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. 2017 Aug 1;10(8):8695–8702.

Association between vitamin D receptor genetic polymorphisms and haplotypes and risk of lumbar degenerative disc disease in a Chinese population

Yu Fang 1,2, Bin Yu 1, Yong Yang 2, Gang Liu 2, Su Yi La Tu 2
PMCID: PMC6965387  PMID: 31966727

Abstract

Degenerative disc disease is a continuous degeneration process of intervertebral discs. We performed a case-control study to investigate the association between 16 common SNPs of VDR and degenerative disc disease risk in a Chinese population. A total of 482 pairs of patients with degenerative disc disease and controls were collected between May 2014 and May 2016. The genotyping of VDR rs1544410, rs2239181, rs2107301, rs2239179, rs2189480, rs3819545, rs2239186, rs2254210, rs2238136, rs4760648, rs11168287, rS4328262, rS4334089, rs3890733, rs10783219 and rS7299460 was done in a 384-well plate format on the sequenom MassARRAY platform (Sequenom, San Diego, USA). We observed that the TC (OR=2.13, 95% CI=1.34-3.40) and CC (OR=2.73, 95% CI=1.75-4.28) genotypes of rs2239179 were associated with an increased risk of degenerative disc disease when compared with the TT genotype. However, there was no significant correlation between other fifth SNPs of VDR and degenerative disc disease risk. The haplotype analysis revealed that the rs2239179 had linkage disequilibrium with rs2107301 (D’=0.97, r2=0.25) and rs2238136 (D’=0.81, r2=0.15). The rs2239179 polymorphism was associated with drinking habit (Spearman correlation coefficient =0.09, P=0.006) in the risk of intervertebral disc disease. In conclusion, our study indicated that the VDR genetic polymorphism may contribute to the development of degenerative disc disease in the Chinese population.

Keywords: VDR, polymorphism, haplotype, degenerative disc disease

Introduction

Degenerative disc disease is a continuous degeneration process of intervertebral discs [1,2]. The development of degenerative disc disease seems to be determined by the many environmental and genetic factors. It is reported that long-term high pressure and low pressure load contribute to the risk of degenerative disc disease [3,4]. A study with 172 monozygotic twins and 154 binovular twins have reported that the 74% at the lumbar spine and 73% at the cervical spine intervertebral disc disease can be attributed to hereditary [5]. Another heritability study has followed up 436 monozygotic twins, and it indicates that heritability contributes to 30% of the intervertebral disc degeneration prevalence [6]. Therefore, heritability plays an important role in the pathogenesis of degenerative disc disease. Identification of molecular factors involves in this disease is essential.

Previous studies have investigated the association between genetic factors and risk of degenerative disc disease in many populations [7,8]. The vitamin D receptor (VDR) is a derivative of steroids and belongs to superfamily members of steroid/thyroid hormone receptor, and it has a function of rachitic properties. Many biological functions of vitamin D are achieved by VDR mediated regulation of target gene transcription [9]. The VDR mediates the biological function of 1,25-dihydroxyvitamin D3 through signal transduction pathways, and plays an important role in the intestinal Ca2+ transport, bone remodeling, electrolyte homeostasis and cell proliferation [10]. The VDR is located on chromosome 12 (12q12-14), and about 25 SNPs are reported in the VDR gene. Previous studies have reported an association between VDR genetic polymorphisms and degenerative disc disease risk [11-14], but the results are inconsistent. Therefore, we performed a case-control study to investigate the role of 16 common SNPs of VDR in the development of degenerative disc disease in a Chinese population. We also examined the effect of gene-environmental interactions on degenerative disc disease risk.

Materials and methods

Subjects

We recruited 482 patients with degenerative disc disease from the Department of Ortho-pedics of the Affiliated Hospital of Inner Mongolia Medical University between May 2014 and May 2016. The disease was diagnosed in all individuals by both X ray and magnetic resonance imaging (MRI). The image classification was based on Schneiderman MRI [15]. Those who had prior history of spinal trauma, spinal deformity, spinal infections and metabolic diseases were excluded.

A total of 482 controls were recruited from the outpatient clinics in physical examination center of the Affiliated Hospital of Inner Mongolia Medical University between May 2014 and May 2016. Controls were matched with patients by sex and age (±5 years). All controls were confirmed to be free of discogenic low back pain and history of intervertebral disc disease.

The demographic and clinical information of all the participants were obtained from medical records. These information included sex, age, body mass index (BMI), physical labor, lumbar injury and Schneiderman stage. The physical labor was defined as never, occasionally and frequently. BMI is defined as the body mass divided by the square of the body height (kg/m2). The performance of our study was approved by the ethics committee of the Affiliated Hospital of Inner Mongolia Medical University. Written informed consents were obtained from all participants prior to enrollment.

DNA extraction and genotyping

Peripheral venous blood samples were kept in tube with 0.5 M ethylene diamine tetraacetic acid, and was stored in a refrigerator at 4°C until utilization. The DNA was extracted by the Blood DNA kit produced by Tiangen Biotech Co., Ltd (Tiangen, Beijing, China) according to the manufacturer’s instructions. The blood samples were kept in -20°C until use. Genotyping of VDR rs1544410, rs2239181, rs2107301, rs2239179, rs2189480, rs3819545, rs2239186, rs2254210, rs2238136, rs4760648, rs11168287, rS4328262, rS4334089, rs3890733, rs10783219 and rS7299460 was done in a 384-well plate format on the sequenom MassARRAY platform (Sequenom, San Diego, USA). Primers of the 16 SNPs for polymerase chain reaction amplification and single base extension assays were designed by Sequenom Assay Design 3.1 software. The PCR reaction was carried out in 5 μL, following by the SAP and iPLEX reaction. Then the PCR products were desalted and dispensed to a SpectroCHIP, and analyzed with MALDI-TOF MS.

Statistical analysis

Categorical variables were displayed as percentages and frequencies (%), and continued variables were expressed by mean ± standard deviation (SD). The differences between patients with degenerative disc disease and controls in terms of demographic and clinical variables were analyzed by Chi-square test or student t test. Departure from the Hardy-Weinberg equilibrium was analyzed by Chi-square (χ2) test with one degree of freedom. Multivariate conditional logistic regression analysis was taken to estimate the relationship between VDR SNPs and degenerative disc disease risk, and the results were displayed by odds ratios (ORs) and 95% confidence intervals (CIs). Linkage disequilibrium and haplotype analyses were evaluated by SHEsis software (http://analysis.bio-x.cn/myAnalysis.php) [16]. All statistical analysis was carried out using IBM SPSS Statistics for Windows, Version 21.0 (Armonk, NY: IBM Corp).

Results

The demographic and clinical characteristics of the subjects are shown in Table 1. When compared with controls, patients with degenerative disc disease were more likely to have high age (t=2.53, P=0.01) and a family history of intervertebral disc disease (χ2=8.67, P=0.003). 214 patients with degenerative disc disease were at II schneiderman stage, and 268 were at III stage.

Table 1.

Demographic and clinical characteristics of enrolled patients and controls

Variables Patients N=482 % Controls N=482 % t or χ2 value P value
Sex
    Male 289 59.96 289 59.96
    Female 193 40.04 193 40.04 - 1
Age, years 45.30±9.55 43.45±10.12 2.53 0.01
BMI
    <24 267 55.39 238 49.38
    ≥24 215 44.61 244 50.62 3.5 0.06
Smoking habit
    No 274 56.85 263 54.56
    Yes 208 43.15 219 45.44 0.51 0.48
Drinking habit
    No 317 65.77 329 68.26
    Yes 165 34.23 153 31.74 0.68 0.41
Physical labor
    No 184 38.17 205 42.53
    Yes 298 61.83 277 57.47 1.9 0.17
Family history of intervertebral disc disease
    No 315 65.35 357 74.07
    Yes 167 34.65 125 25.93 8.67 0.003
Lumbar injury
    No 453 93.98 469 97.3
    Yes 29 6.02 13 2.7 6.37 0.12
Schneiderman stage
    II 214 44.4
    III 268 55.6
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We observed that the TC (OR=2.13, 95% CI=1.34-3.40) and CC (OR=2.73, 95% CI=1.75-4.28) genotypes of rs2239179 were associated with an increased risk of degenerative disc disease when compared with the TT genotype (Table 2). However, there was no significant association between other fifth SNPs of VDR and risk of degenerative disc disease.

Table 2.

Association between 16 SNPs of VDR and risk of degenerative disc disease

SNPs Patients N=482 % Controls N=482 % χ2 P value HWE in controls OR (95% CI)1 P value
rs1544410
    CC 424 87.97 416 86.31 1.0 (Ref.)
    CT 58 12.03 66 13.69 0.81 (0.54-1.20) 0.29
    TT 0 0 0 0 0.59 0.44 0.11 -
rs2239181
    AA 297 61.62 292 60.58 1.0 (Ref.)
    AC 158 32.78 164 34.02 1.14 (0.63-2.07) 0.66
    CC 27 5.6 26 5.39 0.17 0.92 0.64 1.11 (0.62-2.00) 0.72
rs2107301
    GG 236 48.96 239 49.59 1.0 (Ref.)
    GA 202 41.91 201 41.7 0.99 (0.61-1.60) 0.95
    AA 44 9.13 42 8.71 0.07 0.97 0.98 1.05 (0.65-1.69) 0.85
rs2239179
    TT 242 50.21 293 60.79 1.0 (Ref.)
    TC 167 34.65 159 32.99 2.13 (1.34-3.40) 0.002
    CC 73 15.15 33 6.85 20.33 <0.001 0.08 2.73 (1.75-4.28) <0.001
rs2189480
    GG 236 48.96 244 50.62 1.0 (Ref.)
    GT 195 40.46 190 39.42 1.03 (0.66-1.63) 0.89
    TT 51 10.58 48 9.96 0.29 0.87 0.22 1.11 (0.71-1.73) 0.65
rs3819545
    AA 270 56.02 274 56.85 1.0 (Ref.)
    AG 182 37.76 183 37.97 1.20 (0.66-2.16) 0.55
    GG 30 6.22 25 5.19 0.49 0.78 0.43 1.24 (0.70-2.21) 0.46
rs2239186
    AA 139 28.84 156 32.37 1.0 (Ref.)
    AG 232 48.13 220 45.64 0.97 (0.70-1.36) 0.87
    GG 111 23.03 106 21.99 1.41 0.49 0.09 1.17 (0.81-1.68) 0.4
rs2254210
    GG 215 44.61 228 47.3 1.0 (Ref.)
    GA 235 48.76 220 45.64 0.95 (0.56-1.62) 0.85
    AA 32 6.64 34 7.05 0.94 0.63 0.05 1.09 (0.64-1.85) 0.76
rs2238136
    CC 283 58.71 289 59.96 1.0 (Ref.)
    CT 186 38.59 184 38.17 1.50 (0.61-3.70) 0.37
    TT 13 2.7 9 1.87 0.8 0.67 <0.001 1.54 (0.63-3.76) 0.34
rs4760648
    TT 182 37.76 185 38.38 1.0 (Ref.)
    TC 238 49.38 241 50 1.13 (0.74-1.72) 0.57
    CC 62 12.86 56 11.62 0.35 0.84 0.09 1.11 (0.72-1.70) 0.65
rs11168287
    AA 208 43.15 215 44.61 1.0 (Ref.)
    GA 215 44.61 213 44.19 1.12 (0.73-1.72) 0.59
    GG 59 12.24 54 11.2 0.35 0.84 0.91 1.18 (0.77-1.81) 0.45
rs4328262
    TT 198 41.08 185 38.38 1.0 (Ref.)
    GT 210 43.57 220 45.64 0.89 (0.61-1.31) 0.56
    GG 74 15.35 77 15.98 0.73 0.69 0.39 1.03 (0.70-1.51) 0.89
rs4334089
    GG 191 39.63 205 42.53 1.0 (Ref.)
    GA 251 52.07 241 50 1.16 (0.71-1.91) 0.55
    AA 40 8.3 36 7.47 0.91 0.64 0.002 1.27 (0.77-2.10) 0.35
rs3890733
    CC 456 94.61 461 95.64 1.0 (Ref.)
    CT 26 5.39 21 4.36 1.16 (0.63-2.14) 0.63
    TT 0 0 0 0 0.56 0.46 0.62 -
rs10783219
    AA 162 33.61 177 36.72 1.0 (Ref.)
    TA 246 51.04 238 49.38 1.03 (0.70-1.53) 0.86
    TT 74 15.35 67 13.9 1.14 0.57 0.36 1.21 (0.80-1.81) 0.36
rs7299460
    TT 158 32.78 147 30.5 1.0 (Ref.)
    CT 254 52.7 253 52.49 0.90 (0.62-1.31) 0.57
    CC 70 14.52 82 17.01 1.35 0.51 0.13 0.85 (0.57-1.27) 0.43
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1

Adjusted for age, family history of intervertebral disc disease and lumbar injury.

The haplotype analysis revealed linkage disequilibrium between rs2107301 and rs2239179 (D’=0.97, r2=0.25; Figure 1), and rs2238136 and rs2239179 also showed significant linkage disequilibrium (D’=0.81, r2=0.15; Figure 1).

Figure 1.

Figure 1

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The linkage disequilibrium of 16 SNPs of VDR.

We observed a significant interaction between rs2239179 polymorphism and drinking habit (Spearman correlation coefficient=0.09, P=0.006) in the risk of intervertebral disc disease (Table 3).

Table 3.

Interaction between rs2239179 polymorphisms and environmental factors in the risk of intervertebral disc disease

Variables rs2239179 χ2 value P value Spearman correlation coefficient P value
TT TC CC
Sex
    Male 313 212 53
    Female 222 111 53 9.18 0.01 0.009 0.79
Age
    <45 250 152 51
    ≥45 285 171 55 0.07 0.97 -0.008 0.81
BMI
    <24 271 175 59
    ≥24 264 148 47 1.52 0.47 -0.04 0.23
Smoking habit
    No 300 179 58
    Yes 235 144 48 0.08 0.96 0.01 0.77
Drinking habit
    No 382 197 67
    Yes 153 126 39 10.66 0.01 0.09 0.006
Family history of intervertebral disc disease
    No 366 230 76
    Yes 169 93 30 0.97 0.62 -0.03 0.35
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Discussion

The development of degenerative disc disease is involved in multifactorial disease, such as environmental and genetic factors. Pathogenesis of various diseases can be affected by a single base mutation that can lead to alteration of protein expression. This study evaluated the role of VDR SNPs in the pathogenesis of degenerative disc disease, and showed that the TC and CC genotypes of rs2239179 were related to the risk of degenerative disc disease when compared with the TT genotype.

VDR gene is located at 12qchromosome, and its biological effect is mediated through 1,25(OH)2D3. 1,25(OH)2D3 is reported to be involved in the regulators of cell proliferation and production of specific cytokines in the lumbar anulus [17]. Balmain et al. observed the immunoreactive VDR receptors in nucleoli of chondrocytes, especially in the fibrillar component, and VDR may be directly involved in differentiation, proliferation and maturation of cartilage cells [18]. In addition, in vitro study has indicated that vitamin D could influence the synthesis of proteoglycan in articular cartilage cells, and the disc contains rich proteoglycans [19]. VDR participates into metabolism of VDR, and influences the pathogenesis of degenerative disc disease.

Currently, many previous studies have reported the association between VDR genetic polymorphism and degenerative disc disease risk, but the results are inconsistent [13,14,20-25]. Yuan et al. carried out a study with 178 patients and 284 controls, and they reported that individuals carrying the A allele of VDR rs35068180 are more vulnerable to developing lumbar disc degeneration [25]. Eser et al. revealed that VDR genetic polymorphism was associated with risk of disc degeneration [24]. Zawilla et al. performed a case-control study with 84 lumbar disc degeneration and 60 controls, and indicated that VDR Apal polymorphism was correlated with risk of lumbar disc degeneration [23]. Vieira et al. indicated that VDR Fokl/T2C polymorphism was related to the development of intervertebral disc degeneration [22]. Zhao et al. found that VDR rs2228570 polymorphism showed an increased risk for intervertebral disc degeneration in a Chinese population [20]. However, Colombini et al. [23] and Serrano et al. [21] did not report significant association between VDR genetic variants and development or progression of osteoarthritis and intervertebral disc degeneration. In our study, we found the VDR rs2239179 played an important role in the risk of degenerative disc disease. Discrepancies between the previous results may be caused by differences in study design, ethnicities and sample size.

Previous studies reported significant interaction between alcohol intake and vitamin D related gene polymorphisms in risk of diseases [26,27]. Deschasaux M et al. performed a case-control study with 233 women with breast cancer and 466 controls, and reported a correlation between vitamin D-related gene polymorphisms and alcohol intake in breast cancer risk [26]. Gu H et al. indicated that VDR gene polymorphism was associated with a heavy risk of esophageal cancer in patients having drinking habit [27]. Moreover, we observed that the VDR rs2107301 and rs2238136 showed linkage disequilibrium with rs2239179. A previous Chinese study also reported a linkage disequilibrium block between rs2107301 and rs2239179 [28], which is similar with our results. Further studies are greatly required to confirm this finding.

Two limitations should be mentioned in this study. First, enrolled subjects were collected from one hospital, and they may not be sufficiently representative of other population. Second, only VDR gene was considered in this study, and the possibility of gene-gene interaction between other genes and VDR may contribute to the pathogenesis of degenerative disc disease.

In conclusion, our study revealed that the VDR genetic polymorphism may contribute to the development of degenerative disc disease in the Chinese population, suggesting that VDR polymorphisms could be used as biomarkers in early detection of this disease. Further large-scale studies should be conducted to gain better insight into the effect of VDR genetic polymorphism on degenerative disc disease risk.

Acknowledgements

We thank for the great help from staffs in Affiliated Hospital of Inner Mongolia Medical University, and they help us to collect the blood samples from enrolled subjects.

Disclosure of conflict of interest

None.

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