Lumbar degenerative disc diseases might be fought by Vitamin D Receptor activation– many studies

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Lumbar Degenerative Disc Disease 1.8X more likely if VDR type A genotype (but 1.6 X LESS likely if type G) - May 2024

Association of TaqI(rs731236) Polymorphism of Vitamin D Receptor Gene with Lumbar Degenerative Disc Disease
World Neurosurgery, Available online 25 May 2024 https://doi.org/10.1016/j.wneu.2024.05.129 PDF behind paywall
Luay Şerifoğlu 1, Seda Güleç Yılmaz 2, Abdulmutalip karaaslanlı 3, Ali Haluk Düzkalır 4, Mustafa Umut Etli 1, Selçuk Özdoğan 1

Background
Lumbar Degenerative Disc Disease (LDDD) significantly contributes to low back pain, with a complicated etiology involving genetic and environmental facts. The aim of study is to investigate the association between the TaqI(rs731236) polymorphism of the Vitamin D Receptor(VDR) gene with LDDD.

Methods
248 patients with symptomatic LDDD and 146 control subjects were examined. The evaluation of clinical features of LDDD patients are radiodiagnostic magnetic resonance imaging, neurological examinations, pain scores with Visual Analog Scale(VAS), and disability investigation with Oswestry Disability Index(ODI). Genotyping of VDR gene polymorphism was conducted using PCR-based methods.

Results
Individuals of LDDD group with the VDR TaqI AA genotype carriers significantly higher than other group (p = 0.014), while those with GG genotype significantly lower (p=0.028) in patient group. In addition, the VAS and ODI scores significanlty lower in GG genotype carrier group while AA genotype carriers had highest score (p = 0.004).

• Carrying G allele decreasing LDDD risk 1.7 times (p = 0.014) and
• carrying A allele enhancing risk 1.8 times (p = 0.028).

Moreover, G allele carriers had significantly lowest VAS (p=0.002) and ODI scores (p < 0.0001).

Conclusion
VDR TaqI (rs731236) GG genotype and G allele have protective potential while the AA genotype and A allele are risk factors for LDDD. The findings reveals a statitically significant association of the TaqI(rs731236) polymorphism of VDR gene polymorphism with LDDD. This result highlight the potential role of genetic factors in developing LDDD and suggest avenues for future research in genetic screening and personalized treatment strategies.

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Lumbar Spine Disc Degeneration 1.7 X more likely if poor vdr - Meta-analysis April 2021

Association Between FokI Polymorphism of Vitamin D Receptor Gene and Lumbar Spine Disc Degeneration - A Systematic Review and Meta-Analysis
American Journal of Physical Medicine & Rehabilitation: May 2021 - Volume 100 - Issue 5 - p 492-500. doi: 10.1097/PHM.0000000000001588
Castillo-Avila, Rosa Giannina MSc; González-Castro, Thelma Beatriz PhD; Tovilla-Zárate, Carlos Alfonso PhD; Juárez-Rojop, Isela Esther PhD; López-Narváez, María Lilia PhD; Rodríguez-Pérez, José Manuel PhD; Suárez-Méndez, Samuel PhD

Objective
The aim of the present meta-analysis was to explore the association between FokI polymorphism of the vitamin D receptor gene and lumbar spine disc degeneration.

Design
The search was performed in PubMed, Scopus, and Web of Science databases up to January 2020. The authors selected nine studies comprising a total of 1549 cases and 1672 controls. The association analysis included the allelic, dominant, recessive, homozygous, and heterozygous genetic models. Odds ratios with 95% confidence intervals were used to evaluate the association. The Newcastle-Ottawa Scale was used to measure the quality of the studies included in the analyses; a cut-off of 6 stars was applied.

Results
This meta-analysis indicated that FokI polymorphism is significantly associated with lumbar degenerative disc disorder and disc herniation in the homozygous (odds ratio, 1.77; 95% confidence interval, 1.23–2.54; Z test P = 0.002, Q test P = 0.416) and recessive (odds ratio, 1.53; 95% confidence interval, 1.23–1.90; Z test P < 0.000, Q test P = 0.224) models.

Conclusions
This study indicates that the vitamin D receptor gene FokI polymorphism may be correlated with the risk of developing a lumbar degenerative disc disorder and disc herniation. However, the small sample population studied and the lack of an evaluation of environmental factors must be taken as limitations in the present meta-analysis.

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VDR Spine, Lumbar Meta-analysis - increases risk 15-20% - meta-analysis Aug 2017

Genetic analysis of the Vitamin D receptor start codon polymorphism (FokI) in cervical vertebra and lumbar spine pathologies: a meta-analysis.
Oncotarget. 2017 Aug 21;8(42):72921-72932. doi: 10.18632/oncotarget.20380
Hu X1,2, Liu M1, Ni Y2, Zhang G2.

• 1 Dept of Scientific Research, Jiading District Central Hospital Affiliated Shanghai U. of Medicine and Health Sciences, Shanghai, China.
• 2 The Former Dalian Sanatorium of Shenyang Military Region, Dalian, Liaoning, China.

BACKGROUND:
Vitamin D receptor (VDR) FokI polymorphism has been reported to influence the risk of spinal diseases. However, several studies suggest inconsistent results. Therefore, we performed this analysis to reveal the accurate relationship between VDR FokI polymorphism and spinal diseases.

MATERIALS AND METHODS:
8 articles accord with the strict inclusion and exclusion criteria. 1116 cases and 1263 controls are entered into this analysis. The pooled odds ratios (ORs) and 95% confidence intervals (CI) are calculated to evaluate the association between VDR gene polymorphism and spinal diseases.

RESULT:
The results suggest that allele F is a risk factor for spinal diseases and the difference is significant (F vs. f: OR = 1.151, 95% CI, 1.020-1.300). For the genotype analysis of VDR FokI, no statistical differences exist in the models of heterozygote comparison (Ff vs. ff), homozygote comparison (FF vs. ff) and dominant model (FF + Ff vs. ff) (p > 0.05). However, in recessive model (FF vs. Ff + ff), there is a significant association between VDR polymorphism and spinal diseases (OR = 1.209, 95% CI, 1.017-1.436). In subgroup analysis, the results show that allele F is a risk factor for spinal diseases in each estimation. In hospital-based subgroup, the significant differences exist in FF vs. ff and FF vs. Ff + FF models. In degenerative spine diseases group, the results are consistent with that of overall studies.

CONCLUSIONS:
According to results of this meta-analysis, allele F is associated with the increased risk of spinal diseases. FF genotype may contribute to the susceptibility of spinal diseases. Therefore, VDR FokI polymorphism is related with spinal diseases.
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Low back pain and VDR: 5X athletes, 9X if if athlete had family history - Feb 2017

Low back pain and FokI (rs2228570) polymorphism of vitamin D receptor in athletes
BMC Sports Sci Med Rehabil. 2017 Feb 7;9:4. doi: 10.1186/s13102-017-0069-x. eCollection 2017.
Cauci S1,2, Migliozzi F1,3, Trombetta CS1, Venuto I1, Saccheri P4, Travan L4, Chiriacò G3.

BACKGROUND:
Low back pain (LBP) is common in athletes. LBP can be detrimental to athletic performance and health. Factors predisposing to LBP in athletes remain elusive and require further studies. We investigated whether carriage of a specific genotype and/or allele of vitamin D receptor gene (VDR) FokI polymorphism (rs2228570) was a risk factor for LBP in athletes of different sports disciplines.

METHODS:
This genotype/phenotype association case-control study included 60 Italian athletes (25 females and 35 males; mean age 33.9 ± 13.3 years; body-mass-index 23.5 ± 3.5 kg/m2) of which 16.7% were swimmers, 11.7% soccer players, 11.7% volleyball players, 10.0% rugby players and other disciplines. VDR-FokI polymorphism was measured by PCR-RFLP in 24 athletes with LBP and 36 athletes without LBP episodes. Absence or presence of the FokI restriction site was denoted "F" and "f", respectively. Other risk factors were evaluated by a questionnaire.

RESULTS:
The homozygous FF genotype was found in 58.3% (14/24) of athletes with LBP versus 27.8% (10/36) of athletes without LBP, adjusted OR = 5.78, 95% CI 1.41-23.8, P = 0.015.
The F allele was a 2-fold risk factor to develop LBP, adjusted OR = 2.55, 95% CI 1.02-6.43, P = 0.046, while f allele was protective.
Exposure to vehicle vibrations ≥2 h daily, and family history of lumbar spine pathology were significant risk factors for LBP with OR = 3.54, and OR = 9.21, respectively.

CONCLUSIONS:
This is the first study in which an association between VDR-FokI polymorphism and LBP in athletes was found. Further research is needed to extend our results, and to clarify the biochemical pathways associated with how vitamin D modulates LBP in athletes. The VDR-FokI polymorphism should be considered
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VDR Lumbar disc degeneration no evidence in meta-analysis - Jan 2017

Vitamin D receptor gene polymorphisms and lumbar disc degeneration: a systematic review and meta-analysis.
Eur Spine J. 2017 Jan;26(1):267-277. doi: 10.1007/s00586-016-4771-2
Jiang H1, Qin Z1, Zong S1, He M1, Zhan X1, Xiao Z1, Wei Q2.

PURPOSE: To examine the association between Vitamin D receptor (VDR) gene polymorphisms and lumbar disc degeneration (LDD) predisposition.

METHODS: A comprehensive literature search was conducted to identify all the relevant studies. The allele/genotype frequencies were extracted from each study. We calculated the pooled odds ratios (ORs) and 95 % confidence intervals (CI) to assess the strength of the association between the VDR gene polymorphisms and LDD risk. Statistical analysis was performed using RevMan 5.31 software.

RESULTS:
A total of 23 case-control studies (1835 cases and 1923 controls) were included in this systematic review. For the TaqI (rs731236), FokI (rs2228570) and ApaI (rs7975232) polymorphisms of VDR gene, nine studies, seven studies, and five studies, were eventually included in the meta-analysis, respectively. There was no evidence that the VDR gene polymorphisms (TaqI, FokI, ApaI) had significant associations with LDD risk.(for TaqI allelic comparison, OR = 1.07, 95 % CI 0.81-1.40, p = 0.64; for FokI allelic comparison, OR = 1.23, 95 % CI 0.83-1.82, p = 0.31; for ApaI allelic comparison, OR = 0.79, 95 % CI 0.55-1.14, p = 0.20). For stratified analyses by ethnicity and study design, no significant associations were found in Caucasian population and Asian population, as well as the population-based studies and hospital-based studies under all genetic models.

CONCLUSIONS: TaqI, FokI, and ApaI polymorphisms of VDR gene were not significantly associated with the predisposition of LDD. Large-scale and well-designed international studies are needed to further analyze this field.
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Intervertebral Disc Disease 3.1 X more likely if poor VDR - Nov 2016

Genetic Alterations in Intervertebral Disc Disease Nov 2016
Collagin, Vitamin D Receptor (3.1 X more-likely to have disc degeneration if a type of poor VDR)

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VDR alteration might prevent degenerative disc diseases - Oct 2017

Will it be possible to prevent lumbar degenerative disc diseases in the future by means of vitamin D receptor gene
Numan Karaarslan1*, Yasin Emre KAYA2, Ibrahim YILMAZ3, Hanefi OZBEK4, Betul EKIZ BILIR5, Necati KAPLAN6, Duygu YASAR SIRIN7, Yener AKYUVA8, Mehmet Sabri GURBUZ9, Kadir OZNAM10, Semih AKKAYA11, Cagri Ata MUTLU12, Olcay GULER13, Ozkan ATES14 andMahir MAHIROGULLARI15

 Download the PDF from ResearchGate via VitaminDWiki
It is primarily aimed to study polymorphisms in vitamin D receptor gene (VDR), which is one of the genetic factors having a role in the formation of lumbar pathologies and/or causing higher incidence of pathologic processes. Secondarily, it is aimed to create pre-data which may help professionals to administer more effective and protective interventions in this area. Without any language preference, we searched US National Library of Medicine National Institutes of Health, Embase, OVID, Cochrane Library database of clinical trials from 1989 to Mar 11 to 2017 Mar 12, and traced all the references of incorporated documents. The data were evaluated by using descriptive statistics. Results were shown as amount or frequency (%). In literature, some vitamin D receptor gene (VDR) polymorphisms have been found in relation to widespread osteochondral diseases. When VDR polymorphisms, vitamin D level and intervertebral disc pathologies have been examined, a satisfactory answer to the question whether specific pathologies could be suppressed in terms of genetics has not been found. By means of this study, it would be understood the genetic factors inhibiting physio pathological process concerning lumbar degenerative disc disease or the genetic factors playing role in identifying physio pathological process related to lumbar degenerative disc disease by defining them. Accordingly, effective and contraceptive treatment of lumbar degenerative disc disease might be ensured soon.

INTRODUCTION

People have predisposition or susceptibility to some diseases in terms of genetics since they were born. It is well known that whereas, in most cases, genetic predispositions do not cause any diseases in the organisms where immune system works well. So some genetic diseases may occur due to the weakness in the immune system (Euesden et al., 2017; Vincze and Danko, 2012).

There are some studies indicating that immune system and cell control are affected in the deficiency of vitamin D, which is in charge of working of thousands of genes influencing immune system (Alhassan et al., 2017; Kowalczyk et al., 2017).

Vitamin D performs its functions through Vitamin D receptor (VDR) (Zarei et al., 2016). In literature, it is reported that the gene polymorphisms in this receptor play a crucial role in the pathogenesis of various cancers and diseases such as type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis. The progress of these diseases is associated with the dysfuntion of vitamin D on the immune system (Watad et al., 2016; Dambal et al., 2017; Bogdanou et al., 2017).

It is reported that the frequencies of the aforementioned diseases increase in cases of vitamin D deficiency or VDR gene polymorphisms (Tagliabue et al., 2015; Wintermeyer et al., 2016).

Many researchers have started studying genes that have roles in the formation of intervertebral disc pathologies since the results of Human Genome Project were started to be used both in pharmaceutic biotechnology and medicine (Zhao et al., 2016; Casa et al., 2016).

Vitamin D affects bone and cartilage metabolism. A change in this system may be related to pathological situations in the cartilage tissue. In literature, there are some researches about the vitamin D receptor gene (VDR) polymorphisms related to sensitivity to general osteochondral diseases. However, the results are different from each other. Although the overwhelming majority of the researches indicate that there is a relation with lumbar intervertebral disc degeneration, it is seen that findings are related with osteoarthritis also in many of them (Brennan-Speranza et al., 2017; Zhu et al., 2014; Liu et al., 2014).
The aim of this manuscript is to make an up-to-date summary. Besides, it is intended to analyze the relation between VDR polymorphisms, vitamin D status, knee cartilage, disc pathologies and different specific pathologies. In the present manuscript, it is also aimed to bring an initiative for exclusive treatments on the genetic level.

Skipped material

DISCUSSION (details of 20 previous studies)

Until very recently it has been thought that the target organs of active vitamin D are confined to the intestine, kidney and bone. Vitamin D is not a real steroid hormone but works by means of nuclear receptors like steroid hormones.

The biological effects of vitamin D take place via genomic or non-genomic pathways. Genomic responses occur through the nuclear VD receptor. It is known that VDR occurs in more than 30 tissues. In particular, it plays an important role in the regulation of bone cell function and maintenance of serum calcium homeostasis, which are fulfilled by active metabolites of vitamin D (Gunes et al., 2008).

Calcitriol [1,25(OH)2D3] enables calcium absorption by connecting to VDR, provides reabsorption of phosphate and adjust hormone level. VDR osteoporosis is the first gene to be determined to have an effect on bone mass(Ala-Kokko, 2002).

FokI, BsmI, ApaI and TaqI polymorphisms have been found affecting the function of the receptor regarding the association between cancer cases such as breast and colon cancers and allergic/inflammatory cases and oral problems such as periodontitis (Battie et al., 2004).
Lumbar pain is one of the major health issues in developed countries and is generally accompanied by disc degeneration. Lumbar pathologies occur as a result of many factors and result in various problems. A change in vertebral end-plate causes degeneration of the disc by affecting the aliment of the disc.

Colombini et al. (2016) carried out a study by comparing an experimental group comprised of 266 patients diagnosed with lumbar vertebra pathology with the control group comprised of 252 asymptomatic people. They expressed that they intended to evaluate allele, genotype and haplotype frequency of BsmI, ApaI and TaqI with VDR polymorphism. Besides, they conducted a questionnaire to appraise whether the patients were exposed to risk factors. They reported that they detected polymorphism using PCR-RFLP and TaqMan SNP genotyping assay. They found BbAaTT as a risk factor in all cases and bbAATT and bbaaTT genotypes as preservers. In addition, in the cases only diagnosed with a lumbar disc hernia and all lumbar cases except spondylolisthesis and lumbar stenosis, B allele, Bb, Aa and BbAaTT genotypes were found to be risky and b allele, bb, aa and bbaaTT genotypes were found to be preservative. In the cases with osteochondrosis with/without lumbar disc hernia T allele, Aa and bbAaTT genotypes were reported to be risky whereas t allele, AA and tt genotypes to be preservative. They concluded that there is no significant cooccurrence in the cases with spinal stenosis or spondylolisthesis. They emphasized the importance of a detailed clinical evaluation in order to determine haplotype analysis and biomarkers. They signified that it contributes to describe the genetic risk factors for specific lumbar spinal diseases(Colombini et al., 2016).

Tokta§ et al. (2015) reported that the results of studies indicating some gene locus related to intervertebral disc degeneration were obtained from studies carried out in north European countries. They indicated that they aimed to conduct a research in which the patients would be south European people to evaluate radiological severity of lumbar disc degeneration and the relation between gene loci. They formed the experimental group, including 75 patients diagnosed with lumbar disc degeneration. The stage of their disease was from slight to severe. The control group was formed of 25 controls. They indicated that they evaluated each lumbar intervertebral space separately and concluded a total radiological score. Besides, they analyzed single nucleotide polymorphism of the predetermined genetic sample for each participant (COL1A1 Sp1, COL9a2 Trp2, COL9a3 Trp3 and VDR TaqI). They observed that degeneration scores were significantly lower in COL1A1 Sp1, COL9a3 Trp3 and VDR TaqI mutational cases. However, they found that there is no relation between mutations of COL9a2 - Trp2 and disc degeneration. Furthermore, they reported that the disc degeneration scores were much lower in the patients with more than one mutation. They indicated that a single nucleotide polymorphism seen in COL1A1, COL9a3 and VDR genes might be related to lumbar disc degeneration in that group. Yet more they deduced that if a patient had a multi mutation, the degeneration-mutation relation would be more significant. They maintained that multiple prospective studies done in a larger group involving people from different countries could help us to find out its relation to relevant genes and environmental factors. What's more, they claimed that the relation between disc degeneration and genetic mutations could be presented clearly, which might help to sustain a more convenient planning for the people inclined to related pathologies (Tokta§ et al., 2015).

Sansoni et al. (2016) examined RANKL and plasma osteoprotegerin concentration both in healthy population and patients with discogenic pathologies. They aimed to observe whether the expression of lumbar disc hernia, the most widespread epiphenomenon, along with these markers is related to vitamin D receptor gene polymorphism. The experimental group consisted of 110 patients with lumbar disc hernia (detected by MRI) and the control group consisted of 110 healthy people who were categorized according to age and gender. They reported that they excluded cases with other pathologies. They informed that they measured RANKL and osteoprotegerin by immunoassay and used t test to determine the differences between markers. They signified that they expressed the correlation statistically between marker concentrations, antropometric variables and the pathology expression. They also informed that they analyzed the correlation to vitamin D receptor genotype. Although efficient osteoprotegerin concentrations were obtained, they observed that the lower RANKL gene was transcribed and accordingly the RANKL/osteoprotegerin rate was lower in the experimental group (in the whole group or classified by gender). They expressed that RANKL and osteprotegerin concentrations were independent of body mass index and age in the case group, but the concentration of them increased with age in the control group. They indicated that lumbar disc hernia was eloquently relevant to RANKL levels and the F allele of VDR gene. However, they emphasized that it was not known whether cartilage or bone structure degradation occur firstly in intervertebral disc degeneration. They concluded that the decrease in the bone turnover rate in relation to a specific genetic substructure might be one of the most crucial factors in lumbar disc degeneration (Sansoni et al., 2016).

He et al. (2015) expressed that vitamin D receptor gene is an important gene affecting osteoporosis development. They carried out a study with postmenopausal Chinese women .They aimed to evaluate the relationship between genetic variants, BMD (BMD) and osteoporosis. They remarked that the experimental group was composed of 482 women with postmenopausal osteoporosis, whereas the control group contained 488 healthy postmenopausal women. They indicated that they measured BMD of vertebral, femoral neck and thigh using NorlandXR-46 dual energy X-Ray absorptiometry (DEXA). They denoted that genotypes of VDR genetic variants were determined by created restriction site-PCR (CRS-PCR) and verified by means of DNA sequencing method. As a result, they found that genetic variants of VDR p.glisin(Gly), 14 Alanine (Ala), p.histidin(His) and 305 Glutanin (Gln) were statistically relevant to mineral density of the vertebra, femoral neck and thigh. They concluded that VDR p.Gly14Ala and p.His305Gln genetic variants show a high level of relation to decrease in BMD in Chinese postmenopausal women. They proposed that vitamin D receptor genetic variants might be used as a marker when evaluating risk of osteoporosis( He et al., 2015).

Colombini et al. (2014) reported that the relation between fokl polymorphism (rs2228570) in vitamin D receptor and conventional risk factors was detected in Italians, yet they added that a gender analysis hadn't been made in these studies. They included 267 patients (149=male, 118=female) with lumbar vertebra disease diagnosed by magnetic resonance imaging (MRI) and 254 people (127 male, 127 female) as the asymptomatic control group. They expressed that they evaluated whether patients were exposed to the conventional risk factors. They signified that they detected fokl polymorphism by PCR restriction fragment length polymorphism (PCR-RFLP). In male patients, they observed that there was a relation between lumbar vertebra pathologies and advanced age, excess weight, similar family history, limited in free time activities, smoking, exposure to vibration effect for a long time, heavy-duty job and sedentary job. In contrast, in the female, they observed advanced age, limited free time, excess weight and similar family history were seen as a risk factor. They found that FF genotype in both genders doubled the risk of osteochondrosis development or discopathy accompanied by disc herniation. They concluded that heterozygote Ff genotype has preservation characteristics only in females. In males, they reported that only ff genotype was preservative for discopathy and/or osteochondrosis and added that F allele doubled disc hernia, discopathy and/or osteochondrosis. They underlined the importance of determining differences of life styles of both genders, genetic substructures and exposure to environmental factors while deciding treatment approaches in spinal diseases (Colombini et al., 2014).

Martin et al. (2014) reported that congenital adrenal hyperplasia (CAH) patients whose illnesses are based on 21-hydroxylase deficiency received glucocorticoid (GC) treatment and they emphasized that this class of drugs alters bone mineral metabolism. They analyzed gene polymorphisms related to BMD and also clinical and biochemical parameters in CAH patients. They carried out their research, including CAH patients treated by GC and healthy individuals. They evaluated the bone density, bone turnover markers and antropometric parameters. They used polymerase chain reaction technique in order to determine genotypes. They reported that 192-192 genotype frequency (IGF-I) was lower in poorly controlled CAH patients than the control group. They found that FF genotype (vitamin D receptor ,VDR) was in a relation to low lumbar BMD in CAH patients and there was a significant relation among 0-0 genotype (IGF-1), high p- CrossLaps values and low total BMD. They notified that their study contributed to the identification of genetic factors that might affect treatment response in CAH patients receiving glucocorticoids (Martin et al., 2014).

Kostik et al. (2014) examined bone mineralization and metabolism change depended upon VDR polymorphism in juvenile idiopathic arthritis. They included 198 patients (82 male, 116 female) in their study. They expressed that they measured BMD using lumbar spine DXA. They used Osteocalcin, CTX, parathyroid hormone, total and ionized calcium, inorganic phosphate and total alkaline phosphatase activity to evaluate bone metabolism. They reported that they used RFLP while determining TaqI (rs731236) and Cdx2 (rs11568820) VDR polymorphisms. In low and normal BMD, they observed that there was no difference in the distribution of TaqI and Cdx2 haplotype, genotype and alleles. When compared to the children with middle or high linear growth, low linear growth children had more “TaqI VDR with T allele genotypes”. They found that high linear growth children had the highest A allele genotype” (GA+AA) frequency in Cdx2 VDR. They reported that girls with TT TaqI VDR polymorphism who did not receive glucocorticoid had lower BMD-Z scores than the ones carrying C alleles. They also reported that TT TaqI genotype Tanner I girls had higher total and ionic Ca level than C allele carriers. They indicated that TT genotype presence showed a negative correlation with BMD-Z score, yet a positive correlation with LBMD frequency. They reported that boys with GG Cdx2 genotype had lower total calcium values when compared to A allele carriers. They found that CTX level was higher in teenage boys (tanner IV - V) with GG genotype. They reported that the TT genotype of TaqI and GG genotype of Cdx2 VDR was a negative factor in bone mineralization metabolism and linear growth (Kostik et al. 2014).

Kurt et al. (2012) indicated that in their design, oestrogen receptor alpha (ERa) and vitamin D receptor genes played a significant role in BMD decrease present in osteoporosis. They examined the roles of ERa PvuII/XbaI and VDR FokI/TaqI polymorphisms in BMD in Turkish postmenopausal women. They included 81 osteoporotic and 122 osteopenic postmenopausal women. They used PCR-restriction fragment length polymorphism techniques to determine the polymorphisms. They measured lumbar vertebra and BMD in the thigh using Dual-energy X-ray absorptiometry. They found similar results in the distribution of ERa and VDR genotypes. Although the whole osteoporosis prevalence was not related to these genotypes, reduced femur neck BMD value was higher in patients with ERa PvuII "PP" and ERa XbaI "XX" than the patients with "Pp/pp" and "xx" genotypes. Furthermore, they found that BMD in femur neck and total thigh was lower in VDR FokI “FF” genotype patients than “Ff” genotype patients. They emphasized that they confirmed the relation between VDR Fokl “FF” genotype and the risk of fall of femur neck mineral density under 0,8 by Logistic regression analysis. They concluded that the data in their study could contribute to the determination of BMD by ERa PvuII/XbaI and VDR FokI polymorphisms in Turkish postmenopausal women(Kurt et al., 2012).

Stathopolulou et al. (2011) aimed to determine the effect of Vitamin D receptor gene polymorphism on BMD in Greek women. They carried out their research using examinatorial of healthy women (n=578). Density of lumbar vertebra and thigh bone mineral were evaluated by Lunar DPX-MD. The expressions were made by a dual-energy X-ray absorptiometry. They made genotyping for Bsml,Taql and Cdx-2 polymorphisms in the VDR gene. When stratified by daily calcium intake, in the group with <680 mg/day intake of Ca, all studied polymorphisms had an association with lumbar spine BMD. After adjusting potential covariant, they found that BsmI and TaqI polymorphisms were related to osteoporosis development. However, they found that minor A allele presence in Cdx-2 polymorphism was related to low lumbar BMD. They stated that there is no significant difference between polymorphism genotypes in the group with high calcium intake (>680 mg/day). They emphasized that VDR gene affected BMD in the patients with low calcium intake and this effect was masked in patients with high calcium intake. As a result, they concluded that adequate calcium intake was important in postmenopausal women and had positive effect even in the patients with negative genetic susceptibility (Stathopoulou et al., 2011).

Yuan at al. (2010) aimed to find out the synergic connection between MMP-3, VDR gene polymorphisms and occupational hazard risk factors in intervertebral disc degeneration. They included 178 patients with intervertebral disc degeneration and 284 patients as the control group. They made a survey and used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technology. They expressed that they used additive model in order to analyze synergy between gene polymorphism and occupational hazard risk factors. They concluded that hunch/twirling, whole body vibration, heavy workload, presence of 5A allele in MMP-3 (6A5A/5A5A) and A allele presence in VDR-Apa are directly effective in intervertebral disc degeneration by non-conditional logistic regression analysis.

They indicated that there were synergic effects between MMP-3, as a mutation in 5A genotype, and whole body vibration and hunch/twirling movements. They also maintained that there is another synergic effect between VDR-Apa, as a mutation in A allele and whole body vibration exposure in terms of the formation of intervertebral disc degeneration (Yuan et al., 2010).

Eser et al. (2010) aimed to find the relation between VDR and aggrecan genes polymorphisms and degenerative disc disease. They indicated that aggrecan and VDR proteins were the main components of bone and cartilage tissues. They examined 300 patients with disc degeneration and herniation to evaluate the effects of VDR and aggrecan genes polymorphisms. They found that while TT, Tt, FF and Ff genotypes were related to disc herniation in protrusion shape, but tt and ff genotypes are related to disc herniation in extrusion/sequestration shape. Moreover, they identified an association between disc degeneration severity and some VDR gene polymorphisms (TT and FF genotypes with mild degeneration; tt, ff and Ff genotypes with severe degeneration). Also aggrecan allele types were in association with protrusion type disc herniation. They concluded that VDR and aggrecan gene polymorphism were in a relation with disc degeneration and herniation(Eser et al., 2010).

Tantawy et al. (2008), emphasized that low bone mass is a kind of bone disease seen in patients with thalassemia. They indicated that they aimed to determine calcium state and BMD in an adolescent group of transfusion dependent thalassemia. They used DXA scanning to determine femur neck and lumbar vertebral BMD in 40 patients with Beta thalassemia major. They found that the BMD values were associated with calcium, phosphorus, alkaline phosphatase, bone specific alkaline phosphatase, intact parathormone, 25-Oh vitamin D levels and vitamin D receptor gene polymorphism in exon 2 (Fok1). They reported that BMD was lower in the lumbar vertebra than femur neck. They emphasized that serum ferritin level and VDR genotype had only effect on BMD in femur neck and maintained that there might be some different factors determining BMD between two areas. They indicated that the calcium level was low at 75% of the patients and 72.5 % of the patients had hypoparathyroidism. They suggested that low calcium level might be caused by hypoparathyroidism and osteomalacia association. They remarked that sufficient iron chelation, calcium and vitamin D intake are important in order to optimized BMD in this patient group (Tantawy et al., 2008).

Koshizuka et al. (2006) carried out a study, including Japanese postmenopausal women in order to examine the relation between restriction fragment length polymorphisms (RFLPs) in oestrogen receptor (ER), vitamin D receptor (VDR), parathyroid hormone (PTH) and interleukin-1 beta(IL-1 beta) genes and radiologic severity of lumbar spondylosis which is seen from L1/2 to L5/S1.They found that ER and VDR RFLP haplotypes affected the upper spines more than the lower ones. They indicated that while VDR genotype is more effective in the older group, ER genotype is more active in the younger group. They maintained that PTH and IL1 -beta polymorphisms were not related to disease severity on any level. From this point of view they concluded that ER and VDR genes might result in lumbar spondylosis in a dissimilar way, oestrogen sensitivity in the early menopause period might have a more pronounced effect on the severity of the disease, vitamin D was more important in elderly when the spondylosis effect of oestrogen deficiency was lower (Koshizuka et al., 2006).

Jordan et al. (2005) aimed to examine risk factors regarding birth weight and vitamin D receptor gene polymorphism, which is thought to play an important role in adult lumbar vertebra osteoarthritis. They scaled lumbar vertebra graphs according to disc space narrowing (DSN) osteophyte severity and collected demographic data. They obtained weights at birth and 1- year-old from records. They expressed that they analyzed alllele variations of VDR genes in 291 individuals. The mean age was 65.8 and the mean weight of women was 68.9, whereas it was 80.1 for men. They found that osteophyte level was >/=2 in 63.5 % and DSN >/=2 was found in 14.3 %. They deduced that increasing osteophyte severity was related to age, adulthood weight and social class, yet DNS was not related to these. They reported that the presence and severity of osteophyte in men were related to birth weight and low weight at the age of 1. They added that this relation was not statistically significant in women. They expressed that there were no relationship between these weights and DSN. They indicated that B allele in VDR gene was related to increased osteophyte severity. They concluded that there was a significant relation between VDR gene and birth weight while determining osteophyte risk in men. They added that this relation was similar in women, but it was not statistically significant. They concluded that both birth weight and VDR gene polymorphisms were associated to vertebra osteophyte presence and there was a significant relation between these two factors in men (Jordan et al., 2005).

Vidal et al. (2003) analyzed GlA polymorphism on the tip of 3' in VDR gene and TlC transition in the starting codon using BsmI and FokI endonuclease in Maltese postmenopausal women. Their BMD was examined. They found that gene frequency for VDR starting codon polymorphism were CC:60.4%, CT:30.7% and TT:8.9%. Also, it was GG:16.4%, GA:51.9%, AA:31.7 for 3' polymorphism. Both lumbar and femoral BMD were found the highest in CC homozygous in FokI genotype and GG homozygous in BsmI genotype in postmenopausal women. They concluded that there is no evidence indicating that there is a linkage disequilibrium between two alleles (Vidal et al., 2003).

Oishi et al. (2003) studied physical and structural factors affecting disc degeneration, BMD in the vertebra and osteophyte formation in the lumbar vertebra in elderly postmenopausal women. They invited 126 women who were over the age of 60. 80 of these women were studied in terms of their examination, radiography, MRI and DXA data. TaqI polymorphism of vitamin D was detected in 60 individuals. Osteophyte presence (radiographies) was found to be 61%, whereas disc degeneration (in MRI) was 68%. They indicated that body weight and body mass index was prominently correlated with anteroposterior (AP) and lateral (LAT) BMD. They found that mean osteophyte area and body weight were proportional with the number of osteophytic discs. However, they stated that these were not proportional with disc area and/or degenerated disc number. After stepwise regression analysis, they found that bodyweight and LAT-BMD values were independently related to area of osteophytes. Disc area [(r=0.386) for AP plane] and osteophyte area (r=0.384 for AP plane) were significantly associated with BMD. However, they informed that disc area and osteophyte area were not correlated with each other. They found the degenerated disc rate in the lower lumbar discs was high, but the osteophyte disc area was not so. They did not find any relation between the frequencies of T and t alleles in VDR and disc degeneration, osteophyte formation and osteoporosis. They concluded that the increase in BMD and osteophyte formation in lumbar vertebra was triggered by weight gain and body mass index, yet this increase was not correlated with disc area and there was an inverse proportion between disc area and BMD (Oishi et al., 2003).

Nakamura et al. (2001) reported that they determined a polymorphism, which forms CC, CT or TT genotype at the position 1377 in calcitonin receptor gene. They studied 152 healthy Japanese women between 16-43 ages in terms of the relationship between CTR gene polymorphisms and their BMD, height, body weight and osteocalcin levels. They reported that CTR genotype frequencies were 77.0% for Cc, 20.4% for CT and 2.6% for TT. They did not find any significant difference between three genotypes in terms of height, BMD and osteocalcin levels. They indicated that height-adjusted- weight was significantly different in TT, CT and CC genotypes. In combined analyses of VDR genotype (B, b) and Ctr genotype (C, T), they found that there was a significant difference in body height between CCB and others. In addition, to analyze difference between two races in terms of CTR genotypic frequency, 64 blood samples were taken from Japanese and 47 blood samples were taken from Caucasians. A significant difference was detected in CTR genotype frequencies. They reported that C allele was predominant in Japanese, yet C and T were almost similar in Caucasians. As a result, they concluded that CTR allele was one of the genetic factors regulating body weight in Japanese women (Nakamura et al., 2001).

Langdahl et al. (2000) emphasized that vitamin D is necessary in normal bone metabolism. In early studies, vitamin D receptor gene polymorphisms of exon 2 and 9 and intron 8 were related to bone mass and bone turnover. They examined 192 osteoporotic patients and 207 individuals as the control group. They separately and totally examined the effects of these three polymorphisms on BMD, bone turnover and osteoporotic fracture prevalence. They determined 4 polymorphisms using Fok I (T2-C), Bsm I (intron8), Apa I (intron 8) and Taq I (T1055-C) by RFLP. They reported that there was no relation between Fok I polymorphism and bone mass, bone turnover and osteoporotic fracture prevalence. They found that patients with the osteoporotic fracture had more BB +Bb- genotype frequencies. In addition, they observed that the individuals with bb genotype had higher BMD in intertrochanteric area and the whole thigh. They did not find any difference in terms of Apa I and Taq I polymorphisms between osteoporotic and control group. They did not observe any difference in mineral density of lumbar vertebra, femur neck, trochanter and Wards triangle, yet mineral density in the intertrochanteric area in individuals with TT genotype was found to be higher than the individuals with Tt and tt genotype. They emphasized that the combining of genotypes reflected differences caused by Bsm I polymorphism. They concluded that translation starting polymorphism of VDR did not affect BMD and there was no relation to osteoporotic fractures in men and women (Langdahl et al., 2000).

Duncan et al. (1999) studied roles of 23 candidate genes controlling BMD. They included 115 probands (35 men, 80 women) and 499 of their first and second degree relatives (233 men, 276 women). They indicated that they measured BMD in vertebra and femur neck by dualenergy X-Ray absorbsiometer and expressed age and gender matched Z score, which was corrected according to body mass index. They reported that they studied the following candidate genes: androgen receptor, type I collagen A1 (COLIA1), COLIA2, COLIIA1, vitamin D receptor (VDR), colony-stimulating factor 1, calciumsensing receptor, epidermal growth factor (EGF), oestrogen receptor 1 (ESR1), fibrillin type 1, insulin-like growth factor 1, interleukin-1 alpha (IL-1 alpha), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-11 (IL-11), osteopontin, parathyroid hormone (PTH), PTH- related peptide, PTH receptor type 1 (PTHR1), transforming growth factor-beta 1, and tumor necrosis factors alpha and beta. They researched the relation of 44 microsatellite in or nearby these genes with BMD. They underlined that there was a suggestive linkage between BMD and PTHR1 by MapMaker/Sibs program. They detected that there was a moderate relation with EGF, COLIA1, COLIIA1/VDR , ESR1 , IL-1alpha , IL-4 , IL-6 and BMD. They stated that they found connection in/around IL-1 alpha, PTHR1, IL-6, and COLIIA1/VDR genes in the Variance components analysis, which was made by ACT program. They stated that the genes that are responsible and mutations could be verified in the light of these data (Duncan et al., 1999).

Lucotte et al. (1999) examined the relation between BMD and T/C polymorphism seen in the first of two starting codons in VDR gene. They indicated that they determined this polymorphism using a FokI restriction enzyme. They expressed that the presence of F allele indicates the absence of the first codon, whereas f allele presence indicates the presence of the first codon. They reported that they studied FokI genotype in 124 postmenopausal French women with osteoporosis, who are between 45 and 90 ages. They did not observe a significant difference in the distribution of FokI genotype between women with osteoporosis and the women in the control group. They did not find any difference in FokI expression after categorizing the cases in terms of age, the past time after menopause, weight, height, mineral density in vertebra and femur neck. However, when they examined cases under 75 years old (98 cases), they found that BMD in the femur neck area was relatively lower in cases with ff genotype (10% of the cases) than the cases with FF and Ff genotype. From this point of view, they concluded that ff genotype-VDR gene related to low BMD in the femur neck in French postmenopausal women (Lucotte et al., 1999).

After reviewing the studies that have been carried out so far, molecular defects contributing to disc degeneration have been determined in genetics studies. Vitamin D receptor, differences in tandem repetitions in aggrecan gene and some unique genetic relations including Type IX collagen gene mutations and matrix metalloproteinase 3 gene have been found (Takahashi et al., 2001).

In conclusion, many researchers agree in this idea that lumbar degenerative disc diseases, as the largest part of lumbar pain, occur as a result of mutual interaction of genetic and environmental factors due to physical stress. In the literature, it hasn't been found a satisfactory answer to the question whether specific pathologies in terms of genetics may be related to VDR polymorphisms, the status of vitamin D and data regarding lumbar pathologies. There are some controversial reports regarding the relation between VDR polymorphisms and the degeneration of intervertebral disc tissue. Moreover, in some of the researches, genetic factors have been associated with lumbar disc degeneration, but in others not.

It is crystal clear that more experimental and clinical researches are needed in order to present this complicated pathogenesis. Current approaches to disc degeneration are surgical and conservative and they are on the side of preventing disc movement, so this results in inability in disc functions. Instead, in the future, cell based pharmacogenomics researches will be more popular and be among promising studies.

CONCLUSION

In the future, thanks to the identification of genetic factors preventing lumbar degenerative intervertebral disc pathologies or causing their formation on a high rate, doctors will be able to provide more effective and protective treatments.
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VitaminDWiki – Back Pain category contains

• Low back pain 2X more likely if very low Vitamin D – meta-analysis Nov 2017
• Lumbar degenerative disc diseases might be fought by Vitamin D Receptor activation– many studies
• Back pain was found in one study to be relieved in 95% of patients by vitamin D
• Vitamin D treats many types of Chronic Pains
• Vitamin D improves bone health, which decreases back problems
• There are 44 items in the Back Pain category in VitaminDWiki
• Magnesium also reduces back pain
  - by reducing muscle tension and improving bones
• Founder of VitaminDWiki found a combination including Vit D plus Mg to be great

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