中国汉族人群COL9A2基因、MMP-3基因SNP多态性与椎间盘退变性疾病的关联性研究
|
摘要
研究背景:
椎间盘退变性疾病(degenerative disc disease,DDD)是指由椎间盘退变(intervertebral disc degeneration,IDD)引起的以颈、腰腿疼痛为主要表现的临床症候群,包括了临床上常见的颈、腰椎间盘突出症,颈椎病,腰椎管狭窄症,退性行腰椎不稳,退性行腰椎滑脱、退行性脊柱侧凸等。通常认为,椎间盘的退变主要是由于环境因素的积累效应和衰老过程引起。重体力负荷,尤其是与职业相关的重体力负荷,一直被怀疑是椎间盘退变的主要危险因素,但始终无法确认负荷与退变之间的剂量—效应关系。流行病学对单卵双生和双卵双生的双胞胎进行研究发现,环境因素对椎间盘退变作用不明显,说明负重仅是危险因素的一部分,从而改变了传统观点。
随着研究逐渐深入到分子水平,多数学者认为DDD是一种多基因遗传病。同时,已经陆续发现了一些与DDD相关的具有遗传特性的特异性基因和一些与IDD相关的基因位点。目前已基本证实维生素D受体(Vitamin D receptor,VDR)基因的Taq1和Fok1基因型与IDD的有关;其他重要的候选基因,如COL9A2基因、MMP-3基因与DDD的关系还存在争议,结果往往互相矛盾。因此,我们有必要从基因水平出发,对COL9A2基因、MMP-3基因与DDD的关系加以研究。
研究目的:
1、探索COL9A2基因与DDD的关联及发挥的效应;
2、明确COL9A2基因与DDD不同表型的关联。
3、探索MMP-3基因与DDD的关联,明确MMP-3基因与DDD不同表型的关联。
研究方法:本研究采用医院为基础的病例一对照研究设计。
1、研究对象
根据入选和排除标准,选取2006年10月—2008年1月期间北京协和医院骨科病房和门诊确诊的123例中国北方汉族腰椎DDD患者(DDD~+)。以来自北京协和医院骨科门诊和体检中心的123例非腰椎DDD(DDD~-)为对照组,与病例组匹配。123例DDD~-对照组在年龄、性别(年龄差别≤5岁)、体重指数、种族(中国北方汉族)、劳动强度(参照中华人民共和国国家标准GB3869-83)与DDD~+病例组以1:1相匹配。所有DDD~+组与DDD~-组影像学资料完整。
2.实验方法
1、QIAamp DNA Blood Mini Kit试剂盒提取DNA;
2、SNP位点的选择原则:
3、根结合已经研究过的有功能的多态性位点及NCBI数据库和国际人类基因组单体型图计划(http://www.Hapmap.Org)提供的基因型数据,优先选择位于外显子区域或有错译突变的SNPs;其次为标签SNP,以及有文献报道可能与DDD有关的位点。
4、通过对临床表现与L3-4,L4-5,L5-S1椎间盘退变在影像学上的表现分析,进行候选基因多态性与DDD的关联分析。将病例组根据性别、椎间盘退变程度、及是否合并矢状面的畸形(滑脱)和冠状面的畸形(侧凸)分为不同的亚组。
5、在123例DDD~+组和123例DDD~-对照组应用超高通量的SNP分型系统—SNPstream UIT(Genotyping System)对所选SNPs进行鉴定。
6、拟和优度x~2检验(Goodness-of-fit Chi-square test)分析病例、对照组基因型频率的分布是否符合H—W平衡;
7.基于基因型/等位基因频率的关联分析上,应用在线软(SNIP stats)进行非条件Logistic回归模型评估位点基因型与DDD发生风险的相关程度,并计算优势比(OR)及95%可信区间(Cls);
8.连锁不平衡和单倍体型分析:应用Haploview4.0软件计算对照组人群中统一基因SNPs两两间连锁不平衡统计值D'和r,并评估所有单倍体型在病例组和对照组间的分布差异。
3.研究结果
1、DDD~+组和DDD~-组在年龄、性别分布、体重指数无统计学差异。
2、筛查2个候选基因,12个位点。
3.COL9A2基因筛查的6个位点:rs6676013 rs7533552 rs12077871s12722877 rs3737820 rs209914
基因型分布在DDD~-组中和DDD~+组均符合Hardy—Weinberg平衡;在病例/对照组中等位基因分布频率分别为:SNP02(rs1207781)C/T=290.24)/15(0.11);单位点分析显示该位点等位基因在病例和对照组中的分布频率统计学上存在显著差异(P=0.012)。进一步分析得知SNP02(rs1207781)等位基因C/T与DDD~+的易感性升高相关。在非条件Logistic回归分析中,经年龄和性别校正后,SNP02(rs1207781)位点基因型分布符合Codominant(OR=2.23;95%CI=1.14—4.46,p=0.033,AIC=345.4)遗传模型,dominant(OR=2.08;95%CI=1.05—4.12,p=0.032;AIC=345.7)遗传模型和Overdominant(OR=2.25;95%CI=0.97-3.63,p=0.019;AIC=344.8)遗传模型,后者最佳(AIC值较小)。这些结果说明COL9A2基因是中国汉族人群DDD发病的一个易感基因。6个位点今均不符合连锁不平衡,未形成单倍体。
4.MMP—3基因筛查的6个位点:rs520540 rs645419 rs522616rs655403 rs591058 rs602128
基因型分布在对照组中和病例组均符合Hardy—Weinberg平衡;在基于基因型的“病例一对照”关联分析中,我们筛到阳性位点SNP09(rs591058)和病例/对照组中基因型分布频率分别为:SNP09(rs591058)C/T=68(0.65)/49(0.40);单位点分析显示该位点基因型在病例和对照组中的分布频率统计学上存在显著差异(P=0.043),进一步分析得知SNP9基因型CT与DDD的易感性升高相关;在非条件Logistic回归分析中,经年龄、性别校正后,SNP09(rs591058)位点基因型分布符合Overdominant(OR=I.81,95%CI=1.07—3.05,P=0.025,AIC=340.6)。连锁不平衡与单倍体分析显示所有位点不符合连锁不平衡。
5.各SNP位点基因型与DDD~+的中间表型的关联分析中,发现COL9A2基因的SNP2(rs12077871)的C/T型与椎间盘退变程度(MRI分级)的易感性升高有关。
6.在各SNP位点基因型与DDD~+其他中间分型(性别、退变程度、合并冠状面或矢状面的畸形)的关联分析中,没有发现阳性位点。
结论:
1.中国汉族人群中,COL9A2基因与DDD的发生发展有关联。
2.COL9A2基因rs12077871位点的基因型C/T可能是决定DDD遗传易感性的重要因素。
2、COL9A2基因rs12077871位点与椎间盘退变程度有关联。
4.MMP—3基因可能与DDD的发生发展有关联。
Background
Degenerative disc disease(DDD) is a common disorders and is usually found in the neck(cervical) and lower back(lumbar) regions of the spine.DDD is a kind of syndrome that includ prolapse of intervertebral,cervical spondylosis,umbar vertebrae;unsteadiness,lumbar spinal stenosis, degenerative Scoliosis etal.A number of studies have shown an association between genetic influences and disc degeneration.A study of monozygotic twins with different environmental backgrounds research showed that disc degeneration might be explained primarily by genetic influences.Another study on a large population twin sample have shown quantitative measures of disc degeneration to have a large genetic component Indeed,a number of studies have identified specific genetic risk factors(genes) associated with DDD.Although it's still not sure about the genetic methods of DDD,It is also likely that DDD is a complex/multifactorial disease determined by the interplay between gene(s) and the environment.As for the current methods of genetic research,usually,there are two kinds:the linkage analysis and the association analysis.The first is mainly for familial idiopathic scoliosis while the second is the kinless sufferer.
At present,only the association for VDR and COL9A2 has been replicated in more than one population.Lack of replication may be related to the complexity of DDD,different criteria used for genetic studies of DDD and the size of the cohorts.This is not a unique problem to DDD but genetic association studies in general,.Therefore,for genetic association studies to be successful,one needs large sample sizes,small P values.A clear phenotype definition is an important prerequisite for genetic studies.
Objects
1.To examine the association between polymorphic phenotype and different candidate genes(COLA2 Gene AND MMP3 gene).
2.To investigate the relationship between genotypes of SNPs and intermediate phenotype of DDD.
3.Material and Methods
A hospital-based case-control design was applied in this study.
A total of 123 patients with DDD(65 male,57 femal,mean age-49.80 years old),and 123 healthy controls(58 male,65 femal,mean age-45.31 years old).All of the subjects were from Peking Union Medical College Hospital.,Meanwell,,all of them were from north china ban population.
Genolnic DNA was extracted from peripheral blood leukocy' tes of each subject who had Signed informned consellt,using QIAamp DNA Blood Mini KIT.
Single nucleotide polymorphisms were selected.
Hardy—Weinberg equilibrium both in control and in case groups were Analyzed through Goodness-of-fit Chi-square test.
Case group were classified into different phenotypes.
Genotying of all selected SNF's was done by SNPstream technology All the data of 12 SNPs with polynlorphism are analyzed by the association analvsis based on a single SNP the association analysis between phenotyepes and SNPs.
Results
1.COL9A23 gene and Mmp3 gene were genotyped,their polymorphisms were in Hardy-weinberg equilibrium.
2.All of the polymorphisms were not in linkagedis equilibrium.
3.IN the association analysis between the genotyhpes of SNPs and case group,we got two posstive SNPs:SNP02 and SNP09.the minor gentype frequencies in cases/control were,respectively,as followly: SNP02=SNP02 C/T=29(0.24)/15(0.11),SNP09 C/T=68(0.65)/49 (0.40).The single locus analysis realved the genotype distributions of SNP2 and SNP9 were statisticslly signficantly different between case patient and control subject(P=0.012,and P=0.043).In the unconditional logistic regression analysis,after sdjustment for age and gender,SNP2 showed significant in Codominant,dominantand Overdominant model.
4 In the association analysis between the genotyhpes mad the phenotype,,we got one positive SNPs(SNP02),The association analysis between the genotyhpes and other phenotype,we didi not have got any positive SNP.
Conclusion
Genetic variants of COL9A2 gene and MMp-3 genes are associated with DDD and may play an important role developing DDD in a Chinese Han population.
椎间盘退变性疾病(degenerative disc disease,DDD)是指由椎间盘退变(intervertebral disc degeneration,IDD)引起的以颈、腰腿疼痛为主要表现的临床症候群,包括了临床上常见的颈、腰椎间盘突出症,颈椎病,腰椎管狭窄症,退性行腰椎不稳,退性行腰椎滑脱、退行性脊柱侧凸等。通常认为,椎间盘的退变主要是由于环境因素的积累效应和衰老过程引起。重体力负荷,尤其是与职业相关的重体力负荷,一直被怀疑是椎间盘退变的主要危险因素,但始终无法确认负荷与退变之间的剂量—效应关系。流行病学对单卵双生和双卵双生的双胞胎进行研究发现,环境因素对椎间盘退变作用不明显,说明负重仅是危险因素的一部分,从而改变了传统观点。
随着研究逐渐深入到分子水平,多数学者认为DDD是一种多基因遗传病。同时,已经陆续发现了一些与DDD相关的具有遗传特性的特异性基因和一些与IDD相关的基因位点。目前已基本证实维生素D受体(Vitamin D receptor,VDR)基因的Taq1和Fok1基因型与IDD的有关;其他重要的候选基因,如COL9A2基因、MMP-3基因与DDD的关系还存在争议,结果往往互相矛盾。因此,我们有必要从基因水平出发,对COL9A2基因、MMP-3基因与DDD的关系加以研究。
研究目的:
1、探索COL9A2基因与DDD的关联及发挥的效应;
2、明确COL9A2基因与DDD不同表型的关联。
3、探索MMP-3基因与DDD的关联,明确MMP-3基因与DDD不同表型的关联。
研究方法:本研究采用医院为基础的病例一对照研究设计。
1、研究对象
根据入选和排除标准,选取2006年10月—2008年1月期间北京协和医院骨科病房和门诊确诊的123例中国北方汉族腰椎DDD患者(DDD~+)。以来自北京协和医院骨科门诊和体检中心的123例非腰椎DDD(DDD~-)为对照组,与病例组匹配。123例DDD~-对照组在年龄、性别(年龄差别≤5岁)、体重指数、种族(中国北方汉族)、劳动强度(参照中华人民共和国国家标准GB3869-83)与DDD~+病例组以1:1相匹配。所有DDD~+组与DDD~-组影像学资料完整。
2.实验方法
1、QIAamp DNA Blood Mini Kit试剂盒提取DNA;
2、SNP位点的选择原则:
3、根结合已经研究过的有功能的多态性位点及NCBI数据库和国际人类基因组单体型图计划(http://www.Hapmap.Org)提供的基因型数据,优先选择位于外显子区域或有错译突变的SNPs;其次为标签SNP,以及有文献报道可能与DDD有关的位点。
4、通过对临床表现与L3-4,L4-5,L5-S1椎间盘退变在影像学上的表现分析,进行候选基因多态性与DDD的关联分析。将病例组根据性别、椎间盘退变程度、及是否合并矢状面的畸形(滑脱)和冠状面的畸形(侧凸)分为不同的亚组。
5、在123例DDD~+组和123例DDD~-对照组应用超高通量的SNP分型系统—SNPstream UIT(Genotyping System)对所选SNPs进行鉴定。
6、拟和优度x~2检验(Goodness-of-fit Chi-square test)分析病例、对照组基因型频率的分布是否符合H—W平衡;
7.基于基因型/等位基因频率的关联分析上,应用在线软(SNIP stats)进行非条件Logistic回归模型评估位点基因型与DDD发生风险的相关程度,并计算优势比(OR)及95%可信区间(Cls);
8.连锁不平衡和单倍体型分析:应用Haploview4.0软件计算对照组人群中统一基因SNPs两两间连锁不平衡统计值D'和r,并评估所有单倍体型在病例组和对照组间的分布差异。
3.研究结果
1、DDD~+组和DDD~-组在年龄、性别分布、体重指数无统计学差异。
2、筛查2个候选基因,12个位点。
3.COL9A2基因筛查的6个位点:rs6676013 rs7533552 rs12077871s12722877 rs3737820 rs209914
基因型分布在DDD~-组中和DDD~+组均符合Hardy—Weinberg平衡;在病例/对照组中等位基因分布频率分别为:SNP02(rs1207781)C/T=290.24)/15(0.11);单位点分析显示该位点等位基因在病例和对照组中的分布频率统计学上存在显著差异(P=0.012)。进一步分析得知SNP02(rs1207781)等位基因C/T与DDD~+的易感性升高相关。在非条件Logistic回归分析中,经年龄和性别校正后,SNP02(rs1207781)位点基因型分布符合Codominant(OR=2.23;95%CI=1.14—4.46,p=0.033,AIC=345.4)遗传模型,dominant(OR=2.08;95%CI=1.05—4.12,p=0.032;AIC=345.7)遗传模型和Overdominant(OR=2.25;95%CI=0.97-3.63,p=0.019;AIC=344.8)遗传模型,后者最佳(AIC值较小)。这些结果说明COL9A2基因是中国汉族人群DDD发病的一个易感基因。6个位点今均不符合连锁不平衡,未形成单倍体。
4.MMP—3基因筛查的6个位点:rs520540 rs645419 rs522616rs655403 rs591058 rs602128
基因型分布在对照组中和病例组均符合Hardy—Weinberg平衡;在基于基因型的“病例一对照”关联分析中,我们筛到阳性位点SNP09(rs591058)和病例/对照组中基因型分布频率分别为:SNP09(rs591058)C/T=68(0.65)/49(0.40);单位点分析显示该位点基因型在病例和对照组中的分布频率统计学上存在显著差异(P=0.043),进一步分析得知SNP9基因型CT与DDD的易感性升高相关;在非条件Logistic回归分析中,经年龄、性别校正后,SNP09(rs591058)位点基因型分布符合Overdominant(OR=I.81,95%CI=1.07—3.05,P=0.025,AIC=340.6)。连锁不平衡与单倍体分析显示所有位点不符合连锁不平衡。
5.各SNP位点基因型与DDD~+的中间表型的关联分析中,发现COL9A2基因的SNP2(rs12077871)的C/T型与椎间盘退变程度(MRI分级)的易感性升高有关。
6.在各SNP位点基因型与DDD~+其他中间分型(性别、退变程度、合并冠状面或矢状面的畸形)的关联分析中,没有发现阳性位点。
结论:
1.中国汉族人群中,COL9A2基因与DDD的发生发展有关联。
2.COL9A2基因rs12077871位点的基因型C/T可能是决定DDD遗传易感性的重要因素。
2、COL9A2基因rs12077871位点与椎间盘退变程度有关联。
4.MMP—3基因可能与DDD的发生发展有关联。
Background
Degenerative disc disease(DDD) is a common disorders and is usually found in the neck(cervical) and lower back(lumbar) regions of the spine.DDD is a kind of syndrome that includ prolapse of intervertebral,cervical spondylosis,umbar vertebrae;unsteadiness,lumbar spinal stenosis, degenerative Scoliosis etal.A number of studies have shown an association between genetic influences and disc degeneration.A study of monozygotic twins with different environmental backgrounds research showed that disc degeneration might be explained primarily by genetic influences.Another study on a large population twin sample have shown quantitative measures of disc degeneration to have a large genetic component Indeed,a number of studies have identified specific genetic risk factors(genes) associated with DDD.Although it's still not sure about the genetic methods of DDD,It is also likely that DDD is a complex/multifactorial disease determined by the interplay between gene(s) and the environment.As for the current methods of genetic research,usually,there are two kinds:the linkage analysis and the association analysis.The first is mainly for familial idiopathic scoliosis while the second is the kinless sufferer.
At present,only the association for VDR and COL9A2 has been replicated in more than one population.Lack of replication may be related to the complexity of DDD,different criteria used for genetic studies of DDD and the size of the cohorts.This is not a unique problem to DDD but genetic association studies in general,.Therefore,for genetic association studies to be successful,one needs large sample sizes,small P values.A clear phenotype definition is an important prerequisite for genetic studies.
Objects
1.To examine the association between polymorphic phenotype and different candidate genes(COLA2 Gene AND MMP3 gene).
2.To investigate the relationship between genotypes of SNPs and intermediate phenotype of DDD.
3.Material and Methods
A hospital-based case-control design was applied in this study.
A total of 123 patients with DDD(65 male,57 femal,mean age-49.80 years old),and 123 healthy controls(58 male,65 femal,mean age-45.31 years old).All of the subjects were from Peking Union Medical College Hospital.,Meanwell,,all of them were from north china ban population.
Genolnic DNA was extracted from peripheral blood leukocy' tes of each subject who had Signed informned consellt,using QIAamp DNA Blood Mini KIT.
Single nucleotide polymorphisms were selected.
Hardy—Weinberg equilibrium both in control and in case groups were Analyzed through Goodness-of-fit Chi-square test.
Case group were classified into different phenotypes.
Genotying of all selected SNF's was done by SNPstream technology All the data of 12 SNPs with polynlorphism are analyzed by the association analvsis based on a single SNP the association analysis between phenotyepes and SNPs.
Results
1.COL9A23 gene and Mmp3 gene were genotyped,their polymorphisms were in Hardy-weinberg equilibrium.
2.All of the polymorphisms were not in linkagedis equilibrium.
3.IN the association analysis between the genotyhpes of SNPs and case group,we got two posstive SNPs:SNP02 and SNP09.the minor gentype frequencies in cases/control were,respectively,as followly: SNP02=SNP02 C/T=29(0.24)/15(0.11),SNP09 C/T=68(0.65)/49 (0.40).The single locus analysis realved the genotype distributions of SNP2 and SNP9 were statisticslly signficantly different between case patient and control subject(P=0.012,and P=0.043).In the unconditional logistic regression analysis,after sdjustment for age and gender,SNP2 showed significant in Codominant,dominantand Overdominant model.
4 In the association analysis between the genotyhpes mad the phenotype,,we got one positive SNPs(SNP02),The association analysis between the genotyhpes and other phenotype,we didi not have got any positive SNP.
Conclusion
Genetic variants of COL9A2 gene and MMp-3 genes are associated with DDD and may play an important role developing DDD in a Chinese Han population.
引文
1.Kirkaldy-Willis,W.H.,Bernard,T.N.Managing Low Back Pain,Fourth Edition,Pennsylvania:Churchill Livingstone,1999
2.Sobajima,S;Kim,J S;Gilbertson,etal.Gene therapy for degenerative disc disease.Gene Therapy.2004.11:390-401
3.Trends and variations in the use of spine surgery.Deyo RA,Mirza SK.Clin Orthop Relat Res.2006 Feb;443:139-146.
4.Rasmussen C,Nielsen GL,Hansen VK,et al.Rates of lumbar disc surgery before and after implementation of multidisciplinary nonsurgical spine clinics.Spine 2005,30:2469-2473
5.Chan D,Song Y,Sham P,Cheung KMC.Genetics of disc degeneration.Eur Spine J 2006,15(Suppl.3):S317-S325.
6.Jones G,Sambrook P,Sambrook P.Allelic variation in the vitamin D receptor,lifestyle factors and Iumbar spinal degenerative disease Ann Rheum Dis 1998:,57:P 94-99
7.Sambrook PN,MacGregor AJ,Spector TD.Genetic in.uences on cervical and lumbar disc degeneration:a magnetic resonance imaging study in twins.Arthritis Rheum 1999,42:366-372
8.Zortea M,Trevisan CP,Trevisan CP.Genetic mapping of a susceptibility locus for disc herniation and spastic paraplegia on 6q23.3-q24.1 J Med Genet 2002,39:P387-390
9.Videman T,Kaprio J,Kaprio J.Intragenic polymorphisms of the vitamin D receptor gene associated with intervertebral disc degeneration Spine 1998,23:2477-2485
10.Videman T,Battie MC,Battie MC,The relative roles of intragenic polymorphisms of the vitamin D receptor gene in lumbar spine degeneration and bone density Spine 2001,26:7-12
11.Hestbaek L,Leboeuf-Yde C,Leboeuf-Yde C.Heredity of low back pain in a young population:a classical twin study win Res 2004,7:P16-26
12.Ala-Kokko L.Genetic risk factors for lumbar disc disease Ann Med 2002,34:42-47
13.胡明,陈道运,陈道运.人退变椎间盘组织的基因表达谱 解剖学杂志 2004,27:348-351
14. Kawaguchi ,Y Ishihara H, Ishihara H The association of lumbar disc disease with vitamin-D receptor gene polymorphism J Bone Joint Surg(Am ,2002,84 : 2022-2028
15. Kawaguchi, Y Kanamori M, Kanamori M. Association between an aggrecan gene polymorphism and lumbar disc degeneration Spine 1999, 24 : 2456-2460
16. Takahashi M Wakabayashi Y Wakabayashi Y The association of degeneration of the intervertebral disc with 5a/6a polymorphism in the promoter of the human matrix metalloproteinase-3 gene J Bone Joint Surg(Br) 2001 ,83 :491 -495
17. Shinmei M, Masuda K, Kikuchi T et alInterleukin 1, tumor necrosis factor, and interleukin 6 as mediators of cartilage destruction. Semin Arthritis Rheum 1989, 18:27-32
18. .Solovieva S, Lohiniva J, Leino-Arjas P et al COL9A3 gene polymorphism and obesity in intervertebral disc degeneration of the lumbar spine: evidence of gene-environment interaction. Spine 2002 27:2691-2696
19. Solovieva S, Kouhia S, Leino-Arjas P et al .Interleukin 1 polymorphisms and intervertebral disc degeneration. Epidemiology 2004 15:626-633
20. Solovieva S, Leino-Arjas P, Saarela J et alPossible association of interleukin 1 gene locus polymorphisms with low back pain. Pain 2004 1: 109:8-19
21. .Solovieva S, Lohiniva J, Leino-Arjas P et allntervertebral disc degeneration in relation to the COL9A3 and the IL-1ss gene polymorphisms. Eur Spine J 2006 15:613-619
22. Spector TD, MacGregor AJ. Risk factors for osteoarthritis : genetics. Osteoarthritis Cartilage. 2004,12(SupplA):S39-S44
23. Takahashi M, Haro H, Wakabayashi Y et al. The association of degeneration of the intervertebral disc with 5 a/ 6a polymorphism in the promoter of the human matrix me- talloproteinase-3 gene. J Bone Joint Surg B r2001 83:491--495.
24. Thiele H, Sakano M, Kitagawa H et al Loss of chondroitin 6-O-sulfotransferase-l function results in severe human chondrodysplasia with progressive spinal involvement. Proc Natl Acad Sci USA 2004,101:10155-10160.
25. Annunen S, Lohiniva J ,Lohiniva J.An allele of COL9A2 associated with intervertebral disc disease Science 1999,285:409-412
26. Kimura T ,Tsumaki N, Tsumaki N. Progressive degeneration of articular cartilage and intervertebral discs:an experimental study in transgenie mice bearing a type IX collagen mutation Int Orthop 1996 ,20 : 177-181
27. Hagg R, Hedbom E, Mollers U, Aszodi A, etal. Absence of the alpha-1(IX) chain leads to a functional knock-out of the entire collagen IX protein in mice. J Biol Chem 1997;272:20650-4
28. Kanemoto M, Hukuda S, Komiya Y, et al. Immunohistochemical study of matrix metalloproteinase-3 and tissue inhibitor of metalloproteinase-3 human intervertebral discs(J).Spine, 1996,21:1-8.
29. Valdes AM, Hart DJ, Jones KA, Surdulescu G. Association study of candidate genes for the prevalence and progression of knee osteoarthritis. Arthritis Rheum. 2004;50:2497-507.
30. Thomas DC, Clayton DG Betting odds and genetic associations. J Natl Cancer Inst 2004,96:421-423 .
31. .Matsui Y, Wu JJ, Ann WM et al .Matrix deposition of tryptophan-containing allelic variants of type IX collagen in developing human cartilage. Matrix Biol 2003,22:123-129
32. Wrocklage C ,Paulus W, Paulus W. COL9A2 allelotypes in intervertebral disc disease Biochem Biophys Res Commun 2000,279:398-400
33. Kales SN, Linos A, Chatzis C, et al. The role of collagen IX tryptophan polymorphisms in symptomatic intervertebral disc disease in Southern European
34. Seki S, Kawaguchi Y, Mori M, Association study of COL9A2 with lumbar disc disease in the Japanese population. J Hum Genet, 2006, 51: 1063 -1067
35. Karppinen J, Raina S Raina S. Magnetic resonance imaging findings in relation to the COL9A2 tryptophan allele among patients with sciatica Spine 2002,27:78-83
36. .Noponen-Hietala N, Kyllonen E, Mannikko M et al. Sequence variations in the collagen DC and XI genes are associated with degenerative lumbar spinal stenosis. Ann Rheum Dis 2003,62:1208-1214
37. .Paassilta P, Lohiniva J, Goring HH et al .Identi.cation of a novel common genetic risk factor for lumbar disk disease. JAMA2001, 285:1843-1849
38. Paassilta P, Goring HH, Goring HH .Identification of a novel common genetic risk factor for lumbar disk disease JAMA 2001,285:1843-1849
39. Ishuler D, Brooks LD, Chakravarti A et al. A haplotype map of the human genome. Nature2005,437:1299-1320
1 Linmei M,Masuda K,Kikuchi T et allnterleukin 1,tumor necrosis factor,and interleukin 6 as mediators of cartilage destruction.Semin Arthritis Rheum 1989)18:27-32
2 Solovieva S,Lohiniva J,Leino-Arjas P et al COL9A3 gene polymorphism and obesity in intervertebral disc degeneration of the lumbar spine:evidence of gene-environment interaction.Spine 2002 27:2691-2696
3 Solovieva S,Kouhia S,Leino-Arjas P et al Interleukin 1 polymorphisms and intervertebral disc degeneration.Epidemiology 2004 15:626-633
4 Solovieva S,Leino-Arjas P,Saarela J et alPossible association of interleukin 1 gene locus polymorphisms with low back pain.Pain 2004 1:109:8-19
5 Solovieva S,Lohiniva J,Leino-Arjas P et alIntervertebral disc degeneration in relation to the COL9A3 and the IL-lss gene polymorphisms.Eur Spine J 2006 15(5):613-619
6 Spector TD,MacGregor AJ Risk factors for osteoarthritis:genetics Osteoarthritis Cartilage.200412(SupplA):S39-S44
7 Takahashi M, Haro H, Wakabayashi Y et al. The association of degeneration of the intervertebral disc with 5a/ 6a polymorphism in the promoter of the human matrix rae-talloproteinase-3 gene. J Bone Joint Surg Br2001 83:491-495
8 ThieleH, Sakano M, Kitagawa H et al. Loss of chondroitin 6-O-sulfotransferase-1 function results in severe human chondrodysplasia with progressive spinal involvement. Proc Natl Acad Sci USA 2004,101:10155-10160
9 Thomas DC, Clayton DG Betting odds and genetic associations. J Natl Cancer Inst 2004:96:421-423
10 Matsui H, Kanamori M, Ishihara Het al. Familial predisposition for lumbar degenerative disc disease. A case- control study. Spine 1998,23:1029-1034
11 Matsui Y, Wu JJ, Ann WM et al. Matrix deposition of tryptophan-containing allelic variants of type IX collagen in developing human cartilage. Matrix Biol 2003,22:123-129
12 Moore RJ, Vernon-Roberts B, Fraser RD et al. The origin and fate of herniated lumbar intervertebral disc tissue. Spine1996,21:2149-2155
13 Morrison NA, Qi JC, Tokita A et al. Prediction of bone density from vitamin D receptor alleles. Nature1994, 367:284-287
14 Noponen-Hietala N, Kyllonen E, Mannikko M et al. Sequence variations in the collagen IX and XI genes are associated with degenerative lumbar spinal stenosis. Ann Rheum Dis 2003,62:1208-1214
15 Paassilta P, Lohiniva J, Goring HH et al .Identication of a novel common genetic risk factor for lumbar disk disease. JAMA 2001, 285:1843-1849
16 Pluijm SM, van Essen HW, Bravenboer N et al Collagen type I alphal Sp1 polymorphism, osteoporosis, and intervertebral disc degeneration in older men and women. Ann Rheum Dis 2004,63:71-77
17 Pociot F, Molvig J, Wogensen L et al () A TaqI polymorphism in the human interleukin-1 beta (IL-1 beta) gene correlates with IL-1 beta secretion in vitro. Eur J Clin Invest 1992,22:396-402
18 Postacchini F, Lami R, Pugliese O. Familial predisposition to discogenic low-back pain. An epidemiologic and immunogenetic study. Spine1988, 13:1403-1406
19 Richardson JK, Chung T, Schultz JS et al. A familial predisposition toward lumbar disc injury. Spinel 997, 22:1487-1492
20 Riggs BL () Vitamin D-receptor genotypes and bone density. N Engl J Med1997, 337:125-126
21 Rossignol M, Lortie M, Ledoux E Comparison of spinal health indicators in predicting spinal status in a 1-year longitudinal study. Spine 199318:54-60
22 Roughley P, Martens D, Rantakokko Jet al. The involvement of aggrecan polymorphism in degeneration of human intervertebral disc and articular cartilage. Eur Cell Mater 2006,11:1-7
23 Sambrook PN, MacGregor AJ, Spector TD Genetic in (?)uences on cervical and lumbar disc degeneration: a magnetic resonance imaging study in twins. Arthritis Rheum 1999,42:366-372
24 hinmei M, Masuda K, Kikuchi T et al. Interleukin 1, tumor necrosis factor, and interleukin 6 as mediators of cartilage destruction. Semin Arthritis Rheum1989, 18:27-32
25 Solovieva S, Lohiniva J, Leino-Arjas P et al(COL9A3 gene polymorphism and obesity in intervertebral disc degeneration of the lumbar spine: evidence of gene-environment interaction. Spine2002, 27:2691-2696
26 Solovieva S, Kouhia S, Leino-Arjas P et al Interleukin 1 polymorphisms and ntervertebral disc degeneration. Epidemiology 2004,15:626-633
27 Solovieva S, Leino-Arjas P, Saarela J et al. Possible association of interleukin 1 gene locus polymorphisms with low back pain. Pain2004, 109:8-19
28 Solovieva S, Lohiniva J, Leino-Arjas P et al. Intervertebral disc degeneration in relation to the COL9A3 and the IL-lss gene polymorphisms. Eur Spine J 2006,15(5):613-619
29 Takahashi M, Haro H, Wakabayashi Y et al The association of degeneration of the intervertebral disc with 5 a/ 6a polymorphism in the promoter of the human matrix me-talloproteinase-3 gene. J Bone Joint Surg Br2001, 83:491—495
30 ThieleH, Sakano M, Kitagawa H et al Loss of chondroitin 6-O-sulfotransferase-1 function results in severe human chondrodysplasia with progressive spinal involvement. Proc Natl Acad Sci USA.2004, 101:10155-10160
31 Thomas DC, Clayton DG. Betting odds and genetic associations. J Natl Cancer Inst 2004,96:421-423
32 24 Tokita A, Matsumoto H, Morrison NA et al Vitamin D receptor alleles, bone mineral density and turnover in premenopausal Japanese women. J Bone Miner Res 1996,11:1003-1009
33 Uitterlinden AG, Burger H, Huang Q et al. Vitamin D receptor genotype is associated with radiographic osteoarthritis at the knee. J Clin Invest 1997,100:259-263
34 26 Litterlinden AG, Burger H, Huang Q et al. Relation of alleles of the collagen type Ialpha1 gene to bone density and the risk of osteoporotic fractures in postmenopausal women. N Engl J Med,1998, 338:1016-1021
35 itterlinden AG, Fang Y, Van Meurs JB et al. Genetics and biology of vitamin D receptor polymorphisms. Gene,2004, 338:143-156
36 ideman T, Leppavuori J, Kaprio J et al .Intragenic polymorphisms of the vitamin D receptor gene associated with intervertebral disc degeneration. Spine1998, 23:2477-2485
37 Whit(?)eld GK, Remus LS, Jurutka PW et al Functionally relevant polymorphisms in the human nuclear vitamin D receptor gene. Mol Cell Endocrinol2001, 177:145-159
38 Ye S, Watts GF, Mandalia S et al .Preliminary report: genetic variation in the human stromelysin promoter is associated with progression of coronary atherosclerosis. Br Heart J 1995,73:209-215
39 Ye S, Eriksson P, Hamsten A et al. Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression. J Biol Chem 1996,271:13055-13060
40 ltshuler D, Brooks LD, Chakravarti A et al A haplotype map of the human genome. Nature2005,437:1299-1320
41 Annunen S, Paassilta P, Lohiniva J et al .An allele of COL9A2 associated with intervertebral disc disease. Science 1999,285:409-412
42 Antoniou J, Steffen T, Nelson Fet al. The human lumbar intervertebral disc: evidence for changes in the biosynthesis and denaturation of the extracellular matrix with growth, maturation, ageing, and degeneration. J Clin Invest 1996,98:996-1003
43 Aszodi A, Hunziker EB, Olsen BR et al .The role of collagen II and cartilage bril-associated molecules in skeletal development. Osteoarthritis Cartilage 9(Suppl A): 2001,S150-S159
44 Battie MC, Haynor DR, Fisher LD et al. Similarities in degenerative .ndings on magnetic resonance images of the lumbar spines of identical twins. J Bone Joint Surg Am 1995, 77:1662-1670
45 Battie MC, Videman T, Gibbons LE et al .Volvo Award in clinical sciences. Determinants of lumbar disc degeneration. A study relating lifetime exposures and magnetic resonance imaging indings in identical twins. Spine 1995,20:2601-2612
46 Boden SD, Davis DO, Dina TS et al. Abnormal magnetic-resonance scans of the lumbar spine in asymptomatic subjects. A prospective investigation. J Bone Joint Surg Am 1990,72:403-408
47 Boos N, Rieder R, Schade V et al .Volvo Award in clinical sciences. The diagnostic accuracy of magnetic resonance imaging, work perception, and psychosocial factors in identifying symptomatic disc herniations. Spine 1995,20:2613-2625
48 Frymoyer JW. Lumbar disk disease: epidemiology. Instr Course Lect 41:217-223
49 Goldring MB, Birkhead JR, Suen LF et al. Interleukin-1 beta-modulated gene expression in immortalized human chondrocytes. J Clin Invest 1992,94:2307-2316
50 Haussler MR, Whit(?)eld GK, Haussler CA et al. The nuclear vitamin D receptor: biological and molecular regulatory properties revealed. J Bone Miner Res1998, 13:325-349
51 Hirschhorn JN, Daly MJ . Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 2005,6:95-108
52 Ioannidis JP, Ntzani EE, Trikalinos TA et al. Replication validity of genetic association studies. Nat Genet 2001,29:306-309
53 Jim JJ, Noponen-Hietala N, Cheung KM et al .The TRP2 allele of COL9A2 is an age-dependent risk factor for the development and severity of intervertebral disc degeneration. Spine2005, 30:2735-2742
2.Sobajima,S;Kim,J S;Gilbertson,etal.Gene therapy for degenerative disc disease.Gene Therapy.2004.11:390-401
3.Trends and variations in the use of spine surgery.Deyo RA,Mirza SK.Clin Orthop Relat Res.2006 Feb;443:139-146.
4.Rasmussen C,Nielsen GL,Hansen VK,et al.Rates of lumbar disc surgery before and after implementation of multidisciplinary nonsurgical spine clinics.Spine 2005,30:2469-2473
5.Chan D,Song Y,Sham P,Cheung KMC.Genetics of disc degeneration.Eur Spine J 2006,15(Suppl.3):S317-S325.
6.Jones G,Sambrook P,Sambrook P.Allelic variation in the vitamin D receptor,lifestyle factors and Iumbar spinal degenerative disease Ann Rheum Dis 1998:,57:P 94-99
7.Sambrook PN,MacGregor AJ,Spector TD.Genetic in.uences on cervical and lumbar disc degeneration:a magnetic resonance imaging study in twins.Arthritis Rheum 1999,42:366-372
8.Zortea M,Trevisan CP,Trevisan CP.Genetic mapping of a susceptibility locus for disc herniation and spastic paraplegia on 6q23.3-q24.1 J Med Genet 2002,39:P387-390
9.Videman T,Kaprio J,Kaprio J.Intragenic polymorphisms of the vitamin D receptor gene associated with intervertebral disc degeneration Spine 1998,23:2477-2485
10.Videman T,Battie MC,Battie MC,The relative roles of intragenic polymorphisms of the vitamin D receptor gene in lumbar spine degeneration and bone density Spine 2001,26:7-12
11.Hestbaek L,Leboeuf-Yde C,Leboeuf-Yde C.Heredity of low back pain in a young population:a classical twin study win Res 2004,7:P16-26
12.Ala-Kokko L.Genetic risk factors for lumbar disc disease Ann Med 2002,34:42-47
13.胡明,陈道运,陈道运.人退变椎间盘组织的基因表达谱 解剖学杂志 2004,27:348-351
14. Kawaguchi ,Y Ishihara H, Ishihara H The association of lumbar disc disease with vitamin-D receptor gene polymorphism J Bone Joint Surg(Am ,2002,84 : 2022-2028
15. Kawaguchi, Y Kanamori M, Kanamori M. Association between an aggrecan gene polymorphism and lumbar disc degeneration Spine 1999, 24 : 2456-2460
16. Takahashi M Wakabayashi Y Wakabayashi Y The association of degeneration of the intervertebral disc with 5a/6a polymorphism in the promoter of the human matrix metalloproteinase-3 gene J Bone Joint Surg(Br) 2001 ,83 :491 -495
17. Shinmei M, Masuda K, Kikuchi T et alInterleukin 1, tumor necrosis factor, and interleukin 6 as mediators of cartilage destruction. Semin Arthritis Rheum 1989, 18:27-32
18. .Solovieva S, Lohiniva J, Leino-Arjas P et al COL9A3 gene polymorphism and obesity in intervertebral disc degeneration of the lumbar spine: evidence of gene-environment interaction. Spine 2002 27:2691-2696
19. Solovieva S, Kouhia S, Leino-Arjas P et al .Interleukin 1 polymorphisms and intervertebral disc degeneration. Epidemiology 2004 15:626-633
20. Solovieva S, Leino-Arjas P, Saarela J et alPossible association of interleukin 1 gene locus polymorphisms with low back pain. Pain 2004 1: 109:8-19
21. .Solovieva S, Lohiniva J, Leino-Arjas P et allntervertebral disc degeneration in relation to the COL9A3 and the IL-1ss gene polymorphisms. Eur Spine J 2006 15:613-619
22. Spector TD, MacGregor AJ. Risk factors for osteoarthritis : genetics. Osteoarthritis Cartilage. 2004,12(SupplA):S39-S44
23. Takahashi M, Haro H, Wakabayashi Y et al. The association of degeneration of the intervertebral disc with 5 a/ 6a polymorphism in the promoter of the human matrix me- talloproteinase-3 gene. J Bone Joint Surg B r2001 83:491--495.
24. Thiele H, Sakano M, Kitagawa H et al Loss of chondroitin 6-O-sulfotransferase-l function results in severe human chondrodysplasia with progressive spinal involvement. Proc Natl Acad Sci USA 2004,101:10155-10160.
25. Annunen S, Lohiniva J ,Lohiniva J.An allele of COL9A2 associated with intervertebral disc disease Science 1999,285:409-412
26. Kimura T ,Tsumaki N, Tsumaki N. Progressive degeneration of articular cartilage and intervertebral discs:an experimental study in transgenie mice bearing a type IX collagen mutation Int Orthop 1996 ,20 : 177-181
27. Hagg R, Hedbom E, Mollers U, Aszodi A, etal. Absence of the alpha-1(IX) chain leads to a functional knock-out of the entire collagen IX protein in mice. J Biol Chem 1997;272:20650-4
28. Kanemoto M, Hukuda S, Komiya Y, et al. Immunohistochemical study of matrix metalloproteinase-3 and tissue inhibitor of metalloproteinase-3 human intervertebral discs(J).Spine, 1996,21:1-8.
29. Valdes AM, Hart DJ, Jones KA, Surdulescu G. Association study of candidate genes for the prevalence and progression of knee osteoarthritis. Arthritis Rheum. 2004;50:2497-507.
30. Thomas DC, Clayton DG Betting odds and genetic associations. J Natl Cancer Inst 2004,96:421-423 .
31. .Matsui Y, Wu JJ, Ann WM et al .Matrix deposition of tryptophan-containing allelic variants of type IX collagen in developing human cartilage. Matrix Biol 2003,22:123-129
32. Wrocklage C ,Paulus W, Paulus W. COL9A2 allelotypes in intervertebral disc disease Biochem Biophys Res Commun 2000,279:398-400
33. Kales SN, Linos A, Chatzis C, et al. The role of collagen IX tryptophan polymorphisms in symptomatic intervertebral disc disease in Southern European
34. Seki S, Kawaguchi Y, Mori M, Association study of COL9A2 with lumbar disc disease in the Japanese population. J Hum Genet, 2006, 51: 1063 -1067
35. Karppinen J, Raina S Raina S. Magnetic resonance imaging findings in relation to the COL9A2 tryptophan allele among patients with sciatica Spine 2002,27:78-83
36. .Noponen-Hietala N, Kyllonen E, Mannikko M et al. Sequence variations in the collagen DC and XI genes are associated with degenerative lumbar spinal stenosis. Ann Rheum Dis 2003,62:1208-1214
37. .Paassilta P, Lohiniva J, Goring HH et al .Identi.cation of a novel common genetic risk factor for lumbar disk disease. JAMA2001, 285:1843-1849
38. Paassilta P, Goring HH, Goring HH .Identification of a novel common genetic risk factor for lumbar disk disease JAMA 2001,285:1843-1849
39. Ishuler D, Brooks LD, Chakravarti A et al. A haplotype map of the human genome. Nature2005,437:1299-1320
1 Linmei M,Masuda K,Kikuchi T et allnterleukin 1,tumor necrosis factor,and interleukin 6 as mediators of cartilage destruction.Semin Arthritis Rheum 1989)18:27-32
2 Solovieva S,Lohiniva J,Leino-Arjas P et al COL9A3 gene polymorphism and obesity in intervertebral disc degeneration of the lumbar spine:evidence of gene-environment interaction.Spine 2002 27:2691-2696
3 Solovieva S,Kouhia S,Leino-Arjas P et al Interleukin 1 polymorphisms and intervertebral disc degeneration.Epidemiology 2004 15:626-633
4 Solovieva S,Leino-Arjas P,Saarela J et alPossible association of interleukin 1 gene locus polymorphisms with low back pain.Pain 2004 1:109:8-19
5 Solovieva S,Lohiniva J,Leino-Arjas P et alIntervertebral disc degeneration in relation to the COL9A3 and the IL-lss gene polymorphisms.Eur Spine J 2006 15(5):613-619
6 Spector TD,MacGregor AJ Risk factors for osteoarthritis:genetics Osteoarthritis Cartilage.200412(SupplA):S39-S44
7 Takahashi M, Haro H, Wakabayashi Y et al. The association of degeneration of the intervertebral disc with 5a/ 6a polymorphism in the promoter of the human matrix rae-talloproteinase-3 gene. J Bone Joint Surg Br2001 83:491-495
8 ThieleH, Sakano M, Kitagawa H et al. Loss of chondroitin 6-O-sulfotransferase-1 function results in severe human chondrodysplasia with progressive spinal involvement. Proc Natl Acad Sci USA 2004,101:10155-10160
9 Thomas DC, Clayton DG Betting odds and genetic associations. J Natl Cancer Inst 2004:96:421-423
10 Matsui H, Kanamori M, Ishihara Het al. Familial predisposition for lumbar degenerative disc disease. A case- control study. Spine 1998,23:1029-1034
11 Matsui Y, Wu JJ, Ann WM et al. Matrix deposition of tryptophan-containing allelic variants of type IX collagen in developing human cartilage. Matrix Biol 2003,22:123-129
12 Moore RJ, Vernon-Roberts B, Fraser RD et al. The origin and fate of herniated lumbar intervertebral disc tissue. Spine1996,21:2149-2155
13 Morrison NA, Qi JC, Tokita A et al. Prediction of bone density from vitamin D receptor alleles. Nature1994, 367:284-287
14 Noponen-Hietala N, Kyllonen E, Mannikko M et al. Sequence variations in the collagen IX and XI genes are associated with degenerative lumbar spinal stenosis. Ann Rheum Dis 2003,62:1208-1214
15 Paassilta P, Lohiniva J, Goring HH et al .Identication of a novel common genetic risk factor for lumbar disk disease. JAMA 2001, 285:1843-1849
16 Pluijm SM, van Essen HW, Bravenboer N et al Collagen type I alphal Sp1 polymorphism, osteoporosis, and intervertebral disc degeneration in older men and women. Ann Rheum Dis 2004,63:71-77
17 Pociot F, Molvig J, Wogensen L et al () A TaqI polymorphism in the human interleukin-1 beta (IL-1 beta) gene correlates with IL-1 beta secretion in vitro. Eur J Clin Invest 1992,22:396-402
18 Postacchini F, Lami R, Pugliese O. Familial predisposition to discogenic low-back pain. An epidemiologic and immunogenetic study. Spine1988, 13:1403-1406
19 Richardson JK, Chung T, Schultz JS et al. A familial predisposition toward lumbar disc injury. Spinel 997, 22:1487-1492
20 Riggs BL () Vitamin D-receptor genotypes and bone density. N Engl J Med1997, 337:125-126
21 Rossignol M, Lortie M, Ledoux E Comparison of spinal health indicators in predicting spinal status in a 1-year longitudinal study. Spine 199318:54-60
22 Roughley P, Martens D, Rantakokko Jet al. The involvement of aggrecan polymorphism in degeneration of human intervertebral disc and articular cartilage. Eur Cell Mater 2006,11:1-7
23 Sambrook PN, MacGregor AJ, Spector TD Genetic in (?)uences on cervical and lumbar disc degeneration: a magnetic resonance imaging study in twins. Arthritis Rheum 1999,42:366-372
24 hinmei M, Masuda K, Kikuchi T et al. Interleukin 1, tumor necrosis factor, and interleukin 6 as mediators of cartilage destruction. Semin Arthritis Rheum1989, 18:27-32
25 Solovieva S, Lohiniva J, Leino-Arjas P et al(COL9A3 gene polymorphism and obesity in intervertebral disc degeneration of the lumbar spine: evidence of gene-environment interaction. Spine2002, 27:2691-2696
26 Solovieva S, Kouhia S, Leino-Arjas P et al Interleukin 1 polymorphisms and ntervertebral disc degeneration. Epidemiology 2004,15:626-633
27 Solovieva S, Leino-Arjas P, Saarela J et al. Possible association of interleukin 1 gene locus polymorphisms with low back pain. Pain2004, 109:8-19
28 Solovieva S, Lohiniva J, Leino-Arjas P et al. Intervertebral disc degeneration in relation to the COL9A3 and the IL-lss gene polymorphisms. Eur Spine J 2006,15(5):613-619
29 Takahashi M, Haro H, Wakabayashi Y et al The association of degeneration of the intervertebral disc with 5 a/ 6a polymorphism in the promoter of the human matrix me-talloproteinase-3 gene. J Bone Joint Surg Br2001, 83:491—495
30 ThieleH, Sakano M, Kitagawa H et al Loss of chondroitin 6-O-sulfotransferase-1 function results in severe human chondrodysplasia with progressive spinal involvement. Proc Natl Acad Sci USA.2004, 101:10155-10160
31 Thomas DC, Clayton DG. Betting odds and genetic associations. J Natl Cancer Inst 2004,96:421-423
32 24 Tokita A, Matsumoto H, Morrison NA et al Vitamin D receptor alleles, bone mineral density and turnover in premenopausal Japanese women. J Bone Miner Res 1996,11:1003-1009
33 Uitterlinden AG, Burger H, Huang Q et al. Vitamin D receptor genotype is associated with radiographic osteoarthritis at the knee. J Clin Invest 1997,100:259-263
34 26 Litterlinden AG, Burger H, Huang Q et al. Relation of alleles of the collagen type Ialpha1 gene to bone density and the risk of osteoporotic fractures in postmenopausal women. N Engl J Med,1998, 338:1016-1021
35 itterlinden AG, Fang Y, Van Meurs JB et al. Genetics and biology of vitamin D receptor polymorphisms. Gene,2004, 338:143-156
36 ideman T, Leppavuori J, Kaprio J et al .Intragenic polymorphisms of the vitamin D receptor gene associated with intervertebral disc degeneration. Spine1998, 23:2477-2485
37 Whit(?)eld GK, Remus LS, Jurutka PW et al Functionally relevant polymorphisms in the human nuclear vitamin D receptor gene. Mol Cell Endocrinol2001, 177:145-159
38 Ye S, Watts GF, Mandalia S et al .Preliminary report: genetic variation in the human stromelysin promoter is associated with progression of coronary atherosclerosis. Br Heart J 1995,73:209-215
39 Ye S, Eriksson P, Hamsten A et al. Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression. J Biol Chem 1996,271:13055-13060
40 ltshuler D, Brooks LD, Chakravarti A et al A haplotype map of the human genome. Nature2005,437:1299-1320
41 Annunen S, Paassilta P, Lohiniva J et al .An allele of COL9A2 associated with intervertebral disc disease. Science 1999,285:409-412
42 Antoniou J, Steffen T, Nelson Fet al. The human lumbar intervertebral disc: evidence for changes in the biosynthesis and denaturation of the extracellular matrix with growth, maturation, ageing, and degeneration. J Clin Invest 1996,98:996-1003
43 Aszodi A, Hunziker EB, Olsen BR et al .The role of collagen II and cartilage bril-associated molecules in skeletal development. Osteoarthritis Cartilage 9(Suppl A): 2001,S150-S159
44 Battie MC, Haynor DR, Fisher LD et al. Similarities in degenerative .ndings on magnetic resonance images of the lumbar spines of identical twins. J Bone Joint Surg Am 1995, 77:1662-1670
45 Battie MC, Videman T, Gibbons LE et al .Volvo Award in clinical sciences. Determinants of lumbar disc degeneration. A study relating lifetime exposures and magnetic resonance imaging indings in identical twins. Spine 1995,20:2601-2612
46 Boden SD, Davis DO, Dina TS et al. Abnormal magnetic-resonance scans of the lumbar spine in asymptomatic subjects. A prospective investigation. J Bone Joint Surg Am 1990,72:403-408
47 Boos N, Rieder R, Schade V et al .Volvo Award in clinical sciences. The diagnostic accuracy of magnetic resonance imaging, work perception, and psychosocial factors in identifying symptomatic disc herniations. Spine 1995,20:2613-2625
48 Frymoyer JW. Lumbar disk disease: epidemiology. Instr Course Lect 41:217-223
49 Goldring MB, Birkhead JR, Suen LF et al. Interleukin-1 beta-modulated gene expression in immortalized human chondrocytes. J Clin Invest 1992,94:2307-2316
50 Haussler MR, Whit(?)eld GK, Haussler CA et al. The nuclear vitamin D receptor: biological and molecular regulatory properties revealed. J Bone Miner Res1998, 13:325-349
51 Hirschhorn JN, Daly MJ . Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 2005,6:95-108
52 Ioannidis JP, Ntzani EE, Trikalinos TA et al. Replication validity of genetic association studies. Nat Genet 2001,29:306-309
53 Jim JJ, Noponen-Hietala N, Cheung KM et al .The TRP2 allele of COL9A2 is an age-dependent risk factor for the development and severity of intervertebral disc degeneration. Spine2005, 30:2735-2742