The Journal of Bone & Joint Surgery

The Journal of Bone & Joint Surgery, Volume 84, Issue 11

Scientific Article | November 01, 2002

The Association of Lumbar Disc Disease with Vitamin-D Receptor Gene Polymorphism

Yoshiharu Kawaguchi, MD, PhD; Masahiko Kanamori, MD, PhD; Hirokazu Ishihara, MD, PhD; Kazuo Ohmori, MD, PhD; Hisao Matsui, MD, PhD; Tomoatsu Kimura, MD, PhD

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Investigation performed at the Department of Orthopaedic Surgery, Toyama Medical and Pharmaceutical University, Toyama, Japan

Yoshiharu Kawaguchi, MD, PhD
Masahiko Kanamori, MD, PhD
Hirokazu Ishihara, MD, PhD
Kazuo Ohmori, MD, PhD
Tomoatsu Kimura, MD, PhD
Department of Orthopaedic Surgery, Toyama Medical and Pharmaceutical University, Faculty of Medicine, 2630, Sugitani, Toyama 930-0194, Japan. E-mail address for Y. Kawaguchi: zenji@ms.toyama-mpu.ac.jp

Hisao Matsui, MD, PhD
Orthopaedic Surgery, Takaoka City Hospital, 4-1, Takaramachi, Takaoka, Toyama 933-0064, Japan

In support of their research or preparation of this manuscript, one or more of the authors received a grant-in-aid for scientific research (11770794) from the Japanese Ministry of Education, Science and Culture in 1999-2000. None of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

J Bone Joint Surg Am, 2002 Nov 01;84(11):2022-2028

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Abstract

Background: Although the etiology of lumbar disc disease is unknown, it has been suggested that a genetic factor contributes to its development. Recently, some genetic polymorphisms have been found to be related to clinical disorders. We investigated the association between vitamin-D receptor gene and estrogen receptor gene polymorphisms and lumbar disc disease in young adults.

Methods: The participants included 205 young adults (166 women and thirty-nine men) with or without low-back problems. A magnetic resonance imaging scan of the lumbar spine was performed for all subjects, and the grade of disc degeneration was determined, according to the four-grade classification system of Schneiderman et al. The presence or absence of disc herniation was also evaluated. Genomic DNA was extracted from peripheral blood samples. The polymorphisms of the vitamin-D receptor and estrogen receptor genes were detected with use of a polymerase-chain-reaction assay. The restriction fragment length polymorphisms (RFLPs) for the vitamin-D receptor gene were analyzed by TaqI and ApaI restriction enzymes. XbaI and PvuII restriction enzymes were used for the estrogen receptor gene analysis. The distribution of polymorphism in subjects with disc degeneration and/or disc herniation was compared with that in the normal subjects.

Results: The allelic frequencies of both vitamin-D receptor gene and estrogen receptor gene polymorphisms were similar to those in previous analyses of Japanese subjects. The allelic variation in the vitamin-D receptor gene was associated with multilevel and severe disc degeneration and disc herniation. The Tt allele was found to be more frequently associated with multilevel disc disease, severe disc degeneration, and disc herniation than was the TT allele. No additional associations were found.

Conclusions: This study revealed that the Tt allele of the vitamin-D receptor gene was more frequently associated with multilevel and severe disc degeneration and disc herniation than was the TT allele, pointing to an increased risk of disc disease at an early age in subjects with the Tt allele in the vitamin-D receptor gene.

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Introduction

Introduction | Materials and Methods | Results | Discussion | References

In recent years, low-back disorders have been the most common musculoskeletal problems in the industrialized societies ^1,2 . The disorders are a major source of disability and have a substantial impact on the cost of health care ¹ .

Lumbar disc disease is the main cause of low-back disorders. Disc degeneration and disc herniation sometimes contribute to the development of low-back pain and sciatica. These diseases are related in part to the aging process; however, they are not uncommonly seen in the late teenage years ³ . In the United States, lumbar disc disease and back pain are the most common causes of activity limitation in individuals who are less than forty-five years old ¹ . Although the etiology of lumbar disc disease is still unknown, it has been suggested that some environmental risks, such as physical loading ^4-10 , driving motor vehicles ¹¹ , vibration ^12,13 , and smoking ^11,14 , may play a role. On the other hand, lumbar disc disease is also affected by genetic factors and there is a familial predisposition for its development ^15-21 . Furthermore, it has been reported that twins have similarities in the degenerative findings of the lumbar spine ^22-24 . On the basis of these studies, recent research has revealed that some genetic polymorphisms are related to lumbar disc disease ^25-29 . In 1999, we found an association between polymorphism of the aggrecan gene and disc degeneration in young women in their twenties ²⁶ .

The genetic background of lumbar disc disease may be multifactorial. It has been reported that osteoporosis has an inverse relation to osteoarthritis in the spine ^30,31 , while osteoarthritis in the spine is associated with disc degeneration. Recent observations of bone-mineral density in large population surveys have confirmed that subjects with osteoarthritis have a substantially increased bone mass compared with that in age and sex-matched controls, when corrected for body weight ³¹ .

Osteoporosis also has a genetic background. Vitamin-D receptor ^32-34 and estrogen receptor genes ³⁵ have been reported to be related to osteoporosis. Subjects with specific genotypes of vitamin-D receptor and estrogen receptor genes have lower bone density. Therefore, it is reasonable to hypothesize that the vitamin-D receptor gene and estrogen receptor gene polymorphisms might be inversely associated with disc degeneration. Furthermore, recent studies have shown that vitamin-D receptor polymorphism is associated with spinal degeneration in the middle-aged population ^28,29 . In the present study, we selected vitamin-D receptor and estrogen receptor gene polymorphisms as the candidate markers that might be related to lumbar disc disease in the young adult population. The purpose of the present study was to investigate the association between the polymorphisms of these genes and lumbar disc disease.

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Fig. 1:: Schematic drawing of the polymorphic sites of the vitamin-D receptor gene and estrogen receptor gene. In the vitamin-D receptor gene, ApaI polymorphism is in intron 8. TaqI polymorphism is in exon 9, but it is a silent mutation. PvuII and XbaI polymorphisms in the estrogen receptor gene are in intron 1. RFLP = restriction fragment length polymorphism.

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TABLE I: The RFLP Genotype and Frequencies of Vitamin-D Receptor Gene and Estrogen Receptor Gene Polymorphisms*

*RFLP = restriction fragment length polymorphism. The symbols (+) and (-) refer to the presence or absence of the site alleles.

Genotype	No. of Subjects (%)	Frequency
Vitamin-D receptor gene
TaqI
TT	151 (74)	T 0.87 (-)
Tt	54 (26)	t 0.13 (+)
tt	0
ApaI
AA	26 (13)	A 0.34 (-)
Aa	87 (42)	a 0.66 (+)
aa	92 (45)
Estrogen receptor gene
PvuII
PP	43 (21)	P 0.45 (-)
Pp	98 (48)	p 0.55 (+)
pp	64 (31)
XbaI
XX	12 (6)	X 0.18 (-)
Xx	48 (23)	x 0.82 (+)
xx	145 (71)

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TABLE I: The RFLP Genotype and Frequencies of Vitamin-D Receptor Gene and Estrogen Receptor Gene Polymorphisms*

*RFLP = restriction fragment length polymorphism. The symbols (+) and (-) refer to the presence or absence of the site alleles.

Genotype	No. of Subjects (%)	Frequency
Vitamin-D receptor gene
TaqI
TT	151 (74)	T 0.87 (-)
Tt	54 (26)	t 0.13 (+)
tt	0
ApaI
AA	26 (13)	A 0.34 (-)
Aa	87 (42)	a 0.66 (+)
aa	92 (45)
Estrogen receptor gene
PvuII
PP	43 (21)	P 0.45 (-)
Pp	98 (48)	p 0.55 (+)
pp	64 (31)
XbaI
XX	12 (6)	X 0.18 (-)
Xx	48 (23)	x 0.82 (+)
xx	145 (71)

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TABLE II: Relationship Between the Number of Levels of Disc Degeneration and the Vitamin-D Receptor Gene and the Estrogen Receptor Gene Polymorphism

Genotype	Levels with Disc Degeneration (No. of Subjects)				P Value
0	1	2	=3
Vitamin-D receptor gene
TaqI
TT (n = 151)	72	31	31	17
Tt (n = 54)	17	13	13	11	0.037
tt (n = 0)	0	0	0	0
ApaI
AA (n = 26)	9	7	6	4
Aa (n = 87)	39	17	22	9	0.76
aa (n = 92)	41	20	16	15
Estrogen receptor gene
PvuII
PP (n = 43)	18	7	10	8
Pp (n = 98)	44	20	22	12	0.77
pp (n = 64)	27	17	12	8
XbaI
XX (n = 12)	4	2	2	4
Xx (n = 48)	24	11	5	8	0.36
xx (n = 145)	61	31	37	16

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TABLE II: Relationship Between the Number of Levels of Disc Degeneration and the Vitamin-D Receptor Gene and the Estrogen Receptor Gene Polymorphism

Genotype	Levels with Disc Degeneration (No. of Subjects)				P Value
0	1	2	=3
Vitamin-D receptor gene
TaqI
TT (n = 151)	72	31	31	17
Tt (n = 54)	17	13	13	11	0.037
tt (n = 0)	0	0	0	0
ApaI
AA (n = 26)	9	7	6	4
Aa (n = 87)	39	17	22	9	0.76
aa (n = 92)	41	20	16	15
Estrogen receptor gene
PvuII
PP (n = 43)	18	7	10	8
Pp (n = 98)	44	20	22	12	0.77
pp (n = 64)	27	17	12	8
XbaI
XX (n = 12)	4	2	2	4
Xx (n = 48)	24	11	5	8	0.36
xx (n = 145)	61	31	37	16

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TABLE III: Relationship Between Grade of Disc Degeneration and Vitamin-D Receptor Gene and Estrogen Receptor Gene Polymorphism

*The severity of the disc degeneration was determined by the sum of the grades, according to the classification system of Schneiderman et al. ³⁶ , at the involved levels. A score of 5 indicated no degeneration; 6-7, slight degeneration; 8-9, moderate degeneration; and 10, severe degeneration.

Genotype	Total Score for Grade of Disc Degeneration* (No. of Subjects)				P Value
5	6-7	8-9	=10
Vitamin-D receptor gene
TaqI
TT (n = 151)	72	43	27	9
Tt (n = 54)	17	16	12	9	0.017
tt (n = 0)	0	0	0	0
ApaI
AA (n = 26)	9	9	6	2
Aa (n = 87)	39	25	17	6	0.56
aa (n = 92)	41	25	16	10
Estrogen receptor gene
PvuII
PP (n = 43)	18	10	10	5
Pp (n = 98)	44	26	20	8	0.48
pp (n = 64)	27	23	9	5
XbaI
XX (n = 12)	4	3	4	1
Xx (n = 48)	24	13	4	7	0.57
xx (n = 145)	61	43	31	10

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TABLE III: Relationship Between Grade of Disc Degeneration and Vitamin-D Receptor Gene and Estrogen Receptor Gene Polymorphism

Genotype	Total Score for Grade of Disc Degeneration* (No. of Subjects)				P Value
5	6-7	8-9	=10
Vitamin-D receptor gene
TaqI
TT (n = 151)	72	43	27	9
Tt (n = 54)	17	16	12	9	0.017
tt (n = 0)	0	0	0	0
ApaI
AA (n = 26)	9	9	6	2
Aa (n = 87)	39	25	17	6	0.56
aa (n = 92)	41	25	16	10
Estrogen receptor gene
PvuII
PP (n = 43)	18	10	10	5
Pp (n = 98)	44	26	20	8	0.48
pp (n = 64)	27	23	9	5
XbaI
XX (n = 12)	4	3	4	1
Xx (n = 48)	24	13	4	7	0.57
xx (n = 145)	61	43	31	10

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TABLE IV: Relationship Between the Presence of Disc Herniation and the Vitamin-D Receptor Gene and the Estrogen Receptor Gene Polymorphisms

Genotype	Herniation (No. of Subjects)		P Value
Absent	Present
Vitamin-D receptor gene
TaqI
TT (n = 151)	98	53	0.0004
Tt (n = 54)	20	34
tt (n = 0)	0	0
ApaI
AA (n = 26)	13	13	0.78
Aa (n = 87)	52	35
aa (n = 92)	53	39
Estrogen receptor gene
PvuII
PP (n = 43)	26	17	0.89
Pp (n = 98)	55	43
pp (n = 64)	37	27
XbaI
XX (n = 12)	10	2	0.18
Xx (n = 48)	27	21
xx (n = 145)	81	64

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TABLE IV: Relationship Between the Presence of Disc Herniation and the Vitamin-D Receptor Gene and the Estrogen Receptor Gene Polymorphisms

Genotype	Herniation (No. of Subjects)		P Value
Absent	Present
Vitamin-D receptor gene
TaqI
TT (n = 151)	98	53	0.0004
Tt (n = 54)	20	34
tt (n = 0)	0	0
ApaI
AA (n = 26)	13	13	0.78
Aa (n = 87)	52	35
aa (n = 92)	53	39
Estrogen receptor gene
PvuII
PP (n = 43)	26	17	0.89
Pp (n = 98)	55	43
pp (n = 64)	37	27
XbaI
XX (n = 12)	10	2	0.18
Xx (n = 48)	27	21
xx (n = 145)	81	64

Materials and Methods

Introduction | Materials and Methods | Results | Discussion | References

Participants and Magnetic Resonance Imaging Studies

The participants included 205 young adults (166 women and thirty-nine men) with or without low-back problems. One hundred and forty-four were volunteer students from the Faculty of Medicine or Nursing at our university. The others were patients who were treated for low-back problems in the Department of Orthopaedic Surgery at our University Hospital. No subject was obese or had a body-mass index of >20 kg/m ² . None of them engaged in heavy manual labor. The mean age of the participants was twenty-two years (range, twenty to twenty-nine years).

The study was approved by the Ethical Committee at our University Hospital. Informed consent was obtained from all of the participants before they were asked to join the study. A T2-weighted sagittal magnetic resonance imaging scan (with a slice thickness of 5 mm, a repetition of 2500 msec, and an echo time of 90 msec) of the lumbar spine was performed with use of a 1.5-T Magnetom unit (Siemens AG, Erlangen, Germany) for all participants. The scans were independently assessed by four observers. The grade of disc degeneration was determined according to the four-grade classification system described by Schneiderman et al. ³⁶ . Grade 1 (normal) indicated normal signal height and intensity; Grade 2 (intermediate), a speckled pattern or heterogeneous decreased signal intensity; Grade 3 (marked), a diffuse loss of signal; and Grade 4 (absent), a signal void. The grade of the disc degeneration was determined when the evaluation of the disc degeneration was agreed upon by at least three observers. When there was less agreement, the lower grade of disc degeneration was assigned. The presence of disc herniation was also evaluated, and it was judged to be present when three or more observers agreed.

Genomic DNA Analysis

Peripheral blood was collected and genomic DNA was extracted from the samples. The polymorphisms of the vitamin-D receptor and estrogen receptor genes were detected with use of a polymerase-chain-reaction assay ^32,34,35 . The restriction fragment length polymorphisms (RFLPs) for the vitamin-D receptor gene were analyzed by TaqI and ApaI restriction enzymes ^32,34 . XbaI and PvuII restriction enzymes were used for the RFLPs of the estrogen receptor gene analysis ³⁵ . Detection of the ApaI and TaqI RFLPs of the vitamin-D receptor gene was facilitated with use of a single amplification with one primer in intron 8 (primer 1:5'-CAGAGCATGGACAGGGAGCAAG-3') and the other in exon 9 (primer 2:5'-GCAACTCCTCATGGCTGAGGTCTCA-3'), producing a 740-base-pair fragment ( Fig. 1 ) ^32,34 . Amplification of the polymerase chain reaction was carried out in a 20-µL solution containing 50 pmol each of the sense and antisense primers, 200 ng genomic DNA, 0.25 mmol/L diethylnitrophenyl thiophosphate (dNTP), 2.5 µL of DMSO, 2 U of Taq DNA polymerase, 10 mmol/L Tris-HCl (pH 8.3), 1.5 mmol/L MgC12, and 50 mmol/L potassium chloride. Then, the polymerase-chain-reaction products were digested with an endonuclease, TaqI and ApaI (Takara Shuzo, Shiga, Japan). The estrogen receptor gene polymorphisms were detected with use of primer 1:5'-CTGCCACCCTATCTGTATCTTTTCCTATTCTCC-3' and primer 2:5'-TCTTTCTCTGCCACCCTGGCGTCGATTATCTGA-3'. Polymerase chain reaction was performed in a 25-µL solution containing 50 pmol each of the sense and antisense primers, 100 ng genomic DNA, 0.25 mmol/L dNTP, 2.5 µL of DMSO, 2 U of Taq DNA polymerase, 10 mmol/L Tris-HCl (pH 8.3), 1.5 mmol/L MgCl2, and 50 mmol/L potassium chloride. The product revealed a part of intron 1 and exon 2 of the estrogen receptor gene ( Fig. 1 ) ^35,37 . The PvuII and XbaI (Takara Shuzo) RFLPs were detected in this 1.3-k base-pair fragment. The RFLPs were coded as Tt, Aa, Xx, and Pp, where the uppercase letter signifies the absence of the restriction site and the lowercase letter signifies the presence of the site. The polymerase-chain-reaction products, after dealing with the restriction enzymes, were separated on 1% agarose gels and stained with ethidium bromide.

Statistical Analysis

The Mann-Whitney U test was used to assess the difference in the number and the severity of the disc degeneration between genotypes. The Student t test was performed to assess the disc herniation between genotypes. A p value of <0.05 was considered significant.

Results

Introduction | Materials and Methods | Results | Discussion | References

In the magnetic resonance imaging study, the interobserver agreement ratio among all of the observers for disc degeneration was 72% and that for disc herniation was 92%. Eighty-nine subjects had normal intervertebral disc findings without disc herniation. Disc degeneration (Grade 2 or higher) of a single level was found in forty-four subjects and degeneration of two levels was found in forty-four subjects. Twenty-eight subjects had disc degeneration of more than three levels. The overall severity of the disc degeneration was determined by the total score, which was the sum of the grades, according to the classification system of Schneiderman et al. ³⁶ , at each level of the five intervertebral discs. Slight degeneration (a score of 6 to 7) was found in fifty-nine subjects; moderate degeneration (a score of 8 to 9), in thirty-nine; and severe degeneration (a score of >10), in eighteen. Disc herniation was observed in eighty-seven subjects.

Table I shows the RFLP genotype and allele frequencies of vitamin-D receptor gene and estrogen receptor gene polymorphisms. No subject had the tt allele of the TaqI RFLP of the vitamin-D receptor gene, but the allele frequencies of both vitamin-D receptor gene and estrogen receptor gene polymorphisms were similar to those in previous analyses of Japanese subjects ^34,35,37 .

The distribution of each allele among the subjects with disc degeneration and/or disc herniation was compared with that among the subjects with normal discs. A significant difference (p = 0.037) was found in the distribution in TaqI RFLPs of the vitamin-D receptor gene with respect to the number of levels of disc degeneration ( Table II ), but no difference was seen in the estrogen receptor gene polymorphisms. Furthermore, with regard to the severity of disc degeneration, a significant difference (p = 0.017) was found in the distribution in TaqI RFLPs of the vitamin-D receptor gene ( Table III ). The Tt allele was more frequently associated with multilevel disc degeneration and severe disc degeneration than was the TT allele. The findings of TaqI RFLPs of the vitamin-D receptor gene were similar with respect to disc herniation. The distribution of the Tt allele was found to be more frequent in the subjects with disc herniation than in those without disc herniation ( Table IV ). No additional associations were observed in the analysis of the vitamin-D receptor polymorphisms detected by ApaI and the estrogen receptor gene polymorphisms detected by PvuII and XbaI.

Discussion

Introduction | Materials and Methods | Results | Discussion | References

In this study, the subjects were young men and women in their twenties. We excluded subjects who engaged in heavy manual labor and those who were obese. We attempted to exclude any environmental factors that might be related to lumbar disc disease. Since lumbar discs in young individuals have been exposed to environmental risks for only a short period compared with those in elderly individuals, lumbar disc disease in the younger subjects might be more strongly associated with genetic factors. In this study, the rate of lumbar disc disease should be higher than that in the general population, as this study included patients who visited the Orthopaedic Surgery Department at our hospital.

In our study, none of the subjects had tt of TaqI RFLPs of the vitamin-D receptor gene, which might be due to the small sample size. However, the frequency of the alleles in this study was similar to that in previous analyses in Japan ^34,38 . In fact, the tt allele is extremely rare in the Japanese population. Therefore, despite the sample size, we believe that this finding was representative of the alleles of the general population. Furthermore, we believe that the two groups (those with lumbar disc disease and those without) were otherwise genetically matched, as there was no difference between the groups with respect to the proportions of the estrogen receptor gene polymorphisms.

Subjects with the Tt allele of the vitamin-D receptor gene were more frequently found to have multilevel disc disease and more severe disc degeneration and disc herniation than were the subjects with the TT allele. This finding suggests an increased risk for disc disease at an early age in subjects with the Tt allele in the vitamin-D receptor gene. However, this finding was somewhat unexpected, as previous reports have described an association between vitamin-D receptor gene polymorphisms and osteoporosis or osteoarthritis ^30,31 . Disc degeneration is due to the degradation of the disc matrix. This pathogenesis in the disc resembles osteoarthritis in the peripheral joints. Morrison et al. ³² and Tokita et al. ³⁴ reported that subjects with the TT allele of the vitamin-D receptor gene have a high bone-mineral density, whereas those with the tt allele are at an increased risk for osteoporosis. Keen et al. ³⁹ pointed out that the T allele of the vitamin-D receptor gene was associated with an increased risk of osteoarthritis of the knee compared with that associated with the t allele. These findings were in contrast to our results. Thus, it is difficult to interpret the present data merely on the basis of the hypothesis that there is an inverse relationship between osteoporosis and osteoarthritis.

On the other hand, in an evaluation of the association between allelic variations in the vitamin-D receptor gene and spinal degenerative disease, Jones et al. ⁴⁰ found a linear decrease in the risk of spinal osteophytosis and the presence of disc narrowing between tt and TT. Spinal osteophytosis and disc narrowing are closely related to disc degeneration. Furthermore, Videman et al. ²⁸ found apparent discrepancies in the association of the tt genotype with lower signal intensity on magnetic resonance imaging and more frequent anular tears in the intervertebral discs. Their results showed that quantitatively assessed signal intensities in thoracic and lumbar discs in men with the TaqI tt genotype and in men with the Tt genotype were worse, by 12.9% and 4.5%, respectively, than those in men with the TT genotype. Our findings were consistent with their results. Uitterlinden et al. reported that the vitamin-D receptor genotype is associated with radiographic signs of osteoarthritis of the knee ^41,42 ; however, adjustment for bone density at the femoral neck did not change the results, indicating that the association between the RFLPs of the vitamin-D receptor gene and osteoarthritis is not influenced by bone density. On the basis of these results, we believe that other mechanisms might affect the association between vitamin-D receptor gene polymorphisms and disc disease. It has been reported that the vitamin-D receptor is expressed not only in osteoblasts ⁴³ but also in the chondrocytes ⁴⁴ . Balmain et al. found immunoreactive vitamin-D receptor in the nucleoli of the chondrocyte, particularly in the fibrillar component, suggesting that vitamin D is directly involved in the differentiation, proliferation, and maturation of cartilage cells ⁴⁴ . In addition, vitamin D can influence proteoglycan synthesis by articular chondrocytes in vitro ⁴⁵ . Since the intervertebral disc is also rich in proteoglycan, these findings suggest that the vitamin-D receptor may be directly involved in the pathophysiology of the degenerated intervertebral disc. With regard to the estrogen receptor gene, some reports have described the relationship between some allelic variations of the estrogen receptor gene and osteoporosis or osteoarthritis ^35,37 . However, in the current study, we found no difference in the distribution of estrogen receptor gene alleles between the subjects with lumbar disc disease and those without disease.

We do not know how the genetic variants of the vitamin-D receptor gene affect the clinical picture of disc disease. We speculate that this polymorphism in the vitamin-D receptor gene might alter the structural characteristics of the matrix in the intervertebral disc. Furthermore, we must consider the possibility that vitamin-D receptor gene polymorphism is not directly involved in the pathogenesis of lumbar disc disease but is merely a marker for other genes. The vitamin-D receptor gene is located on chromosome 12q12 ⁴⁶ . The type-2 collagen (COL2A1) gene and insulin-like growth factor (IGF) type-1 gene are also located nearby ⁴⁷ . Many studies have shown that generalized osteoarthritis is closely linked to the COL2A1 gene ^48-50 , and the mutation of this gene is associated with chondrodysplasia ^48,49 . The physical distance between the vitamin-D receptor gene and the COL2A1 gene is <740 kb ⁴⁶ . IGF is expressed in intervertebral disc tissue, and IGF-1 stimulates proteoglycan synthesis in cells of the nucleus pulposus ⁵¹ . Further study of the linkage of the vitamin-D receptor gene and the COL2A1 gene and/or the IGF gene might help in the evaluation of the genetic background of lumbar disc disease.

Recent studies have revealed that several genetic polymorphisms are related to lumbar disc disease. There are three categories of such genes. One category consists of the genes that are responsible for the construction of the structural component of the intervertebral disc, such as the aggrecan gene ²⁶ and the collagen IX genes (COL9A2 and COL9A3) ^25,52 . We previously reported that subjects with polymorphism of the aggrecan gene are at risk for early disc degeneration ²⁶ . Two studies have shown that alleles of COL9A2 and COL9A3 are associated with the development of lumbar disc disease ^25,52 . The second category includes the genes that produce the degradation enzymes of the disc matrix. For example, Takahashi et al. ²⁷ proposed that a specific allele (the 5A allele) in the promoter region of the matrix metalloprotease-3 is a possible risk factor for the acceleration of degenerative changes in the lumbar disc in elderly subjects. The third category involves the genes that are related to bone structure. The osteoporosis-related genes, other than vitamin-D receptor and estrogen receptor genes, have an association with lumbar disc disease. Additional studies may reveal an association between other genetic factors and lumbar disc disease. These analyses should yield useful insight into the prevention and/or treatment of disc disease.

References

Introduction | Materials and Methods | Results | Discussion | References

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Topics

polymorphism ; hernias ; receptors, estrogen ; vibration ; vitamin d ; lumbar disc disease ; degenerative disc disease

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Yoshiharu Kawaguchi, Masahiko Kanamori, Hirokazu Ishihara, Kazuo Ohmori, Hisao Matsui, Tomoatsu Kimura; The Association of Lumbar Disc Disease with Vitamin-D Receptor Gene Polymorphism. The Journal of Bone & Joint Surgery. 2002 Nov;84(11):2022-2028.

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