Neurol Sci DOI 10.1007/s10072-014-1928-9
ORIGINAL ARTICLE
Vitamin D receptor gene polymorphisms and the risk of Parkinson’s disease Chunlei Li • Huiping Qi • Shuqin Wei • Le Wang • Xiaoxue Fan • Shurong Duan Sheng Bi
•
Received: 24 May 2014 / Accepted: 18 August 2014 Ó Springer-Verlag Italia 2014
Abstract The effect of vitamin D receptor (VDR) gene polymorphisms on Parkinson’s disease (PD) has recently gained interest. However, evidence on this relationship is controversial. We searched PubMed, EMBASE and the Cochrane Library database targeted all studies that evaluated VDR gene polymorphisms and PD up to April 2,014. A meta-analysis was conducted on the association between VDR ApaI, BsmI, TaqI and FokI polymorphisms and PD using (1) allelic contrast, (2) dominant, (3) recessive, and (4) additive models. A total of five relevant studies involving PD patients (n = 1,266) and controls (n = 1,649) were included in the analysis. There was a significant association between FokI polymorphism and PD. In the pooled allelic analysis, the F allele was associated with increased risk of PD (OR 1.41, 95 % CI 1.14–1.75). In the genotype analysis, FF ? Ff versus ff
showed a significant association with PD in the dominant model (OR 2.32, 95 % CI 1.49–3.61, P = 0.0002). FF versus ff showed a significant association with PD in the additive model (OR 2.45, 95 % CI 1.52–3.93, P = 0.0002). There was also a statistically significant association between VDR BsmI polymorphisms in the recessive model, BB versus Bb ? bb showed a significant increased risk of PD (OR 1.37, 95 % CI 1.01–1.87, P = 0.04). No significant associations were observed between VDR ApaI and TaqI polymorphisms and PD. To sum up, VDR BsmI and FokI polymorphisms were associated with increased risk of PD. Keywords Vitamin D receptor gene Parkinson’s disease Polymorphisms Meta-analysis
Introduction Electronic supplementary material The online version of this article (doi:10.1007/s10072-014-1928-9) contains supplementary material, which is available to authorized users. C. Li Department of Rehabilitation, The First Affiliated Hospital, Harbin Medical University, 150001 Harbin, China H. Qi Department of Neurology, The Fourth Affiliated Hospital, Harbin Medical University, 150001 Harbin, China S. Wei Saint-Justine Research Center, University of Montreal, Montreal, Canada L. Wang X. Fan S. Duan S. Bi (&) Department of Neurology, The First Affiliated Hospital, Harbin Medical University, 150001 Harbin, China e-mail: [email protected]; [email protected]
Parkinson’s disease (PD) is a progressive movement disorder, characterized clinically by bradykinesia, tremor, rigidity, flexed posture, postural instability, and freezing of gait. The majority of PD cases result from complex interplay between environmental and genetic factors [1]. Several genetic risk factors and gene–environment interactions for PD have been reported [2–6]. Vitamin D level is an environmentally modifiable factor as it is largely determined by diet and sunlight exposure. The effects of vitamin D and genetic variants in the vitamin D receptor (VDR) gene have recently gained interest in PD and neurodegenerative research in general [7–9]. VDR is the primary mediator of vitamin D’s biological actions. VDR gene polymorphisms influence on VDR protein function [10]. Within the brain, the highest expression of VDR and 1a-hydroxylase was found in the
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hypothalamus and in the dopaminergic neurons of the substantia nigra [11]. VDR gene polymorphisms, occurring in intron 8 (BsmI and ApaI sites), exon 9 (TaqI site) and exon 2 (FokI site), have been reported to be associated with several neurodegenerative diseases, including multiple sclerosis and Alzheimer disease [12, 13]. To date, a number of studies have reported the relationship between VDR (ApaI, BsmI, FokI and TaqI) gene polymorphisms and the risk of PD [14–16]. However, the results were controversial. There are two recently published meta-analyses [17, 18] on the relationship between VDR genetic variants and PD, however, the results are conflict. With the accumulating evidence, we therefore performed this meta-analysis to investigate the association between VDR gene polymorphisms and the susceptibility of PD, with the aim of providing a much more reliable finding on the significance of the association.
quality of each study which meets the predefined methodological quality assessment criteria for non-randomized observational studies (Table 1) [22]. Statistical analysis The strength of the associations between VDR (ApaI, BsmI, FokI, TaqI) gene polymorphisms and risk of PD were estimated by pooled odds ratio (OR) with 95 % confidence intervals (CIs). The statistical analyses were performed using (1) the allelic contrast, (2) the dominant, (3) the recessive, and (4) the additive genetic models. All statistical analyses were performed using Revman 5.2 provided by the Cochrane Collaboration (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008).
Results Methods
Literature search
All procedure followed the guidelines for meta-analysis of observational studies in epidemiology (MOOSE) [19].
We first retrieved 78 relevant citations from the PubMed, EMBASE and the Cochrane Library database. A total of five relevant studies involving PD patients (n = 1,266) and controls (n = 1,649) were included in the analysis. Figure 1 summarizes the process of literature search and selection of these studies. Table 2 shows the frequencies of M (A, B, F, T) allele of VDR gene in cases and controls.
Data sources The electronic searches on PubMed, EMBASE and the Cochrane Library database targeted all studies that evaluated VDR gene polymorphisms and PD up to April 2014. The keywords were: ‘Parkinson’s disease’ or ‘PD’ and ‘ApaI (rs7975232), BsmI (rs1544410), FokI (rs2228570) and TaqI (rs731236)’ and ‘polymorphism’ or ‘mutation’ or ‘variant’ or ‘genotype’ or ‘SNP’. An additional search was performed through the references cited in identified articles. Inclusion and exclusion criteria Inclusion criteria: (1) observational study including cohort study, case–control study; (2) the outcome was PD; (3) the diagnostic criteria for PD—clinical signs, Hoehn & Yahr (HY) stage [20]. Unified Parkinson’s Disease Rating Stage (UPDRS) [21]; and (4) at least two comparison groups (PD group versus control group). Exclusion criteria: (1) case reports, editorials and reviews; (2) Secondary forms of parkinsonism were excluded.; (3) relationship between other genes and PD risk; (4) duplicated or overlapping studies; and (5) study of the role of VDR to diseases. Data extraction and synthesis Data were recorded as follows: first author’s surname, year of publication, country, number of cases and controls for VDR (ApaI, BsmI, FokI, TaqI) genotype. We assessed the
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Quality scale Table 3 presents the quality scores of the five included studies. The characteristics of the included studies are summarized in Table 4. Total citations identified from electronic searches on VDR polymorphisms and Parkinson’s disease (n=78) Citations excluded after screening titles and /or abstracts (n=32) Primary articles retrieved for more detailed evaluation (n=46) Exclusions: reviews=5, not genetic polymorphism =18, not Parkinson’s disease =16 Full text articles potentially to be included (n=7) Exclusions for not meeting the quality assessment criteria=2 Included studies in systematic review (n=5)
Fig. 1 Flow chart of study selection process in this meta-analysis
Neurol Sci Table 1 Quality assessment of observational studies (total 10 points) Selection of participants (1/0) Cohort studies (1/0) Selected cohort was representative of the general population (population-based studies) or target catchment population (hospital-based studies) (1) Cohort was a selected unrepresentative group (0) Case control studies (1/0) Cases and controls drawn from the same population (1) Cases and controls drawn from different sources or the selection of groups (0) 2. Comparability of groups (2/0) No significant differences between the groups reported in terms of age, plurality, smoking, history of preterm birth, preeclampsia or gestational diabetes, pre-existing medical conditions were explicitly reported, or these differences were adjusted for (2) Differences between groups were not examined (1) Groups differed and no adjustment results provided (0) 3. Definition of outcomes (2/0) Definition of outcomes Referenced or standard definition (2) Explicit non-standard definition (1) Unspecified or unacceptable definition (0) 4. Ascertainment of outcomes (2/0) How the diagnosis was made Prospectively diagnosed or review of notes/hospital discharge records (2) Retrospective chart review or database coding (1) Process not described (0) 5. Sample size (1/0) C200 participants in a cohort study; C50 participants in either group (case/control) (1) 100B participants \200 in a cohort; 25B participants \50 in either group (case/control) (0.5) Participants \100 or total number of events \10 in a cohort; participants \25 in either group (case/control) (0) 6. Study design (2/0) Prospective cohort or nested case-control within a prospective cohort (2) Cross-sectional, case-control or retrospective cohort (1) Not described or poorly designed (0) Exclusion : score zero in any item (1–6) or a total score \7 out of 10 maximal points A score based quality assessment criteria for non-randomized observational studies adapted from Duckitt and Harrington [22]
Study characteristics for ApaI polymorphism with the risk of PD
association with PD (OR 1.37, 95 % CI 1.01–1.87, P = 0.04, Fig. 2).
A total of 921 cases and 1,136 controls were included. In the pooled allelic analysis, the A allele was not associated with risk of PD. In the genotype analysis, there were no significant associations at the dominant, recessive and additive genetic models (Table 5).
Study characteristics for FokI polymorphism with the risk of PD
Study characteristics for BsmI polymorphism with the risk of PD A total of 566 cases and 857 controls were included in four studies. In the genotype analysis, BB versus Bb ? bb (recessive model) showed a statistically significant
There was two studies including 751 participants presented at Table 2. In the pooled allelic analysis, the F allele was associated with increased risk of PD (OR1.41, 95 % CI 1.14–1.75, Fig. 3, Table 5). In the genotype analysis, FF ? Ff versus ff (dominant model) showed a significant association with PD (OR 2.32, 95 % CI 1.49–3.61, P = 0.0002, Fig. 4). FF versus ff (additive model) showed a significant association with PD (OR 2.45, 95 % CI 1.52–3.93, P = 0.0002, Fig. 5).
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Neurol Sci Table 2 Characteristics of studies of VDR gene polymorphisms on the risk of Parkinson’s disease Polymorphism
Case
Control
First author, year
MM
MN
NN
234
361
34
62
42
M allele (%)
Total
MM
MN
NN
Total
Case
Control
105
700
250
401
141
792
59.2
56.9
25
121
58
120
56
235
53.7
50.4
43
15
100
42
46
21
109
63.5
59.6
ApaIa Lin [25] Petersen [26] To¨ro¨k [28] BsmIb Han [23] Kim [24] Petersen [26] To¨ro¨k [28]
4
34
222
260
2
36
244
282
8.1
7.1
72 48
11 53
2 20
85 121
168 84
60 117
3 34
231 235
91.2 61.6
85.7 60.6
27
49
24
100
27
57
25
109
51.5
51.0
114
124
22
260
109
126
47
282
67.7
61.0
42
48
10
100
35
49
25
109
66.0
54.6
47
54
20
121
81
119
34
235
61.2
60.0
17
48
35
100
16
46
47
109
41.0
35.8
FokIc Han [23] To¨ro¨k [28] TaqId Petersen [26] To¨ro¨k [28] a
M = A, N = a
b
M = B, N = b
c
M = F, N = f
d
M = T, N = t VDR vitamin D receptor
Table 3 Quality scores of included studies on vitamin D receptor gene BsmI, FokI, ApaI and TaqI polymorphisms and the risk of Parkinson’s disease
Study
Selection of participants
Comparability of groups
Ascertainment
Sample size
Study design
Total score
Han [23]
1
2
2
2
1
1
9
Lin [25]
1
2
2
2
1
1
9
Kim [24]
1
2
2
2
1
1
9
Petersen [26] To¨ro¨k [28]
1
2
2
2
1
1
9
1
2
2
2
1
1
9
Study characteristics for TaqI polymorphism with the risk of PD A total of 221 cases and 344 controls were included in two studies. In the pooled allelic analysis, the A allele was not associated with risk of PD. In the genotype analysis, there were no significant associations at the dominant, recessive and additive genetic models (Table 5).
Discussion The main findings of this meta-analysis are that VDR gene BsmI polymorphism was associated with an increased risk of PD. And in the pooled allelic analysis, the FokI polymorphism F allele was associated with 1.4 odds increased
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Outcomes definition
risk of PD. In the genotype analysis, FF ? Ff versus ff showed a significant association with PD in dominant model. FF versus ff (additive model) showed a significant association with PD. However, no significant risk of PD was observed either in the ApaI polymorphism or the TaqI polymorphism in VDR gene. There are two recent meta-analysis [17, 18] on the associations between VDR polymorphisms and PD, however, their results are conflict. Zi Teng Zhang et al. [17] conducted a meta-analysis on VDR polymorphisms and PD, their results indicate that VDR genetic polymorphisms Bsml, Apal and Taql were not associated with susceptibility to PD. We found that their data analysis included repeated studies’ data which might contribute the different results. In addition, they did not evaluate the relationship between FokI polymorphisms and PD in their
China
China, Taiwan
South Korea
Faroe Islands
Hungary
Han [23]
Lin [25]
Kim [24]
Petersen [26]
To¨ro¨k [28] Case–control
Case–control
Case–control
Case–control
Case–control
Study design
209
356
316
1,492
542
Sample size (n)
56/44
48/73
55/30
305/395
94/166
55/54
93/142
NA
NA
113/169
66.4 (9.3)
74.5 (9.9)
64.55 (8.86)
68.7 (11.2)
70.9 (6.1)
64.0 (8.2)
75.0 (9.9)
62.05 (10.44)
NA
69.4 (9.7)
Control
PD
PD
Control
Mean age (year)
Gender (females/males)
PCR polymerase chain reaction-restriction, PCR–RFLP fragment length polymorphism, NA not available
Country
Study
Table 4 Characteristics of the included studies of VDR gene polymorphisms and the risk of PD
PCR–RFLP
BsmI
PCR
TaqI
FokI
BsmI
ApaI
TaqI
ApaI
BsmI
ApaI
FokI
BsmI
Polymorphism
Real-time
PCR–RFLP
PCR
Real-time
PCR–RFLP
Method
Evaluated by movement disorders in terms of the Hoehn and Yahr stage [20] and the Unified Parkinson’s Disease Rating Scale (UPDRS)
The United Kingdom Parkinson’s Disease Brain Bank criteria [37]
(UPDRS) [21] motor subscale
Tremor, rigidity, bradykinesia. unified Parkinson’s disease rating scale
The UK PD Society Brain Bank clinical diagnostic criteria [36]
Canadian Neurodegenerative Disorders centre [35]
Diagnoses criteria
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Neurol Sci Table 5 Vitamin D receptor gene polymorphisms and the risk of Parkinson’s disease Polymorphism
Level of heterogeneity I2 (X2 P)
Analysis model
OR(95 % CI)
Test for overall effect Z (P)
ApaI A versus a
0 % (0.93)
Fixed effect
1.12 (0.98–1.26)
1.72 (0.09)
AA ? Aa versus aa (dominant)
0 % (0.97)
Fixed effect
1.24 (0.98–1.56)
1.82 (0.07)
AA versus Aa ?aa (recessive)
0 % (0.94)
Fixed effect
1.11 (0.92–1.34
1.10 (0.27)
AA versus aa (additive)
0 % (0.97)
Fixed effect
1.28 (0.99–1.67)
1.86 (0.06)
B versus b BB ?Bb versus bb (dominant)
0 % (0.48) 0 % (0.84)
Fixed effect Fixed effect
1.12 (0.92–1.37) 0.97 (0.70–1.33)
1.18 (0.24) 0.22 (0.83)
BB versus Bb ?bb (recessive)
0 % (0.45)
Fixed effect
1.37 (1.01–1.87)
2.01 (0.04)
BB versus bb (additive)
0 % (0.79)
Fixed effect
1.04 (0.65–1.65)
0.15 (0.88)
F versus f
0 % (0.43)
Fixed effect
1.41 (1.14–1.75)
3.21 (0.001)
FF ? Ff versus ff (dominant)
0 % (0.66)
Fixed effect
2.32 (1.49–3.61)
3.71 (0.0002)
FF versus Ff ? ff (recessive)
0 % (0.53)
Fixed effect
1.31 (0.98–1.76)
1.82 (0.07)
FF versus ff (additive)
0 % (0.58)
Fixed effect
2.45 (1.52–3.93)
3.69 (0.0002)
0 % (0.55)
Fixed effect
1.14 (0.89–1.46)
1.01 (0.31)
BsmI
FokI
TaqI T versus t TT ?Tt versus tt (dominant)
19 % (0.27)
Fixed effect
1.14 (0.75–1.71)
0.61 (0.54)
TT versus Tt ? tt (recessive)
0 % (0.97)
Fixed effect
1.20 (0.82–1.77)
0.93 (0.35)
TT versus tt (additive)
0 % (0.49)
Fixed effect
1.14 (0.68–1.91)
0.51 (0.61)
Bold values indicate the results were considered statistically significant
Fig. 2 Forest plot of BsmI polymorphism BB versus Bb ? bb in the recessive model
Fig. 3 Forest plot of FokI polymorphism F allele versus f allele
study [17]. Young Ho Lee et al. [18] conducted a metaanalysis on VDR gene variants and susceptibility to PD and Alzheimer’s disease; however, they performed the different analysis and found an association between the
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BsmI polymorphisms and PD only in a subgroup analysis (including two studies) [18]. Until now, there are only eight individual studies [14, 15, 23–28] on the relationship between VDR polymorphisms and PD. However, the
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Fig. 4 Forest plot of FokI polymorphism FF ? Ff versus ff in the dominant model
Fig. 5 Forest plot of FokI polymorphism FF versus ff in the additive model
results are controversial. The association between VDR FokI polymorphism was observed in Chinese PD patients [23] and in Japanese PD patients [27]. Joong-Seok Kim et al. [24] found a marginal association between BsmI polymorphism and risk of PD. However, Zhanyun Lv et al. [15], Xun Han et al. [23] and Masahiko Suzuki et al. [27] found no association between genotype or allele in BsmI polymorphism and PD. These debatable results may be due to different ethnic groups, or environmental factors, or gene–gene and gene–environment interactions, or small sample size to detect such an effect. Moreover, it has been speculated that a poor vitamin D status would outpace the effect of VDR polymorphism and that the VDR polymorphisms only manifest phenotypic variations in the presence of certain vitamin D level [14]. The included studies in this meta-analysis varied in terms of ethnicity, geography and divergent evolutionary populations, which differ greatly in PD prevalence, environmental UV exposure, and allelic architecture of the VDR gene [29]. There are several plausible mechanisms for the VDRmediated vitamin D effects on PD. Upon binding to 1,25dihydroxy vitamin D3, VDR is activated and interacts with vitamin D responsive elements in the promoters of vitamin D target genes to regulate their expression [10]. In addition, vitamin D has its anti-inflammatory property, which may play a role in neurodegenerative diseases [30]. The ApaI, BsmI and TaqI SNPs of the VDR gene are in high linkage disequilibrium, while FokI is in linkage equilibrium with them [31–33]. The three SNPs have been shown to affect the stability of VDR mRNA but not the structure of the VDR protein [34]. Besides, they may influence the
bioactivity of VDR and other relevant genes independently or by linkage disequilibrium with another functional variant. However, the BsmI, ApaI, and TaqI variants may have little effect on the disease because they belong to 30 nonfunctional polymorphisms. The major strength of our meta-analysis is that it is a comprehensive coverage of available observational studies on the associations between VDR genetic polymorphisms and the risk of PD up to now. Second, the studies included in our meta-analysis were of relatively high quality. Some limitations of this review should be acknowledged. First, PD is a multi-factorial disease that results from complex interactions between environmental and genetic factors. Because most of the included studies were lacking information in co-variables for the data analysis, our results were only based on unadjusted effect estimates. Second, some other relevant gene polymorphisms, such as polymorphisms of apolipoprotein E gene, low-density lipoprotein receptor-related protein-associated protein 1 gene, and the sphingomyelin phosphodiesterase 1 gene may exert their complex and interacting functions with each other. Third, heterogeneity was found in some studies, this could be due to uncontrolled confounding factors and potential selection biases. Fourth, the number of studies of VDR gene polymorphisms was small. There was insufficient statistical power to explore the real relationship between VDR polymorphisms and PD. In addition, the small sample of studies does not cover adequately PD population. Finally, as the demographic region were mainly Europeans and Asians, the results might be applicable to only these ethnic groups, a generalization to other ethnic groups should be cautious.
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In conclusion, BsmI and FokI polymorphisms are associated with the risk of PD, while no associations are observed between ApaI, TaqI polymorphisms and PD. Further well-designed prospective cohort study with larger sample size is needed to confirm these associations. Moreover, confounding factors such as serum vitamin D levels, body mass index, ethnicity and other potential risk factors should be included in the exploration of such association. Finally, gene–gene and gene-environment interactions should be considered in future studies. Acknowledgments This work was supported by the Harbin Special Funds for Research of Scientific and Technological Innovative Talents (No. 2011RFQYS092) and Innovative Foundation of the Harbin Medical University (HCXS2010014). The following authors contributed substantially to conception and design (SB, HPQ, SRD, CLL), data collection (SB, CLL, HPQ, LW, XXF, SRD), and analyses and interpretation of data (SB, SQW, CLL, HPQ, LW, XXF, SRD). All authors revised the paper critically for important intellectual content and gave final approval of the version to be published. Conflict of interest
The authors report no conflict of interest.
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33. Uitterlinden AG, Fang Y, Van Meurs JB, Pols HA, Van Leeuwen JP (2004) Genetics and biology of vitamin D receptor polymorphisms. Gene 338(2):143–156 34. Jurutka PW, Whitfield GK, Hsieh JC, Thompson PD, Haussler CA, Haussler MR (2001) Molecular nature of the vitamin D receptor and its role in regulation of gene expression. Rev Endocr Metab Disord 2(2):203–216 35. Calne DB, Snow BJ, Lee C (1992) Criteria for diagnosing Parkinson’s disease. Ann Neurol 32:S125–S127 36. Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinicopathological study of 100 cases. J Neurol Neurosurg Psychiatry 55(3):181–184 37. Hughes AJ, Ben-Shlomo Y, Daniel SE, Lees AJ (1992) What features improve the accuracy of clinical diagnosis in Parkinson’s disease: a clinicopathologic study. Neurology 42(6):1142–1146
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ORIGINAL ARTICLE
Vitamin D receptor gene polymorphisms and the risk of Parkinson’s disease Chunlei Li • Huiping Qi • Shuqin Wei • Le Wang • Xiaoxue Fan • Shurong Duan Sheng Bi
•
Received: 24 May 2014 / Accepted: 18 August 2014 Ó Springer-Verlag Italia 2014
Abstract The effect of vitamin D receptor (VDR) gene polymorphisms on Parkinson’s disease (PD) has recently gained interest. However, evidence on this relationship is controversial. We searched PubMed, EMBASE and the Cochrane Library database targeted all studies that evaluated VDR gene polymorphisms and PD up to April 2,014. A meta-analysis was conducted on the association between VDR ApaI, BsmI, TaqI and FokI polymorphisms and PD using (1) allelic contrast, (2) dominant, (3) recessive, and (4) additive models. A total of five relevant studies involving PD patients (n = 1,266) and controls (n = 1,649) were included in the analysis. There was a significant association between FokI polymorphism and PD. In the pooled allelic analysis, the F allele was associated with increased risk of PD (OR 1.41, 95 % CI 1.14–1.75). In the genotype analysis, FF ? Ff versus ff
showed a significant association with PD in the dominant model (OR 2.32, 95 % CI 1.49–3.61, P = 0.0002). FF versus ff showed a significant association with PD in the additive model (OR 2.45, 95 % CI 1.52–3.93, P = 0.0002). There was also a statistically significant association between VDR BsmI polymorphisms in the recessive model, BB versus Bb ? bb showed a significant increased risk of PD (OR 1.37, 95 % CI 1.01–1.87, P = 0.04). No significant associations were observed between VDR ApaI and TaqI polymorphisms and PD. To sum up, VDR BsmI and FokI polymorphisms were associated with increased risk of PD. Keywords Vitamin D receptor gene Parkinson’s disease Polymorphisms Meta-analysis
Introduction Electronic supplementary material The online version of this article (doi:10.1007/s10072-014-1928-9) contains supplementary material, which is available to authorized users. C. Li Department of Rehabilitation, The First Affiliated Hospital, Harbin Medical University, 150001 Harbin, China H. Qi Department of Neurology, The Fourth Affiliated Hospital, Harbin Medical University, 150001 Harbin, China S. Wei Saint-Justine Research Center, University of Montreal, Montreal, Canada L. Wang X. Fan S. Duan S. Bi (&) Department of Neurology, The First Affiliated Hospital, Harbin Medical University, 150001 Harbin, China e-mail: [email protected]; [email protected]
Parkinson’s disease (PD) is a progressive movement disorder, characterized clinically by bradykinesia, tremor, rigidity, flexed posture, postural instability, and freezing of gait. The majority of PD cases result from complex interplay between environmental and genetic factors [1]. Several genetic risk factors and gene–environment interactions for PD have been reported [2–6]. Vitamin D level is an environmentally modifiable factor as it is largely determined by diet and sunlight exposure. The effects of vitamin D and genetic variants in the vitamin D receptor (VDR) gene have recently gained interest in PD and neurodegenerative research in general [7–9]. VDR is the primary mediator of vitamin D’s biological actions. VDR gene polymorphisms influence on VDR protein function [10]. Within the brain, the highest expression of VDR and 1a-hydroxylase was found in the
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hypothalamus and in the dopaminergic neurons of the substantia nigra [11]. VDR gene polymorphisms, occurring in intron 8 (BsmI and ApaI sites), exon 9 (TaqI site) and exon 2 (FokI site), have been reported to be associated with several neurodegenerative diseases, including multiple sclerosis and Alzheimer disease [12, 13]. To date, a number of studies have reported the relationship between VDR (ApaI, BsmI, FokI and TaqI) gene polymorphisms and the risk of PD [14–16]. However, the results were controversial. There are two recently published meta-analyses [17, 18] on the relationship between VDR genetic variants and PD, however, the results are conflict. With the accumulating evidence, we therefore performed this meta-analysis to investigate the association between VDR gene polymorphisms and the susceptibility of PD, with the aim of providing a much more reliable finding on the significance of the association.
quality of each study which meets the predefined methodological quality assessment criteria for non-randomized observational studies (Table 1) [22]. Statistical analysis The strength of the associations between VDR (ApaI, BsmI, FokI, TaqI) gene polymorphisms and risk of PD were estimated by pooled odds ratio (OR) with 95 % confidence intervals (CIs). The statistical analyses were performed using (1) the allelic contrast, (2) the dominant, (3) the recessive, and (4) the additive genetic models. All statistical analyses were performed using Revman 5.2 provided by the Cochrane Collaboration (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008).
Results Methods
Literature search
All procedure followed the guidelines for meta-analysis of observational studies in epidemiology (MOOSE) [19].
We first retrieved 78 relevant citations from the PubMed, EMBASE and the Cochrane Library database. A total of five relevant studies involving PD patients (n = 1,266) and controls (n = 1,649) were included in the analysis. Figure 1 summarizes the process of literature search and selection of these studies. Table 2 shows the frequencies of M (A, B, F, T) allele of VDR gene in cases and controls.
Data sources The electronic searches on PubMed, EMBASE and the Cochrane Library database targeted all studies that evaluated VDR gene polymorphisms and PD up to April 2014. The keywords were: ‘Parkinson’s disease’ or ‘PD’ and ‘ApaI (rs7975232), BsmI (rs1544410), FokI (rs2228570) and TaqI (rs731236)’ and ‘polymorphism’ or ‘mutation’ or ‘variant’ or ‘genotype’ or ‘SNP’. An additional search was performed through the references cited in identified articles. Inclusion and exclusion criteria Inclusion criteria: (1) observational study including cohort study, case–control study; (2) the outcome was PD; (3) the diagnostic criteria for PD—clinical signs, Hoehn & Yahr (HY) stage [20]. Unified Parkinson’s Disease Rating Stage (UPDRS) [21]; and (4) at least two comparison groups (PD group versus control group). Exclusion criteria: (1) case reports, editorials and reviews; (2) Secondary forms of parkinsonism were excluded.; (3) relationship between other genes and PD risk; (4) duplicated or overlapping studies; and (5) study of the role of VDR to diseases. Data extraction and synthesis Data were recorded as follows: first author’s surname, year of publication, country, number of cases and controls for VDR (ApaI, BsmI, FokI, TaqI) genotype. We assessed the
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Quality scale Table 3 presents the quality scores of the five included studies. The characteristics of the included studies are summarized in Table 4. Total citations identified from electronic searches on VDR polymorphisms and Parkinson’s disease (n=78) Citations excluded after screening titles and /or abstracts (n=32) Primary articles retrieved for more detailed evaluation (n=46) Exclusions: reviews=5, not genetic polymorphism =18, not Parkinson’s disease =16 Full text articles potentially to be included (n=7) Exclusions for not meeting the quality assessment criteria=2 Included studies in systematic review (n=5)
Fig. 1 Flow chart of study selection process in this meta-analysis
Neurol Sci Table 1 Quality assessment of observational studies (total 10 points) Selection of participants (1/0) Cohort studies (1/0) Selected cohort was representative of the general population (population-based studies) or target catchment population (hospital-based studies) (1) Cohort was a selected unrepresentative group (0) Case control studies (1/0) Cases and controls drawn from the same population (1) Cases and controls drawn from different sources or the selection of groups (0) 2. Comparability of groups (2/0) No significant differences between the groups reported in terms of age, plurality, smoking, history of preterm birth, preeclampsia or gestational diabetes, pre-existing medical conditions were explicitly reported, or these differences were adjusted for (2) Differences between groups were not examined (1) Groups differed and no adjustment results provided (0) 3. Definition of outcomes (2/0) Definition of outcomes Referenced or standard definition (2) Explicit non-standard definition (1) Unspecified or unacceptable definition (0) 4. Ascertainment of outcomes (2/0) How the diagnosis was made Prospectively diagnosed or review of notes/hospital discharge records (2) Retrospective chart review or database coding (1) Process not described (0) 5. Sample size (1/0) C200 participants in a cohort study; C50 participants in either group (case/control) (1) 100B participants \200 in a cohort; 25B participants \50 in either group (case/control) (0.5) Participants \100 or total number of events \10 in a cohort; participants \25 in either group (case/control) (0) 6. Study design (2/0) Prospective cohort or nested case-control within a prospective cohort (2) Cross-sectional, case-control or retrospective cohort (1) Not described or poorly designed (0) Exclusion : score zero in any item (1–6) or a total score \7 out of 10 maximal points A score based quality assessment criteria for non-randomized observational studies adapted from Duckitt and Harrington [22]
Study characteristics for ApaI polymorphism with the risk of PD
association with PD (OR 1.37, 95 % CI 1.01–1.87, P = 0.04, Fig. 2).
A total of 921 cases and 1,136 controls were included. In the pooled allelic analysis, the A allele was not associated with risk of PD. In the genotype analysis, there were no significant associations at the dominant, recessive and additive genetic models (Table 5).
Study characteristics for FokI polymorphism with the risk of PD
Study characteristics for BsmI polymorphism with the risk of PD A total of 566 cases and 857 controls were included in four studies. In the genotype analysis, BB versus Bb ? bb (recessive model) showed a statistically significant
There was two studies including 751 participants presented at Table 2. In the pooled allelic analysis, the F allele was associated with increased risk of PD (OR1.41, 95 % CI 1.14–1.75, Fig. 3, Table 5). In the genotype analysis, FF ? Ff versus ff (dominant model) showed a significant association with PD (OR 2.32, 95 % CI 1.49–3.61, P = 0.0002, Fig. 4). FF versus ff (additive model) showed a significant association with PD (OR 2.45, 95 % CI 1.52–3.93, P = 0.0002, Fig. 5).
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Neurol Sci Table 2 Characteristics of studies of VDR gene polymorphisms on the risk of Parkinson’s disease Polymorphism
Case
Control
First author, year
MM
MN
NN
234
361
34
62
42
M allele (%)
Total
MM
MN
NN
Total
Case
Control
105
700
250
401
141
792
59.2
56.9
25
121
58
120
56
235
53.7
50.4
43
15
100
42
46
21
109
63.5
59.6
ApaIa Lin [25] Petersen [26] To¨ro¨k [28] BsmIb Han [23] Kim [24] Petersen [26] To¨ro¨k [28]
4
34
222
260
2
36
244
282
8.1
7.1
72 48
11 53
2 20
85 121
168 84
60 117
3 34
231 235
91.2 61.6
85.7 60.6
27
49
24
100
27
57
25
109
51.5
51.0
114
124
22
260
109
126
47
282
67.7
61.0
42
48
10
100
35
49
25
109
66.0
54.6
47
54
20
121
81
119
34
235
61.2
60.0
17
48
35
100
16
46
47
109
41.0
35.8
FokIc Han [23] To¨ro¨k [28] TaqId Petersen [26] To¨ro¨k [28] a
M = A, N = a
b
M = B, N = b
c
M = F, N = f
d
M = T, N = t VDR vitamin D receptor
Table 3 Quality scores of included studies on vitamin D receptor gene BsmI, FokI, ApaI and TaqI polymorphisms and the risk of Parkinson’s disease
Study
Selection of participants
Comparability of groups
Ascertainment
Sample size
Study design
Total score
Han [23]
1
2
2
2
1
1
9
Lin [25]
1
2
2
2
1
1
9
Kim [24]
1
2
2
2
1
1
9
Petersen [26] To¨ro¨k [28]
1
2
2
2
1
1
9
1
2
2
2
1
1
9
Study characteristics for TaqI polymorphism with the risk of PD A total of 221 cases and 344 controls were included in two studies. In the pooled allelic analysis, the A allele was not associated with risk of PD. In the genotype analysis, there were no significant associations at the dominant, recessive and additive genetic models (Table 5).
Discussion The main findings of this meta-analysis are that VDR gene BsmI polymorphism was associated with an increased risk of PD. And in the pooled allelic analysis, the FokI polymorphism F allele was associated with 1.4 odds increased
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Outcomes definition
risk of PD. In the genotype analysis, FF ? Ff versus ff showed a significant association with PD in dominant model. FF versus ff (additive model) showed a significant association with PD. However, no significant risk of PD was observed either in the ApaI polymorphism or the TaqI polymorphism in VDR gene. There are two recent meta-analysis [17, 18] on the associations between VDR polymorphisms and PD, however, their results are conflict. Zi Teng Zhang et al. [17] conducted a meta-analysis on VDR polymorphisms and PD, their results indicate that VDR genetic polymorphisms Bsml, Apal and Taql were not associated with susceptibility to PD. We found that their data analysis included repeated studies’ data which might contribute the different results. In addition, they did not evaluate the relationship between FokI polymorphisms and PD in their
China
China, Taiwan
South Korea
Faroe Islands
Hungary
Han [23]
Lin [25]
Kim [24]
Petersen [26]
To¨ro¨k [28] Case–control
Case–control
Case–control
Case–control
Case–control
Study design
209
356
316
1,492
542
Sample size (n)
56/44
48/73
55/30
305/395
94/166
55/54
93/142
NA
NA
113/169
66.4 (9.3)
74.5 (9.9)
64.55 (8.86)
68.7 (11.2)
70.9 (6.1)
64.0 (8.2)
75.0 (9.9)
62.05 (10.44)
NA
69.4 (9.7)
Control
PD
PD
Control
Mean age (year)
Gender (females/males)
PCR polymerase chain reaction-restriction, PCR–RFLP fragment length polymorphism, NA not available
Country
Study
Table 4 Characteristics of the included studies of VDR gene polymorphisms and the risk of PD
PCR–RFLP
BsmI
PCR
TaqI
FokI
BsmI
ApaI
TaqI
ApaI
BsmI
ApaI
FokI
BsmI
Polymorphism
Real-time
PCR–RFLP
PCR
Real-time
PCR–RFLP
Method
Evaluated by movement disorders in terms of the Hoehn and Yahr stage [20] and the Unified Parkinson’s Disease Rating Scale (UPDRS)
The United Kingdom Parkinson’s Disease Brain Bank criteria [37]
(UPDRS) [21] motor subscale
Tremor, rigidity, bradykinesia. unified Parkinson’s disease rating scale
The UK PD Society Brain Bank clinical diagnostic criteria [36]
Canadian Neurodegenerative Disorders centre [35]
Diagnoses criteria
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Neurol Sci Table 5 Vitamin D receptor gene polymorphisms and the risk of Parkinson’s disease Polymorphism
Level of heterogeneity I2 (X2 P)
Analysis model
OR(95 % CI)
Test for overall effect Z (P)
ApaI A versus a
0 % (0.93)
Fixed effect
1.12 (0.98–1.26)
1.72 (0.09)
AA ? Aa versus aa (dominant)
0 % (0.97)
Fixed effect
1.24 (0.98–1.56)
1.82 (0.07)
AA versus Aa ?aa (recessive)
0 % (0.94)
Fixed effect
1.11 (0.92–1.34
1.10 (0.27)
AA versus aa (additive)
0 % (0.97)
Fixed effect
1.28 (0.99–1.67)
1.86 (0.06)
B versus b BB ?Bb versus bb (dominant)
0 % (0.48) 0 % (0.84)
Fixed effect Fixed effect
1.12 (0.92–1.37) 0.97 (0.70–1.33)
1.18 (0.24) 0.22 (0.83)
BB versus Bb ?bb (recessive)
0 % (0.45)
Fixed effect
1.37 (1.01–1.87)
2.01 (0.04)
BB versus bb (additive)
0 % (0.79)
Fixed effect
1.04 (0.65–1.65)
0.15 (0.88)
F versus f
0 % (0.43)
Fixed effect
1.41 (1.14–1.75)
3.21 (0.001)
FF ? Ff versus ff (dominant)
0 % (0.66)
Fixed effect
2.32 (1.49–3.61)
3.71 (0.0002)
FF versus Ff ? ff (recessive)
0 % (0.53)
Fixed effect
1.31 (0.98–1.76)
1.82 (0.07)
FF versus ff (additive)
0 % (0.58)
Fixed effect
2.45 (1.52–3.93)
3.69 (0.0002)
0 % (0.55)
Fixed effect
1.14 (0.89–1.46)
1.01 (0.31)
BsmI
FokI
TaqI T versus t TT ?Tt versus tt (dominant)
19 % (0.27)
Fixed effect
1.14 (0.75–1.71)
0.61 (0.54)
TT versus Tt ? tt (recessive)
0 % (0.97)
Fixed effect
1.20 (0.82–1.77)
0.93 (0.35)
TT versus tt (additive)
0 % (0.49)
Fixed effect
1.14 (0.68–1.91)
0.51 (0.61)
Bold values indicate the results were considered statistically significant
Fig. 2 Forest plot of BsmI polymorphism BB versus Bb ? bb in the recessive model
Fig. 3 Forest plot of FokI polymorphism F allele versus f allele
study [17]. Young Ho Lee et al. [18] conducted a metaanalysis on VDR gene variants and susceptibility to PD and Alzheimer’s disease; however, they performed the different analysis and found an association between the
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BsmI polymorphisms and PD only in a subgroup analysis (including two studies) [18]. Until now, there are only eight individual studies [14, 15, 23–28] on the relationship between VDR polymorphisms and PD. However, the
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Fig. 4 Forest plot of FokI polymorphism FF ? Ff versus ff in the dominant model
Fig. 5 Forest plot of FokI polymorphism FF versus ff in the additive model
results are controversial. The association between VDR FokI polymorphism was observed in Chinese PD patients [23] and in Japanese PD patients [27]. Joong-Seok Kim et al. [24] found a marginal association between BsmI polymorphism and risk of PD. However, Zhanyun Lv et al. [15], Xun Han et al. [23] and Masahiko Suzuki et al. [27] found no association between genotype or allele in BsmI polymorphism and PD. These debatable results may be due to different ethnic groups, or environmental factors, or gene–gene and gene–environment interactions, or small sample size to detect such an effect. Moreover, it has been speculated that a poor vitamin D status would outpace the effect of VDR polymorphism and that the VDR polymorphisms only manifest phenotypic variations in the presence of certain vitamin D level [14]. The included studies in this meta-analysis varied in terms of ethnicity, geography and divergent evolutionary populations, which differ greatly in PD prevalence, environmental UV exposure, and allelic architecture of the VDR gene [29]. There are several plausible mechanisms for the VDRmediated vitamin D effects on PD. Upon binding to 1,25dihydroxy vitamin D3, VDR is activated and interacts with vitamin D responsive elements in the promoters of vitamin D target genes to regulate their expression [10]. In addition, vitamin D has its anti-inflammatory property, which may play a role in neurodegenerative diseases [30]. The ApaI, BsmI and TaqI SNPs of the VDR gene are in high linkage disequilibrium, while FokI is in linkage equilibrium with them [31–33]. The three SNPs have been shown to affect the stability of VDR mRNA but not the structure of the VDR protein [34]. Besides, they may influence the
bioactivity of VDR and other relevant genes independently or by linkage disequilibrium with another functional variant. However, the BsmI, ApaI, and TaqI variants may have little effect on the disease because they belong to 30 nonfunctional polymorphisms. The major strength of our meta-analysis is that it is a comprehensive coverage of available observational studies on the associations between VDR genetic polymorphisms and the risk of PD up to now. Second, the studies included in our meta-analysis were of relatively high quality. Some limitations of this review should be acknowledged. First, PD is a multi-factorial disease that results from complex interactions between environmental and genetic factors. Because most of the included studies were lacking information in co-variables for the data analysis, our results were only based on unadjusted effect estimates. Second, some other relevant gene polymorphisms, such as polymorphisms of apolipoprotein E gene, low-density lipoprotein receptor-related protein-associated protein 1 gene, and the sphingomyelin phosphodiesterase 1 gene may exert their complex and interacting functions with each other. Third, heterogeneity was found in some studies, this could be due to uncontrolled confounding factors and potential selection biases. Fourth, the number of studies of VDR gene polymorphisms was small. There was insufficient statistical power to explore the real relationship between VDR polymorphisms and PD. In addition, the small sample of studies does not cover adequately PD population. Finally, as the demographic region were mainly Europeans and Asians, the results might be applicable to only these ethnic groups, a generalization to other ethnic groups should be cautious.
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In conclusion, BsmI and FokI polymorphisms are associated with the risk of PD, while no associations are observed between ApaI, TaqI polymorphisms and PD. Further well-designed prospective cohort study with larger sample size is needed to confirm these associations. Moreover, confounding factors such as serum vitamin D levels, body mass index, ethnicity and other potential risk factors should be included in the exploration of such association. Finally, gene–gene and gene-environment interactions should be considered in future studies. Acknowledgments This work was supported by the Harbin Special Funds for Research of Scientific and Technological Innovative Talents (No. 2011RFQYS092) and Innovative Foundation of the Harbin Medical University (HCXS2010014). The following authors contributed substantially to conception and design (SB, HPQ, SRD, CLL), data collection (SB, CLL, HPQ, LW, XXF, SRD), and analyses and interpretation of data (SB, SQW, CLL, HPQ, LW, XXF, SRD). All authors revised the paper critically for important intellectual content and gave final approval of the version to be published. Conflict of interest
The authors report no conflict of interest.
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