the meta - analysis following the inclusion and exclusion criteria . 
 overall , no significant association between apai , bsmi , and taqi gene polymorphisms and pd susceptibility in all four genetic models was found ( t vs. g : or = 1.00 , 95% ci : 0.891.12 , p = 0.97 ; a vs. g : or = 0.94 , 95% ci : 0.771.15 , p = 0.53 ; c vs. t : or = 1.03 , 95% ci : 0.851.25 , p = 0.77 ) while a significant association between foki ( c / t ) and pd risk was observed ( c vs. t : or = 1.41 , 95% ci : 1.141.75 , p = 0.001 ; cc vs. tt : or = 2.45 , 95% ci : 1.523.93 , p = 0.0002 ; ct vs. tt : or = 2.21 , 95% ci : 1.383.52 , p = 0.0009 , cc vs. ct+tt : or = 2.32 , 95% ci : 1.493.61 , p = 0.0002).conclusions : polymorphisms of apai , bsmi , and taqi may not be associated with the susceptibility to pd while the foki ( c / t ) polymorphism is possibly associated with increased pd risk . 
 however , conclusions should be cautiously interpreted due to the relatively small number of studies included . 