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Association between vitamin D receptor gene polymorphisms and intervertebral disc degeneration: A meta-analysis
Journal of Orthopaedic Science xxx (2016) 1e6
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Journal of Orthopaedic Science journal homepage: http://www.elsevier.com/locate/jos
Original Article
Association between vitamin D receptor gene polymorphisms and intervertebral disc degeneration: A meta-analysis Lin Chen, Song Zhao, Feng Niu*, Gui-Bin Bi Department of Spine Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, PR China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 December 2015 Received in revised form 18 October 2016 Accepted 14 November 2016 Available online xxx
Background: Studies that have investigated the association between vitamin D receptor (VDR) gene polymorphisms and intervertebral disc degeneration (IDD) have yielded inconsistent results. Methods: To investigate the association between VDR gene polymorphisms and IDD, a systematic literature search for relevant published studies was performed on PubMed, Embase, Web of Science, Cochrane library, Wan-Fang, and CNKI databases. A random effects model was used for heterogeneous data; while a fixed effect model was used for homogenous data. Odds ratios (OR) and 95% confidence intervals (CI) were calculated to evaluate the strength of the association. Results: We observed no association between VDR FokI, TaqI-ApaI polymorphisms and IDD. However, on subgroup analysis by ethnicity, VDR FokI mutation was associated with a significantly lower risk for IDD [dominant model: OR ¼ 0.78, 95% CI ¼ 0.65e0.93; heterozygote model: OR ¼ 0.76, 95% CI ¼ 0.63e0.92; allele model: OR ¼ 0.86, 95% CI ¼ 0.75e0.98] among Caucasians. Conclusion: These results suggest that the VDR FokI polymorphism may be associated with IDD among Caucasians. However, the association between VDR TaqI-ApaI polymorphisms and IDD in Asians is still not clear. Further well-designed studies are needed to arrive at a definitive conclusion. © 2016 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.
1. Introduction Intervertebral disc degeneration (IDD), a musculoskeletal disorder attributed to an aberrant cell-mediated response, is characterized by structural failure and accelerated signs of aging. Disc degeneration may lead to disc herniation, sciatic pain, degenerative spondylolisthesis, degenerative scoliosis and spinal stenosis. The condition has been attributed to genetic, environmental and occupational factors. Genetic factors are thought to be one of the key determinants of the causation of IDD. Several predisposing genetic factors have been identified. Videman et al. [1] reported association of VDR polymorphisms TaqI and FokI with disc degeneration in a study conducted on 85 pairs of male monozygotic twins. These results are indicative of a possible association between VDR polymorphisms and disc degeneration. Subsequent research revealed that the Tt allele of the VDR gene was more frequently associated with disc degeneration as compared to the TT allele [2]. Cheung et al. [3], too, showed that allele of VDR TaqI was a high risk factor for IDD, in * Corresponding author. Department of Spine Surgery, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, Jilin 130021, PR China. E-mail address: [email protected] (F. Niu).
individuals < 40 years of age. However, results from other studies appear to refute the association of VDR single nucleotide polymorphisms (SNP) with IDD [4e6]. Recently, Cervin et al. [7] reported no significant association of VDR gene polymorphisms with IDD in a Mexican population. However, another study conducted on Italian patients with lumbar spine pathology, appeared to implicate the VDR FokI FF genotype and F allele in the promotion of spinal tissue degeneration [8]. Although several studies have indicated the association between VDR gene polymorphisms and IDD, the results of these studies are controversial. For instance, a meta-analysis [9] found no significant association of VDR FokI, TaqI, ApaI polymorphisms with the risk of IDD. TaqI and ApaI polymorphisms are in strong linkage disequilibrium with each other [10] and thus should to be combined in one meta-analysis. However, previous studies have not analyzed this angle. In addition, some other recent studies have also reported different results [11e15]. We performed a meta-analysis to investigate whether the polymorphism of VDR was a potential risk factor for IDD. The objective was to gain insights into the molecular mechanisms underlying IDD and its association with the VDR gene (FokI: rs2228570, TaqI: rs731236, ApaI: rs7975232). It may also contribute
http://dx.doi.org/10.1016/j.jos.2016.11.009 0949-2658/© 2016 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Chen L, et al., Association between vitamin D receptor gene polymorphisms and intervertebral disc degeneration: A meta-analysis, Journal of Orthopaedic Science (2016), http://dx.doi.org/10.1016/j.jos.2016.11.009
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L. Chen et al. / Journal of Orthopaedic Science xxx (2016) 1e6
towards the development of a specific gene knockout animal model of IDD. Moreover, susceptibility genes for IDD, if identified, could serve as new therapeutic targets besides facilitating an early diagnosis of the disorder. 2. Methods 2.1. Search strategy Online databases such as PubMed, Embase, Web of Science, Cochrane library, Wan-Fang data, and CNKI were searched for relevant studies. The keywords and search strategy were as follows: (“vitamin d receptor” or “vitamin d 3 receptor” or “calcitriol receptor” or “1,25-dihydroxyvitamin d3 receptor” or “vdr”) and (“polymorphism” or “mutation” or “genetic variation”) in combination with (“intervertebral disc” or “disc degeneration”). The parameters of the search were defined as “human studies published in English between 1995 and November 2015”. 2.2. Inclusion and exclusion criteria Studies were included if they met the following criteria: 1) evaluated the association of VDR (FokI, TaqI, ApaI) polymorphisms with IDD; 2) case-control or cohort design; 3) appropriate diagnostic criteria, such as magnetic resonance imaging (MRI); 4) availability of sufficient data. When genotype or allele frequencies were insufficiently described, the relevant additional information was requested from the authors. Studies that lacked an appropriate healthy control-group, literature reviews, and studies, for which data on genotype or allele frequencies were not available, were excluded from this meta-analysis. 2.3. Data abstraction Data were independently extracted by two investigators. Any disagreement was resolved by consensus after involving a third independent expert. Data on the following variables were extracted: name of first author, year of publication, country of origin, ethnicity of subjects, genotype frequencies, and HardyeWeinberg equilibrium (HWE) in control group. 2.4. Statistical analyses The HWE tests were performed on controls using a Pearson's goodness-of-fit chi-square from https://ihg.gsf.de/cgi-bin/hw/ hwa1.pl. The association between the VDR polymorphisms and IDD was assessed under the following genetic models: a dominant model, a recessive model, a homozygous model, a heterozygous model, an additive model, and an allele model. Odds ratio (OR) and 95% confidence interval (95% CI) were calculated to assess the strength of the association. Data analysis was performed using STATA software version 12.1 (Stata Corp College Station, TX). Statistical heterogeneity was assessed using the I2 tests. A value of I2 > 25% was considered indicative of heterogeneity, and a random effect model (the DerSimonianeLaird model) was used. In other cases, the fixed effect model (the ManteleHaenszel model) was employed. Step-down Bonferroni and BenjaminieHochberg tests were used to adjust the values for multiple comparisons. Subgroup analyses were stratified by ethnicity. Potential publication bias was assessed by Begg funnel plot and further evaluated for funnel plot symmetry by Egger test. Sensitivity analyses were performed by evaluating the stability of the results after exclusion of one study at a time. A probability of P < 0.05 was considered statistically significant.
3. Results 3.1. Search results A total of 158 relevant studies were retrieved out of which 52 were excluded after screening of the titles and abstracts; 17 studies were excluded after reviewing the full-texts. Only 16 studies qualified the inclusion criteria and were included in this metaanalysis [2,3,6,7,11e13,15e23]. The flow diagram of the selection process is showed in Fig. 1. 3.2. Demographic characteristics The characteristics of the included studies are summarized in Table 1. A total of 9 studies [6,7,11,15,17e21] were included for examining the association between VDR FokI polymorphism and risk of IDD; 10 studies [2,3,7,13,16e18,20,22,23] for that between TaqI polymorphism and risk of IDD; and 4 studies [2,12,16,23] were included for examining the association between the ApaI polymorphisms and the risk of IDD. In three [18e20] out of 16 studies, the genotype frequencies in the control populations deviated from HWE. 3.3. Quantitative data synthesis A summary of the meta-analysis results for the association between VDR gene polymorphisms and IDD is shown in Table 2. Owing to the significant heterogeneity between the study groups for VDR FokI (I2 ¼ 87.0%), a random effects model was employed (Fig. 2a, dominant model). No significant association was found between VDR FokI polymorphism and IDD risk. However, the results of subgroup analyses by ethnicity showed a significant association of VDR FokI mutation with IDD (dominant model: OR ¼ 0.78, 95% CI ¼ 0.65e0.93; heterozygote model: OR ¼ 0.76, 95% CI ¼ 0.63e0.92; allele model: OR ¼ 0.86, 95% CI ¼ 0.75e0.98; Table 2). Owing to significant heterogeneity between the 14 studies included for the assessment of the association between VDR TaqIApaI polymorphism and IDD risk (I2 ¼ 68.4%), a random effect model was used (Fig. 2b, dominant model). There was no significant association between VDR TaqI polymorphism and IDD risk. However, after omission of the study by Chen et al. (who concluded that common homozygotes were a risk factor for IDD, which was significantly different from previous information) [16] a significant association was observed among Asians between VDR TaqI-ApaI polymorphism and IDD (Fig. 2c, dominant model) (dominant model: OR ¼ 1.54, 95% CI ¼ 1.22e1.95; heterozygote model: OR ¼ 1.52, 95% CI ¼ 1.19e1.94; allele model: OR ¼ 1.38, 95% CI ¼ 1.14e1.67; Table 2). 3.4. Publication bias diagnostics The Begg funnel plot and Egger test revealed no strong evidence of publication bias that could have influenced the results of this meta-analysis (Fig. 3). (Begg test: P ¼ 0.193, Egger test: P ¼ 0.058 for VDR FokI; Begg test: P ¼ 0.251 Egger test: P ¼ 0.067 for VDR TaqIApaI, respectively). However, the data of FokI was dominated by studies among Caucasians. On the contrary, the data of TaqI-ApaI was dominated by studies among Asians. We considered that genetic association studies with non-significant findings were unlikely to be published, which suggests a potential for publication bias. 3.5. Sensitivity analyses Results based on aggregate data were significantly different from those of subgroup analysis for the investigated
Please cite this article in press as: Chen L, et al., Association between vitamin D receptor gene polymorphisms and intervertebral disc degeneration: A meta-analysis, Journal of Orthopaedic Science (2016), http://dx.doi.org/10.1016/j.jos.2016.11.009
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Fig. 1. Schematic illustration of the study selection procedure.
Table 1 Characteristics of the studies included in the meta-analysis. Author
FokI (rs2228570) Colombini et al. [15] Eser et al. [17] Eskola et al. [18] Kelempisioti et al. [19] Noponen-Hietala et al. [20] Vieira et al. [11] Nunes FTB et al. [21] Cervin et al. [7] Chen et al. [6] TaqI (rs731236) Chen et al. [16] Cheung et al. [3] Oishi et al. [22] Xu et al. [13] Yuan et al. [23] Kawaguchi et al. [2] Eskola et al. [18] Eser et al. [17] Noponen-Hietala et al. [20] Cervin et al. [7] ApaI (rs7975232) Chen et al. [16] Kawaguchi et al. [2] Yuan et al. [23] Zawilla et al. [12]
Year
Country
Ethnicity
Case
Control
HWE
11
12
22
11
12
22
P
2015 2010 2010 2011 2003 2014 2007 2014 2007
Italy Turkey Denmark Finland Finland Brazil Brazil Mexico China
Caucasian Caucasian Caucasian Caucasian Caucasian Brazilian Brazilian Mexican Asian
117 81 29 81 11 54 9 20 18
120 52 27 57 12 50 54 65 51
30 17 10 12 6 17 3 15 12
101 67 45 111 25 75 61 32 36
117 67 90 119 26 46 27 51 48
36 16 19 16 5 10 0 17 17
0.821 0.902 0.012 0.032 0.630 0.434 0.089 0.664 0.883
2012 2006 2003 2014 2010 2002 2010 2010 2003 2014
China China Japan China China Japan Denmark Turkey Finland Mexico
Asian Asian Asian Asian Asian Asian Caucasian Caucasian Caucasian Mexican
79 354 31 75 156 79 29 65 12 69
2 33 8 3 22 37 28 67 11 27
0 1 0 0 0 0 9 18 6 4
86 183 16 153 256 72 57 67 26 62
14 8 5 3 28 17 74 67 19 35
1 0 0 0 0 0 23 16 11 3
0.617 0.768 0.536 0.903 0.382 0.319 0.898 0.902 0.044 0.461
2012 2002 2010 2014
China Japan China Egypt
Asian Asian Asian Egyptian
44 51 58 17
28 48 100 48
9 17 20 19
43 41 128 34
46 39 129 22
12 9 27 4
0.955 0.951 0.500 0.863
11, 12, 22 represent common homozygous, heterozygote and rare homozygous, respectively. P values for HardyeWeinberg equilibrium test in control group.
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Table 2 Summary odds ratio (95% confidence intervals) for intervertebral disc degeneration in patients with vitamin D receptor (VDR) polymorphisms. I2 FokI (rs2228570) Dominant model 87.0% Caucasian Dominant model 0.0% Recessive model 0.0% Homozygous model 0.0% Heterozygote model 0.0% Additive model 0.0% Allele model 0.0% TaqI (rs731236)-ApaI (rs7975232) Dominant model 68.4% Chen et al. (2012) omitted among Asian Dominant model 0.0% Recessive model 0.0% Homozygous model 0.0% Heterozygote model 0.0% Additive model 0.0% Allele model 0.0%
Model
OR
95% CI
P
Bon
FDR
REM
1.35
0.82e2.23
0.237
0.948
0.336
FEM FEM FEM FEM FEM FEM
0.78 1.05 0.84 0.76 1.08 0.86
0.65e0.93 0.75e1.45 0.62e1.13 0.63e0.92 0.80e1.45 0.75e0.98
0.006 0.787 0.240 0.005 0.610 0.027
0.036 1.000 0.948 0.035 1.000 0.135
0.021 0.787 0.336 0.021 0.712 0.063
REM
1.20
0.87e1.66
0.265
0.795
0.323
FEM FEM FEM FEM FEM FEM
1.54 1.31 1.59 1.52 1.11 1.38
1.22e1.95 0.80e2.14 0.94e2.69 1.19e1.94 0.67e1.85 1.14e1.67
0.000 0.277 0.083 0.001 0.692 0.001
0.000 0.795 0.332 0.006 0.795 0.006
0.000 0.323 0.145 0.002 0.692 0.002
OR, odds ratio; CI, confidence interval. FEM, fixed effect model; REM, random effect model. Bon, P value in step-down Bonferroni testing; FDR, P value from BenjaminieHochberg method control for false discovery rate.
polymorphisms and risk of IDD. After omitting the studies that deviated from HWE in the subgroup analyses by ethnicity, the pooled results showed no significant influence for VDR FokI (data not shown). However, when we excluded the study by Chen et al. [16] for VDR TaqI-ApaI, a significant association was found in Asians (Table 2).
4. Discussion Intervertebral disc degeneration is characterized by disc dehydration and herniation. The etiology of this condition is thought to be multi-factorial, including, genetic, environmental, occupational, and age related etiological factors. Because of the above-mentioned conflicting results, a meta-analysis should be an appropriate approach to investigate the association between VDR gene polymorphisms and IDD. In this study, the combined data on VDR FokI, TaqI-ApaI polymorphisms did not demonstrate any association with IDD. However, after disaggregating the data by ethnicity, a significant association was observed between VDR FokI polymorphism and IDD risk in the Caucasian population (dominant model: OR ¼ 0.78, 95% CI ¼ 0.65e0.93; heterozygote model: OR ¼ 0.76, 95% CI ¼ 0.63e0.92; allele model: OR ¼ 0.86, 95% CI ¼ 0.75e0.98). Similarly, for Asians, the results showed no significant association between VDR TaqI-ApaI polymorphisms and IDD. However, a significant association was found after exclusion of the study by Chen et al. [16] for VDR TaqIApaI (dominant model: OR ¼ 1.54, 95% CI ¼ 1.22e1.95; heterozygote model: OR ¼ 1.52, 95% CI ¼ 1.19e1.94; allele model: OR ¼ 1.38, 95% CI ¼ 1.14e1.67). Our findings indicate that the association of VDR TaqI-ApaI gene in the Asian population requires further investigation. After excluding studies that deviated from HWE in controls, the pooled results showed no significant influence for VDR FokI among Caucasians in all genetic models. Although, no potential publication bias was identified by Begg funnel plot and Egger test, publication bias may also exist because it is reasonable to assume that genetic association studies with non-significant findings were more unlikely to be published.
Fig. 2. a: Forest plot of the association between vitamin D receptor (VDR) FokI polymorphism and intervertebral disc degeneration (dominant model). b: Forest plot of the association between vitamin D receptor (VDR) TaqI-ApaI polymorphisms and intervertebral disc degeneration (dominant model). c: Forest plot of the association between vitamin D receptor (VDR) TaqI-ApaI polymorphisms and intervertebral disc degeneration among Caucasians (dominant model).
1,25-Dihydroxy vitamin D3 is an active metabolite of vitamin D that regulates local calcium and phosphorus homeostasis and aggrecan synthesis through a VDR-dependent mechanism. The VDR gene is expressed in nucleus pulposus and annulus fibrosus cells of the intervertebral disc. Thus, the VDR gene may affect the disc metabolism of calcium and phosphorus and possibly have a role in
Please cite this article in press as: Chen L, et al., Association between vitamin D receptor gene polymorphisms and intervertebral disc degeneration: A meta-analysis, Journal of Orthopaedic Science (2016), http://dx.doi.org/10.1016/j.jos.2016.11.009
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Fig. 3. Begg funnel plot and Egger test for assessing potential influence of publication bias on the observed association between the vitamin D receptor (VDR) polymorphisms and intervertebral disc degeneration (dominant model).
the causation of IDD. The novel nonsense mutation c.1066 C > T is known to result in a VDR protein with <71 amino acids, which may affect the normal VDR function [24]. Sequencing studies have suggested that the VDR gene mutation results in a premature stop codon (R50X) in patients with vitamin D resistant rickets [25]. Therefore, it is conceivable that the VDR gene polymorphisms may affect the translation efficiency of mRNA and its encoded protein, which in turn may affect the vitality, structure and the number of receptor proteins. Vitamin D receptor TaqI gene polymorphism was reported as a potential risk factor for intervertebral disc degeneration. Studies have also reported the association of VDR FokI, TaqI, and ApaI polymorphisms with IDD risk. However, the evidence has largely been inconsistent. Recently, Colombini et al. [8] reported that the f allele of VDR FokI was protective and that the FokI FF genotype was a risk factor for disc herniation in the Italian population. However, Cervin et al. [7] found no evidence supporting this association in a Mexican Mestizo population; similar findings of a lack of association were reported from a study conducted in a Chinese population [6]. Thus, we speculate that ethnicity, environmental factors and lifestyle appear to be the key variables that influence the susceptibility to IDD. The VDR tt genotype was shown to be associated with a higher prevalence of annular tears and back pain as compared to the TT genotype [26]. Another study indicated that the t and Tt alleles of VDR TaqI confer an increased risk of disc disease at an early age among Asians, which indicates that the t allele may be a major susceptibility locus in Asian population, especially in those <40 years of age [2,3]. In some studies the AA mutation genotype was one of the genetic risk factors associated with lumbar disc degeneration [12,23], which suggests a linkage between an allele and risk of IDD. A significant association was found when we excluded the study by Chen et al. Thus, the associations between VDR TaqI-ApaI gene polymorphisms and the risks of IDD could not be excluded in the Asian population. Some limitations in our study need to be acknowledged. The small sample size in our study limits the statistical power of the observed associations. Secondly, we might have missed some studies as the literature search was conducted according to the principles of PICOS. Thirdly, we could not make precise OR adjustments for age and sex. Finally, we did not perform multivariate analysis, which is another limitation of our study. 5. Conclusion Our meta-analysis suggests that the VDR FokI polymorphism may be associated with IDD among Caucasians; however, the association between VDR TaqI-ApaI polymorphisms and IDD in Asian population is still not clear. Due to the study limitations, additional investigations are required on a larger population base
to confirm the association between the VDR polymorphism and IDD risk. Conflict of interest We declare that we have no conflict of interest. References [1] Videman T, Leppavuori J, Kaprio J, Battie MC, Gibbons LE, Peltonen L, Koskenvuo M. Intragenic polymorphisms of the vitamin D receptor gene associated with intervertebral disc degeneration. Spine (Phila Pa 1976) 1998 Dec 1;23(23):2477e85. [2] Kawaguchi Y, Kanamori M, Ishihara H, Ohmori K, Matsui H, Kimura T. The association of lumbar disc disease with vitamin-D receptor gene polymorphism. J Bone Joint Surg Am 2002 Nov;84-a(11):2022e8. [3] Cheung KM, Chan D, Karppinen J, Chen Y, Jim JJ, Yip SP, Ott J, Wong KK, Sham P, Luk KD, Cheah KS, Leong JC, Song YQ. Association of the Taq I allele in vitamin D receptor with degenerative disc disease and disc bulge in a Chinese population. Spine (Phila Pa 1976) 2006 May 1;31(10):1143e8. [4] Karppinen J, Daavittila I, Solovieva S, Kuisma M, Taimela S, Natri A, Haapea M, Korpelainen R, Niinimaki J, Tervonen O, Ala-Kokko L, Mannikko M. Genetic factors are associated with modic changes in endplates of lumbar vertebral bodies. Spine (Phila Pa 1976) 2008 May 15;33(11):1236e41. [5] Virtanen IM, Karppinen J, Taimela S, Ott J, Barral S, Kaikkonen K, Heikkila O, Mutanen P, Noponen N, Mannikko M, Tervonen O, Natri A, Ala-Kokko L. Occupational and genetic risk factors associated with intervertebral disc disease. Spine (Phila Pa 1976) 2007 May 1;32(10):1129e34. [6] Chen WJ, Ye W, Ding Y, Su PQ, Li GT, Huang DS, Liu SL. Association of vitamin D receptor gene TruⅠ and FokⅠ polymorphisms with lumbar degenerative disc disease in Han nationality. Orthop J China 2007;15(05). 373e5þ9. [7] Cervin Serrano S, Gonzalez Villareal D, Aguilar-Medina M, Romero-Navarro JG, Romero Quintana JG, Arambula Meraz E, Osuna Ramirez I, Picos-Cardenas V, Granados J, Estrada-Garcia I, Sanchez-Schmitz G, Ramos-Payan R. Genetic polymorphisms of interleukin-1 alpha and the vitamin d receptor in Mexican Mestizo patients with intervertebral disc degeneration. Int J Genomics 2014 Nov 20;2014:302568. http://dx.doi.org/10.1155/2014/302568. [8] Colombini A, Brayda-Bruno M, Lombardi G, Croiset SJ, Vrech V, Maione V, Banfi G, Cauci S. FokI polymorphism in the vitamin D receptor gene (VDR) and its association with lumbar spine pathologies in the Italian population: a casecontrol study. PLoS One 2014;9(5):e97027. [9] Xu G, Mei Q, Zhou D, Wu J, Han L. Vitamin D receptor gene and aggrecan gene polymorphisms and the risk of intervertebral disc degeneration e a metaanalysis. PLoS One 2012 Nov 28;7(11):e50243. [10] Pani MA, Knapp M, Donner H, Braun J, Baur MP, Usadel KH, Badenhoop K. Vitamin D receptor allele combinations influence genetic susceptibility to type 1 diabetes in Germans. Diabetes 2000 Mar;49(3):504e7. [11] Vieira LA, De Marchi PL, dos Santos AA, Christofolini DM, Barbosa CP, Fonseca FL, Bianco B, Rodrigues LM. Analysis of FokI polymorphism of vitamin D receptor gene in intervertebral disc degeneration. Genet Test Mol Biomarkers 2014 Sep;18(9):625e9. [12] Zawilla NH, Darweesh H, Mansour N, Helal S, Taha FM, Awadallah M, El Shazly R. Matrix metalloproteinase-3, vitamin D receptor gene polymorphisms, and occupational risk factors in lumbar disc degeneration. J Occup Rehabil 2014 Jun;24(2):370e81. [13] Xu GH, Xu J, Xu B, Yang SX, Lin XZ. Association of vitamin D receptor TaqⅠ gene polymorphisms with lumbar degenerative disc disease in Han nationality of Fujian. Chin J Bone Joint Inj 2014;29(09):882e4. [14] Sansoni V, Perego S, Colombini A, Banfi G, Brayda-Bruno M, Lombardi G. Interplay between low plasma RANKL and VDR-FokI polymorphism in lumbar disc herniation independently from age, body mass, and environmental factors: a case-control study in the Italian population. Eur Spine J 2016 Jan;25(1): 192e9.
Please cite this article in press as: Chen L, et al., Association between vitamin D receptor gene polymorphisms and intervertebral disc degeneration: A meta-analysis, Journal of Orthopaedic Science (2016), http://dx.doi.org/10.1016/j.jos.2016.11.009
6
L. Chen et al. / Journal of Orthopaedic Science xxx (2016) 1e6
[15] Colombini A, Brayda-Bruno M, Ferino L, Lombardi G, Maione V, Banfi G, Cauci S. Gender differences in the VDR-FokI polymorphism and conventional non-genetic risk factors in association with lumbar spine pathologies in an Italian case-control study. Int J Mol Sci 2015;16(2):3722e39. [16] Chen W, Li G, Sun H, Ye W, Huang D, Su P, Zhang Z. Association of vitamin D receptor gene polymorphism in Han people with lumbar degenerative disc disease. Afr J Pharm Pharmacol 2012;6(16):1211e5. [17] Eser B, Cora T, Eser O, Kalkan E, Haktanir A, Erdogan MO, Solak M. Association of the polymorphisms of vitamin D receptor and aggrecan genes with degenerative disc disease. Genet Test Mol Biomarkers 2010 Jun;14(3):313e7. [18] Eskola PJ, Kjaer P, Daavittila IM, Solovieva S, Okuloff A, Sorensen JS, Wedderkopp N, Ala-Kokko L, Mannikko M, Karppinen JI. Genetic risk factors of disc degeneration among 12e14-year-old Danish children: a population study. Int J Mol Epidemiol Genet 2010;1(2):158e65. [19] Kelempisioti A, Eskola P, Okuloff A, Karjalainen U, Takatalo J, Daavittila I, €ki J, Sequeiros R, Tervonen O, Solovieva S, Kao P, Song Y-Q, Cheung K, Niinima € M. Genetic susChan D, Ala-Kokko L, J€ arvelin M-R, Karppinen J, M€ annikko ceptibility of intervertebral disc degeneration among young Finnish adults. BMC Med Genet 2011;12(1):1e8. [20] Noponen-Hietala N, Kyllonen E, Mannikko M, Ilkko E, Karppinen J, Ott J, AlaKokko L. Sequence variations in the collagen IX and XI genes are associated with degenerative lumbar spinal stenosis. Ann Rheum Dis 2003 Dec;62(12):1208e14. ticos e [21] Nunes FTB, Conforti-Froes NDT, Negrelli WF, Souza DRS. Fatores gene ~o do disco intervertebral. Acta ambientais envolvidos na degeneraça dica Bras 2007;15:9e13. Ortope
[22] Oishi Y, Shimizu K, Katoh T, Nakao H, Yamaura M, Furuko T, Narusawa K, Nakamura T. Lack of association between lumbar disc degeneration and osteophyte formation in elderly Japanese women with back pain. Bone 2003 Apr;32(4):405e11. [23] Yuan HY, Tang Y, Liang YX, Lei L, Xiao GB, Wang S, Xia ZL. Matrix metalloproteinase-3 and vitamin d receptor genetic polymorphisms, and their interactions with occupational exposure in lumbar disc degeneration. J Occup Health 2010;52(1):23e30. [24] Papadopoulou A, Bountouvi E, Gole E, Doulgeraki A, Tournis S, Papadimitriou A, Nicolaidou P. Identification of a novel nonsense mutation in the ligand-binding domain of the vitamin d receptor gene and clinical description of two Greek patients with hereditary vitamin d-resistant rickets and alopecia. Horm Res Paediatr 2014;82(3):206e12. [25] Forghani N, Lum C, Krishnan S, Wang J, Wilson DM, Blackett PR, Malloy PJ, Feldman D. Two new unrelated cases of hereditary 1,25-dihydroxyvitamin Dresistant rickets with alopecia resulting from the same novel nonsense mutation in the vitamin D receptor gene. J Pediatr Endocrinol Metab 2010 Aug;23(8):843e50. [26] Videman T, Gibbons LE, Battie MC, Maravilla K, Vanninen E, Leppavuori J, Kaprio J, Peltonen L. The relative roles of intragenic polymorphisms of the vitamin D receptor gene in lumbar spine degeneration and bone density. Spine (Phila Pa 1976) 2001 Feb 1;26(3):E7ee12.
Please cite this article in press as: Chen L, et al., Association between vitamin D receptor gene polymorphisms and intervertebral disc degeneration: A meta-analysis, Journal of Orthopaedic Science (2016), http://dx.doi.org/10.1016/j.jos.2016.11.009
Contents lists available at ScienceDirect
Journal of Orthopaedic Science journal homepage: http://www.elsevier.com/locate/jos
Original Article
Association between vitamin D receptor gene polymorphisms and intervertebral disc degeneration: A meta-analysis Lin Chen, Song Zhao, Feng Niu*, Gui-Bin Bi Department of Spine Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, PR China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 December 2015 Received in revised form 18 October 2016 Accepted 14 November 2016 Available online xxx
Background: Studies that have investigated the association between vitamin D receptor (VDR) gene polymorphisms and intervertebral disc degeneration (IDD) have yielded inconsistent results. Methods: To investigate the association between VDR gene polymorphisms and IDD, a systematic literature search for relevant published studies was performed on PubMed, Embase, Web of Science, Cochrane library, Wan-Fang, and CNKI databases. A random effects model was used for heterogeneous data; while a fixed effect model was used for homogenous data. Odds ratios (OR) and 95% confidence intervals (CI) were calculated to evaluate the strength of the association. Results: We observed no association between VDR FokI, TaqI-ApaI polymorphisms and IDD. However, on subgroup analysis by ethnicity, VDR FokI mutation was associated with a significantly lower risk for IDD [dominant model: OR ¼ 0.78, 95% CI ¼ 0.65e0.93; heterozygote model: OR ¼ 0.76, 95% CI ¼ 0.63e0.92; allele model: OR ¼ 0.86, 95% CI ¼ 0.75e0.98] among Caucasians. Conclusion: These results suggest that the VDR FokI polymorphism may be associated with IDD among Caucasians. However, the association between VDR TaqI-ApaI polymorphisms and IDD in Asians is still not clear. Further well-designed studies are needed to arrive at a definitive conclusion. © 2016 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.
1. Introduction Intervertebral disc degeneration (IDD), a musculoskeletal disorder attributed to an aberrant cell-mediated response, is characterized by structural failure and accelerated signs of aging. Disc degeneration may lead to disc herniation, sciatic pain, degenerative spondylolisthesis, degenerative scoliosis and spinal stenosis. The condition has been attributed to genetic, environmental and occupational factors. Genetic factors are thought to be one of the key determinants of the causation of IDD. Several predisposing genetic factors have been identified. Videman et al. [1] reported association of VDR polymorphisms TaqI and FokI with disc degeneration in a study conducted on 85 pairs of male monozygotic twins. These results are indicative of a possible association between VDR polymorphisms and disc degeneration. Subsequent research revealed that the Tt allele of the VDR gene was more frequently associated with disc degeneration as compared to the TT allele [2]. Cheung et al. [3], too, showed that allele of VDR TaqI was a high risk factor for IDD, in * Corresponding author. Department of Spine Surgery, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, Jilin 130021, PR China. E-mail address: [email protected] (F. Niu).
individuals < 40 years of age. However, results from other studies appear to refute the association of VDR single nucleotide polymorphisms (SNP) with IDD [4e6]. Recently, Cervin et al. [7] reported no significant association of VDR gene polymorphisms with IDD in a Mexican population. However, another study conducted on Italian patients with lumbar spine pathology, appeared to implicate the VDR FokI FF genotype and F allele in the promotion of spinal tissue degeneration [8]. Although several studies have indicated the association between VDR gene polymorphisms and IDD, the results of these studies are controversial. For instance, a meta-analysis [9] found no significant association of VDR FokI, TaqI, ApaI polymorphisms with the risk of IDD. TaqI and ApaI polymorphisms are in strong linkage disequilibrium with each other [10] and thus should to be combined in one meta-analysis. However, previous studies have not analyzed this angle. In addition, some other recent studies have also reported different results [11e15]. We performed a meta-analysis to investigate whether the polymorphism of VDR was a potential risk factor for IDD. The objective was to gain insights into the molecular mechanisms underlying IDD and its association with the VDR gene (FokI: rs2228570, TaqI: rs731236, ApaI: rs7975232). It may also contribute
http://dx.doi.org/10.1016/j.jos.2016.11.009 0949-2658/© 2016 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Chen L, et al., Association between vitamin D receptor gene polymorphisms and intervertebral disc degeneration: A meta-analysis, Journal of Orthopaedic Science (2016), http://dx.doi.org/10.1016/j.jos.2016.11.009
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towards the development of a specific gene knockout animal model of IDD. Moreover, susceptibility genes for IDD, if identified, could serve as new therapeutic targets besides facilitating an early diagnosis of the disorder. 2. Methods 2.1. Search strategy Online databases such as PubMed, Embase, Web of Science, Cochrane library, Wan-Fang data, and CNKI were searched for relevant studies. The keywords and search strategy were as follows: (“vitamin d receptor” or “vitamin d 3 receptor” or “calcitriol receptor” or “1,25-dihydroxyvitamin d3 receptor” or “vdr”) and (“polymorphism” or “mutation” or “genetic variation”) in combination with (“intervertebral disc” or “disc degeneration”). The parameters of the search were defined as “human studies published in English between 1995 and November 2015”. 2.2. Inclusion and exclusion criteria Studies were included if they met the following criteria: 1) evaluated the association of VDR (FokI, TaqI, ApaI) polymorphisms with IDD; 2) case-control or cohort design; 3) appropriate diagnostic criteria, such as magnetic resonance imaging (MRI); 4) availability of sufficient data. When genotype or allele frequencies were insufficiently described, the relevant additional information was requested from the authors. Studies that lacked an appropriate healthy control-group, literature reviews, and studies, for which data on genotype or allele frequencies were not available, were excluded from this meta-analysis. 2.3. Data abstraction Data were independently extracted by two investigators. Any disagreement was resolved by consensus after involving a third independent expert. Data on the following variables were extracted: name of first author, year of publication, country of origin, ethnicity of subjects, genotype frequencies, and HardyeWeinberg equilibrium (HWE) in control group. 2.4. Statistical analyses The HWE tests were performed on controls using a Pearson's goodness-of-fit chi-square from https://ihg.gsf.de/cgi-bin/hw/ hwa1.pl. The association between the VDR polymorphisms and IDD was assessed under the following genetic models: a dominant model, a recessive model, a homozygous model, a heterozygous model, an additive model, and an allele model. Odds ratio (OR) and 95% confidence interval (95% CI) were calculated to assess the strength of the association. Data analysis was performed using STATA software version 12.1 (Stata Corp College Station, TX). Statistical heterogeneity was assessed using the I2 tests. A value of I2 > 25% was considered indicative of heterogeneity, and a random effect model (the DerSimonianeLaird model) was used. In other cases, the fixed effect model (the ManteleHaenszel model) was employed. Step-down Bonferroni and BenjaminieHochberg tests were used to adjust the values for multiple comparisons. Subgroup analyses were stratified by ethnicity. Potential publication bias was assessed by Begg funnel plot and further evaluated for funnel plot symmetry by Egger test. Sensitivity analyses were performed by evaluating the stability of the results after exclusion of one study at a time. A probability of P < 0.05 was considered statistically significant.
3. Results 3.1. Search results A total of 158 relevant studies were retrieved out of which 52 were excluded after screening of the titles and abstracts; 17 studies were excluded after reviewing the full-texts. Only 16 studies qualified the inclusion criteria and were included in this metaanalysis [2,3,6,7,11e13,15e23]. The flow diagram of the selection process is showed in Fig. 1. 3.2. Demographic characteristics The characteristics of the included studies are summarized in Table 1. A total of 9 studies [6,7,11,15,17e21] were included for examining the association between VDR FokI polymorphism and risk of IDD; 10 studies [2,3,7,13,16e18,20,22,23] for that between TaqI polymorphism and risk of IDD; and 4 studies [2,12,16,23] were included for examining the association between the ApaI polymorphisms and the risk of IDD. In three [18e20] out of 16 studies, the genotype frequencies in the control populations deviated from HWE. 3.3. Quantitative data synthesis A summary of the meta-analysis results for the association between VDR gene polymorphisms and IDD is shown in Table 2. Owing to the significant heterogeneity between the study groups for VDR FokI (I2 ¼ 87.0%), a random effects model was employed (Fig. 2a, dominant model). No significant association was found between VDR FokI polymorphism and IDD risk. However, the results of subgroup analyses by ethnicity showed a significant association of VDR FokI mutation with IDD (dominant model: OR ¼ 0.78, 95% CI ¼ 0.65e0.93; heterozygote model: OR ¼ 0.76, 95% CI ¼ 0.63e0.92; allele model: OR ¼ 0.86, 95% CI ¼ 0.75e0.98; Table 2). Owing to significant heterogeneity between the 14 studies included for the assessment of the association between VDR TaqIApaI polymorphism and IDD risk (I2 ¼ 68.4%), a random effect model was used (Fig. 2b, dominant model). There was no significant association between VDR TaqI polymorphism and IDD risk. However, after omission of the study by Chen et al. (who concluded that common homozygotes were a risk factor for IDD, which was significantly different from previous information) [16] a significant association was observed among Asians between VDR TaqI-ApaI polymorphism and IDD (Fig. 2c, dominant model) (dominant model: OR ¼ 1.54, 95% CI ¼ 1.22e1.95; heterozygote model: OR ¼ 1.52, 95% CI ¼ 1.19e1.94; allele model: OR ¼ 1.38, 95% CI ¼ 1.14e1.67; Table 2). 3.4. Publication bias diagnostics The Begg funnel plot and Egger test revealed no strong evidence of publication bias that could have influenced the results of this meta-analysis (Fig. 3). (Begg test: P ¼ 0.193, Egger test: P ¼ 0.058 for VDR FokI; Begg test: P ¼ 0.251 Egger test: P ¼ 0.067 for VDR TaqIApaI, respectively). However, the data of FokI was dominated by studies among Caucasians. On the contrary, the data of TaqI-ApaI was dominated by studies among Asians. We considered that genetic association studies with non-significant findings were unlikely to be published, which suggests a potential for publication bias. 3.5. Sensitivity analyses Results based on aggregate data were significantly different from those of subgroup analysis for the investigated
Please cite this article in press as: Chen L, et al., Association between vitamin D receptor gene polymorphisms and intervertebral disc degeneration: A meta-analysis, Journal of Orthopaedic Science (2016), http://dx.doi.org/10.1016/j.jos.2016.11.009
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Fig. 1. Schematic illustration of the study selection procedure.
Table 1 Characteristics of the studies included in the meta-analysis. Author
FokI (rs2228570) Colombini et al. [15] Eser et al. [17] Eskola et al. [18] Kelempisioti et al. [19] Noponen-Hietala et al. [20] Vieira et al. [11] Nunes FTB et al. [21] Cervin et al. [7] Chen et al. [6] TaqI (rs731236) Chen et al. [16] Cheung et al. [3] Oishi et al. [22] Xu et al. [13] Yuan et al. [23] Kawaguchi et al. [2] Eskola et al. [18] Eser et al. [17] Noponen-Hietala et al. [20] Cervin et al. [7] ApaI (rs7975232) Chen et al. [16] Kawaguchi et al. [2] Yuan et al. [23] Zawilla et al. [12]
Year
Country
Ethnicity
Case
Control
HWE
11
12
22
11
12
22
P
2015 2010 2010 2011 2003 2014 2007 2014 2007
Italy Turkey Denmark Finland Finland Brazil Brazil Mexico China
Caucasian Caucasian Caucasian Caucasian Caucasian Brazilian Brazilian Mexican Asian
117 81 29 81 11 54 9 20 18
120 52 27 57 12 50 54 65 51
30 17 10 12 6 17 3 15 12
101 67 45 111 25 75 61 32 36
117 67 90 119 26 46 27 51 48
36 16 19 16 5 10 0 17 17
0.821 0.902 0.012 0.032 0.630 0.434 0.089 0.664 0.883
2012 2006 2003 2014 2010 2002 2010 2010 2003 2014
China China Japan China China Japan Denmark Turkey Finland Mexico
Asian Asian Asian Asian Asian Asian Caucasian Caucasian Caucasian Mexican
79 354 31 75 156 79 29 65 12 69
2 33 8 3 22 37 28 67 11 27
0 1 0 0 0 0 9 18 6 4
86 183 16 153 256 72 57 67 26 62
14 8 5 3 28 17 74 67 19 35
1 0 0 0 0 0 23 16 11 3
0.617 0.768 0.536 0.903 0.382 0.319 0.898 0.902 0.044 0.461
2012 2002 2010 2014
China Japan China Egypt
Asian Asian Asian Egyptian
44 51 58 17
28 48 100 48
9 17 20 19
43 41 128 34
46 39 129 22
12 9 27 4
0.955 0.951 0.500 0.863
11, 12, 22 represent common homozygous, heterozygote and rare homozygous, respectively. P values for HardyeWeinberg equilibrium test in control group.
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Table 2 Summary odds ratio (95% confidence intervals) for intervertebral disc degeneration in patients with vitamin D receptor (VDR) polymorphisms. I2 FokI (rs2228570) Dominant model 87.0% Caucasian Dominant model 0.0% Recessive model 0.0% Homozygous model 0.0% Heterozygote model 0.0% Additive model 0.0% Allele model 0.0% TaqI (rs731236)-ApaI (rs7975232) Dominant model 68.4% Chen et al. (2012) omitted among Asian Dominant model 0.0% Recessive model 0.0% Homozygous model 0.0% Heterozygote model 0.0% Additive model 0.0% Allele model 0.0%
Model
OR
95% CI
P
Bon
FDR
REM
1.35
0.82e2.23
0.237
0.948
0.336
FEM FEM FEM FEM FEM FEM
0.78 1.05 0.84 0.76 1.08 0.86
0.65e0.93 0.75e1.45 0.62e1.13 0.63e0.92 0.80e1.45 0.75e0.98
0.006 0.787 0.240 0.005 0.610 0.027
0.036 1.000 0.948 0.035 1.000 0.135
0.021 0.787 0.336 0.021 0.712 0.063
REM
1.20
0.87e1.66
0.265
0.795
0.323
FEM FEM FEM FEM FEM FEM
1.54 1.31 1.59 1.52 1.11 1.38
1.22e1.95 0.80e2.14 0.94e2.69 1.19e1.94 0.67e1.85 1.14e1.67
0.000 0.277 0.083 0.001 0.692 0.001
0.000 0.795 0.332 0.006 0.795 0.006
0.000 0.323 0.145 0.002 0.692 0.002
OR, odds ratio; CI, confidence interval. FEM, fixed effect model; REM, random effect model. Bon, P value in step-down Bonferroni testing; FDR, P value from BenjaminieHochberg method control for false discovery rate.
polymorphisms and risk of IDD. After omitting the studies that deviated from HWE in the subgroup analyses by ethnicity, the pooled results showed no significant influence for VDR FokI (data not shown). However, when we excluded the study by Chen et al. [16] for VDR TaqI-ApaI, a significant association was found in Asians (Table 2).
4. Discussion Intervertebral disc degeneration is characterized by disc dehydration and herniation. The etiology of this condition is thought to be multi-factorial, including, genetic, environmental, occupational, and age related etiological factors. Because of the above-mentioned conflicting results, a meta-analysis should be an appropriate approach to investigate the association between VDR gene polymorphisms and IDD. In this study, the combined data on VDR FokI, TaqI-ApaI polymorphisms did not demonstrate any association with IDD. However, after disaggregating the data by ethnicity, a significant association was observed between VDR FokI polymorphism and IDD risk in the Caucasian population (dominant model: OR ¼ 0.78, 95% CI ¼ 0.65e0.93; heterozygote model: OR ¼ 0.76, 95% CI ¼ 0.63e0.92; allele model: OR ¼ 0.86, 95% CI ¼ 0.75e0.98). Similarly, for Asians, the results showed no significant association between VDR TaqI-ApaI polymorphisms and IDD. However, a significant association was found after exclusion of the study by Chen et al. [16] for VDR TaqIApaI (dominant model: OR ¼ 1.54, 95% CI ¼ 1.22e1.95; heterozygote model: OR ¼ 1.52, 95% CI ¼ 1.19e1.94; allele model: OR ¼ 1.38, 95% CI ¼ 1.14e1.67). Our findings indicate that the association of VDR TaqI-ApaI gene in the Asian population requires further investigation. After excluding studies that deviated from HWE in controls, the pooled results showed no significant influence for VDR FokI among Caucasians in all genetic models. Although, no potential publication bias was identified by Begg funnel plot and Egger test, publication bias may also exist because it is reasonable to assume that genetic association studies with non-significant findings were more unlikely to be published.
Fig. 2. a: Forest plot of the association between vitamin D receptor (VDR) FokI polymorphism and intervertebral disc degeneration (dominant model). b: Forest plot of the association between vitamin D receptor (VDR) TaqI-ApaI polymorphisms and intervertebral disc degeneration (dominant model). c: Forest plot of the association between vitamin D receptor (VDR) TaqI-ApaI polymorphisms and intervertebral disc degeneration among Caucasians (dominant model).
1,25-Dihydroxy vitamin D3 is an active metabolite of vitamin D that regulates local calcium and phosphorus homeostasis and aggrecan synthesis through a VDR-dependent mechanism. The VDR gene is expressed in nucleus pulposus and annulus fibrosus cells of the intervertebral disc. Thus, the VDR gene may affect the disc metabolism of calcium and phosphorus and possibly have a role in
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Fig. 3. Begg funnel plot and Egger test for assessing potential influence of publication bias on the observed association between the vitamin D receptor (VDR) polymorphisms and intervertebral disc degeneration (dominant model).
the causation of IDD. The novel nonsense mutation c.1066 C > T is known to result in a VDR protein with <71 amino acids, which may affect the normal VDR function [24]. Sequencing studies have suggested that the VDR gene mutation results in a premature stop codon (R50X) in patients with vitamin D resistant rickets [25]. Therefore, it is conceivable that the VDR gene polymorphisms may affect the translation efficiency of mRNA and its encoded protein, which in turn may affect the vitality, structure and the number of receptor proteins. Vitamin D receptor TaqI gene polymorphism was reported as a potential risk factor for intervertebral disc degeneration. Studies have also reported the association of VDR FokI, TaqI, and ApaI polymorphisms with IDD risk. However, the evidence has largely been inconsistent. Recently, Colombini et al. [8] reported that the f allele of VDR FokI was protective and that the FokI FF genotype was a risk factor for disc herniation in the Italian population. However, Cervin et al. [7] found no evidence supporting this association in a Mexican Mestizo population; similar findings of a lack of association were reported from a study conducted in a Chinese population [6]. Thus, we speculate that ethnicity, environmental factors and lifestyle appear to be the key variables that influence the susceptibility to IDD. The VDR tt genotype was shown to be associated with a higher prevalence of annular tears and back pain as compared to the TT genotype [26]. Another study indicated that the t and Tt alleles of VDR TaqI confer an increased risk of disc disease at an early age among Asians, which indicates that the t allele may be a major susceptibility locus in Asian population, especially in those <40 years of age [2,3]. In some studies the AA mutation genotype was one of the genetic risk factors associated with lumbar disc degeneration [12,23], which suggests a linkage between an allele and risk of IDD. A significant association was found when we excluded the study by Chen et al. Thus, the associations between VDR TaqI-ApaI gene polymorphisms and the risks of IDD could not be excluded in the Asian population. Some limitations in our study need to be acknowledged. The small sample size in our study limits the statistical power of the observed associations. Secondly, we might have missed some studies as the literature search was conducted according to the principles of PICOS. Thirdly, we could not make precise OR adjustments for age and sex. Finally, we did not perform multivariate analysis, which is another limitation of our study. 5. Conclusion Our meta-analysis suggests that the VDR FokI polymorphism may be associated with IDD among Caucasians; however, the association between VDR TaqI-ApaI polymorphisms and IDD in Asian population is still not clear. Due to the study limitations, additional investigations are required on a larger population base
to confirm the association between the VDR polymorphism and IDD risk. Conflict of interest We declare that we have no conflict of interest. References [1] Videman T, Leppavuori J, Kaprio J, Battie MC, Gibbons LE, Peltonen L, Koskenvuo M. Intragenic polymorphisms of the vitamin D receptor gene associated with intervertebral disc degeneration. Spine (Phila Pa 1976) 1998 Dec 1;23(23):2477e85. [2] Kawaguchi Y, Kanamori M, Ishihara H, Ohmori K, Matsui H, Kimura T. The association of lumbar disc disease with vitamin-D receptor gene polymorphism. J Bone Joint Surg Am 2002 Nov;84-a(11):2022e8. [3] Cheung KM, Chan D, Karppinen J, Chen Y, Jim JJ, Yip SP, Ott J, Wong KK, Sham P, Luk KD, Cheah KS, Leong JC, Song YQ. Association of the Taq I allele in vitamin D receptor with degenerative disc disease and disc bulge in a Chinese population. Spine (Phila Pa 1976) 2006 May 1;31(10):1143e8. [4] Karppinen J, Daavittila I, Solovieva S, Kuisma M, Taimela S, Natri A, Haapea M, Korpelainen R, Niinimaki J, Tervonen O, Ala-Kokko L, Mannikko M. Genetic factors are associated with modic changes in endplates of lumbar vertebral bodies. Spine (Phila Pa 1976) 2008 May 15;33(11):1236e41. [5] Virtanen IM, Karppinen J, Taimela S, Ott J, Barral S, Kaikkonen K, Heikkila O, Mutanen P, Noponen N, Mannikko M, Tervonen O, Natri A, Ala-Kokko L. Occupational and genetic risk factors associated with intervertebral disc disease. Spine (Phila Pa 1976) 2007 May 1;32(10):1129e34. [6] Chen WJ, Ye W, Ding Y, Su PQ, Li GT, Huang DS, Liu SL. Association of vitamin D receptor gene TruⅠ and FokⅠ polymorphisms with lumbar degenerative disc disease in Han nationality. Orthop J China 2007;15(05). 373e5þ9. [7] Cervin Serrano S, Gonzalez Villareal D, Aguilar-Medina M, Romero-Navarro JG, Romero Quintana JG, Arambula Meraz E, Osuna Ramirez I, Picos-Cardenas V, Granados J, Estrada-Garcia I, Sanchez-Schmitz G, Ramos-Payan R. Genetic polymorphisms of interleukin-1 alpha and the vitamin d receptor in Mexican Mestizo patients with intervertebral disc degeneration. Int J Genomics 2014 Nov 20;2014:302568. http://dx.doi.org/10.1155/2014/302568. [8] Colombini A, Brayda-Bruno M, Lombardi G, Croiset SJ, Vrech V, Maione V, Banfi G, Cauci S. FokI polymorphism in the vitamin D receptor gene (VDR) and its association with lumbar spine pathologies in the Italian population: a casecontrol study. PLoS One 2014;9(5):e97027. [9] Xu G, Mei Q, Zhou D, Wu J, Han L. Vitamin D receptor gene and aggrecan gene polymorphisms and the risk of intervertebral disc degeneration e a metaanalysis. PLoS One 2012 Nov 28;7(11):e50243. [10] Pani MA, Knapp M, Donner H, Braun J, Baur MP, Usadel KH, Badenhoop K. Vitamin D receptor allele combinations influence genetic susceptibility to type 1 diabetes in Germans. Diabetes 2000 Mar;49(3):504e7. [11] Vieira LA, De Marchi PL, dos Santos AA, Christofolini DM, Barbosa CP, Fonseca FL, Bianco B, Rodrigues LM. Analysis of FokI polymorphism of vitamin D receptor gene in intervertebral disc degeneration. Genet Test Mol Biomarkers 2014 Sep;18(9):625e9. [12] Zawilla NH, Darweesh H, Mansour N, Helal S, Taha FM, Awadallah M, El Shazly R. Matrix metalloproteinase-3, vitamin D receptor gene polymorphisms, and occupational risk factors in lumbar disc degeneration. J Occup Rehabil 2014 Jun;24(2):370e81. [13] Xu GH, Xu J, Xu B, Yang SX, Lin XZ. Association of vitamin D receptor TaqⅠ gene polymorphisms with lumbar degenerative disc disease in Han nationality of Fujian. Chin J Bone Joint Inj 2014;29(09):882e4. [14] Sansoni V, Perego S, Colombini A, Banfi G, Brayda-Bruno M, Lombardi G. Interplay between low plasma RANKL and VDR-FokI polymorphism in lumbar disc herniation independently from age, body mass, and environmental factors: a case-control study in the Italian population. Eur Spine J 2016 Jan;25(1): 192e9.
Please cite this article in press as: Chen L, et al., Association between vitamin D receptor gene polymorphisms and intervertebral disc degeneration: A meta-analysis, Journal of Orthopaedic Science (2016), http://dx.doi.org/10.1016/j.jos.2016.11.009
6
L. Chen et al. / Journal of Orthopaedic Science xxx (2016) 1e6
[15] Colombini A, Brayda-Bruno M, Ferino L, Lombardi G, Maione V, Banfi G, Cauci S. Gender differences in the VDR-FokI polymorphism and conventional non-genetic risk factors in association with lumbar spine pathologies in an Italian case-control study. Int J Mol Sci 2015;16(2):3722e39. [16] Chen W, Li G, Sun H, Ye W, Huang D, Su P, Zhang Z. Association of vitamin D receptor gene polymorphism in Han people with lumbar degenerative disc disease. Afr J Pharm Pharmacol 2012;6(16):1211e5. [17] Eser B, Cora T, Eser O, Kalkan E, Haktanir A, Erdogan MO, Solak M. Association of the polymorphisms of vitamin D receptor and aggrecan genes with degenerative disc disease. Genet Test Mol Biomarkers 2010 Jun;14(3):313e7. [18] Eskola PJ, Kjaer P, Daavittila IM, Solovieva S, Okuloff A, Sorensen JS, Wedderkopp N, Ala-Kokko L, Mannikko M, Karppinen JI. Genetic risk factors of disc degeneration among 12e14-year-old Danish children: a population study. Int J Mol Epidemiol Genet 2010;1(2):158e65. [19] Kelempisioti A, Eskola P, Okuloff A, Karjalainen U, Takatalo J, Daavittila I, €ki J, Sequeiros R, Tervonen O, Solovieva S, Kao P, Song Y-Q, Cheung K, Niinima € M. Genetic susChan D, Ala-Kokko L, J€ arvelin M-R, Karppinen J, M€ annikko ceptibility of intervertebral disc degeneration among young Finnish adults. BMC Med Genet 2011;12(1):1e8. [20] Noponen-Hietala N, Kyllonen E, Mannikko M, Ilkko E, Karppinen J, Ott J, AlaKokko L. Sequence variations in the collagen IX and XI genes are associated with degenerative lumbar spinal stenosis. Ann Rheum Dis 2003 Dec;62(12):1208e14. ticos e [21] Nunes FTB, Conforti-Froes NDT, Negrelli WF, Souza DRS. Fatores gene ~o do disco intervertebral. Acta ambientais envolvidos na degeneraça dica Bras 2007;15:9e13. Ortope
[22] Oishi Y, Shimizu K, Katoh T, Nakao H, Yamaura M, Furuko T, Narusawa K, Nakamura T. Lack of association between lumbar disc degeneration and osteophyte formation in elderly Japanese women with back pain. Bone 2003 Apr;32(4):405e11. [23] Yuan HY, Tang Y, Liang YX, Lei L, Xiao GB, Wang S, Xia ZL. Matrix metalloproteinase-3 and vitamin d receptor genetic polymorphisms, and their interactions with occupational exposure in lumbar disc degeneration. J Occup Health 2010;52(1):23e30. [24] Papadopoulou A, Bountouvi E, Gole E, Doulgeraki A, Tournis S, Papadimitriou A, Nicolaidou P. Identification of a novel nonsense mutation in the ligand-binding domain of the vitamin d receptor gene and clinical description of two Greek patients with hereditary vitamin d-resistant rickets and alopecia. Horm Res Paediatr 2014;82(3):206e12. [25] Forghani N, Lum C, Krishnan S, Wang J, Wilson DM, Blackett PR, Malloy PJ, Feldman D. Two new unrelated cases of hereditary 1,25-dihydroxyvitamin Dresistant rickets with alopecia resulting from the same novel nonsense mutation in the vitamin D receptor gene. J Pediatr Endocrinol Metab 2010 Aug;23(8):843e50. [26] Videman T, Gibbons LE, Battie MC, Maravilla K, Vanninen E, Leppavuori J, Kaprio J, Peltonen L. The relative roles of intragenic polymorphisms of the vitamin D receptor gene in lumbar spine degeneration and bone density. Spine (Phila Pa 1976) 2001 Feb 1;26(3):E7ee12.
Please cite this article in press as: Chen L, et al., Association between vitamin D receptor gene polymorphisms and intervertebral disc degeneration: A meta-analysis, Journal of Orthopaedic Science (2016), http://dx.doi.org/10.1016/j.jos.2016.11.009