CALM1基因SNP多态性与青少年特发性脊柱侧凸遗传易感性的关联研究
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摘要
【研究背景】
特发性脊柱侧凸(Idiopathic scoliosis,IS)是最常见的脊柱畸形,发病率约1%～3%,其中,青少年特发性脊柱侧凸(Adolescent idiopathic scoliosis,AIS)约占80%。虽然AIS的病因还不明确,但随着分子生物学和遗传学水平的发展,AIS的遗传病因学研究逐渐深入。目前,人们普遍认为它是一种多因素作用的遗传性疾病,且有学者采用全基因扫描法将AIS相关基因定位于有限的几个染色体位点。
对于研究复杂多基因相关疾病,候选基因法、关联分析、单倍体型分析法具有先进和准确的特点,如今它们已成为群体遗传学研究和疾病相关基因检测的重要手段,能够直接、简便、准确地阐述疾病相关基因的关联性和作用机制。
另外,AIS作为一种临床表型复杂的疾病,目前尚无从不同的临床表型角度如PUMC分型,分组分层对AIS不同临床表型的遗传病因学机制进行研究的相关报道。
【研究目的】
1.通过对钙调蛋白1基因(Calmodulin 1,CALM1基因)与AIS之间的关联分析,明确其在AIS发病机制中发挥的效应。
2.通过对CALM1基因SNPs位点等位基因/基因型与AIS临床表型的关联分析,在基因水平上探索CALM1基因与AIS不同临床表型之间的关系,从遗传学上丰富AIS临床表型的内容。
3.根据研究结果提出可能的AIS病因学假说。
【研究方法】本实验采用以医院为基础的“病例-对照”研究。
1.研究对象:根据入选和排除标准选取2005年10月至2008年2月期间北京协和医院骨科收治并已确诊的汉族青少年特发性脊柱侧凸患者,共146例,其中男性24例,女性122例,平均年龄14.89岁(10～20岁)。对照组则为同期北京协和医院收治的感染或创伤患者、健康查体者等汉族患者,共146例,男性24例,女性122例,平均年龄15.18岁(10～20岁)。
2.研究方法
(1)QIAamp(?) DNA Blood Mini Kit试剂盒提取DNA;
(2)根据国际人类基因组单倍体型图计划(http://www.hapmap.org/)提供的基因型数据,应用Haploview 4.0软件选取CALM1基因的SNPs位点,优先选取杂合度高于10%,位于外显子区域或有错义突变的SNPs和位于3'-、5'-调控区的SNPs作为遗传标记、共选取14个SNPs;
(3)分别按照侧凸顶点所在位置(主弯)、PUMC分型对病例组进行分组;
(4)在所有146例AIS患者和146例对照组中应用超高通量的SNP分型系统——SNPstream UHT Genotyping System对所选SNPs进行基因型鉴定;
(5)拟合优度x2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;
(6)基于基因型/等位基因频率的“病例-对照”关联分析及病例组不同临床表型之间的关联分析;
(7)在基因型/等位基因频率关联分析基础上,应用在线软件(SNPstats)进行非条件Logistic回归模型评估单位点基因型与AIS发生风险的相关程度,并计算优势比(OR)及95%可信区间(CIs);
(8)连锁不平衡和单倍体型分析:应用Haploview 4.0软件计算CALM1基因所有单倍体型在病例组和对照组之间的分布差异。
【研究结果】
1.流行病学资料分析:病例组和对照组之间年龄、性别分布无统计学差异。
2.因rs12885713、rs5871引物设计失败,故研究中放弃这两个位点,最终对CALM1基因的12个SNPs位点进行统计分析,这12个SNPs位点均具有多态性,其等位基因和基因型在病例组和对照组中均符合Hardy-Weinberg平衡。
3.SNPs等位基因多态性—AIS:rs2300496、rs2300500和rs3213718等位基因在病例组和对照组中的分布频率统计学上存在显著差异(P值分别为0.0079,0.0079,0.0257),进一步分析得知rs2300496位点等位基因C、rs2300500位点等位基因G和rs3213718位点等位基因C与AIS的易感性升高有关。
4.基因型多态性—AIS
(1)rs2300496、rs2300500和rs3213718基因型在病例组和对照组中的分布频率统计学上存在显著差异(P值分别为0.0196,0.0196,0.0378),进一步分析得知rs2300496基因型C/C、rs2300500基因型G/G和rs3213718基因型C/C与AIS的易感性升高有关。在非条件Logistic回归分析中,经年龄和性别校正后,rs2300496和rs2300500基因型分布符合Codominant遗传模型(OR=0.12,95%CI=0.01-0.99,p=0.015,AIC=402.4)、Dominant遗传模型(OR=0.56,95%CI=0.34-0.92,p=0.022,AIC=403.6)和Log-additive遗传模型(OR=0.54,95%CI=0.35-0.86,p=0.0073,AIC=401.6),后者最佳(AIC值较小);rs3213718基因型分布符合Log-additive遗传模型(OR=0.60,95%CI=0.39-0.93,p=0.022,AIC=403.5)。
(2)单倍体-AIS:在多位点单倍体型分析中,发现1种阳性单倍体型:SNP8C-SNP1A-SNP13C-SNP14C-SNP2C-SNP3T-SNP4G-SNP5T-SNP11C。
(3)结合PUMC分型,rs2300496和rs2300500基因型在PUMCⅡ型和对照组中的分布频率统计学上存在显著差异(P值分别为0.0470,0.0470),进一步分析得知rs2300496基因型C/C、rs2300500基因型G/G与PUMCⅡ型的发生有关。
(4)结合AIS主弯顶点分析,rs2300496、rs2300500和rs3213718基因型在胸弯和对照组中的分布频率统计学上存在显著差异(P值分别为0.0180,0.0180,0.0402),进一步分析得知rs2300496基因型C/C、rs2300500基因型G/G和rs3213718基因型C/C与胸弯的发生有关。
(5)12个SNPs位点基因型与病例组主侧弯Cobb's角度数之间无统计学差异。
【结论】
1.CALM1基因遗传变异可能与青少年特发性脊柱侧凸(AIS)发生相关,有可能是影响AIS易感性的重要因素。
2.PUMCⅡ型AIS的发生可能与rs2300496和rs2300500基因型多态性有关;胸弯AIS的发生可能和rs2300496、rs2300500和rs3213718基因型多态性有关。
3.AIS不同的临床表型可能和不同的SNP位点多态性有关,初步显示AIS的PUMC分型可能和不同的SNP位点多态性有关,提示PUMC分型不仅是指导临床治疗的可靠标准,而且可能是符合遗传病因学机制的合理分型。
Background
Idiopathic scoliosis is the most common pediatric spinal deformity affecting 1%to 3%of the population,and adolescent idiopathic scoliosis(AIS) accounts for approximately 80%of these cases.The etiology of AIS is still uncertain,but with the rapid development of genetics and molecular biology in recent years,genetics researches of AIS are brought into focus gradually.Nowadays,AIS is widely believed a multifactorial inheritance disease.Recent linkage studies on familial idiopathic scoliosis revealed multiple putative predisposition loci.
As for investigating complicated multigenetic disease,candidate gene analysis, association analysis and haplotype analysis are advanced and exact methods,and they are direct and effective means of elucidating the mechanism of disease-related gene.
In addition,AIS has complex clinical phenotypes,such as PUMC classification classification,yet there are no report about the association of genetic mechanism with different clinical classifications.
Objects
1.To identify the relationship between CALM1 gene and AIS,and to investigate the major effect of CALM1 Gene in AIS patients,
2.To identify the relationship between the genotypes of SNPs and the clinical phenotypes of AIS.
3.To explore possible etiologic hypothesis contributed to the development of AIS and the different clinical phenotypes of AIS at gene level.
Methods
A hospital-based case-ontrol design was applied in this study.A total of 146 patients(24 boys,122 girls,mean age 14.89 y/o) diagnosed with adolescent idiopathic scoliosis admitted in Peking Union Medical College(PUMC) hospital were enrolled in this study according to inclusion and exclusion criteria between October 2005 and February 2008.The control group also comprised 146 patients(24 boys,122 girls,mean age 15.18 y/o) and consisted of infection(64),inflammatory disease(53),trauma(11),hypersensitive disease(6)and others(12) at PUMC hospital during the same period.All the control subjects were frequency-matched to the cases on age(±3 years),gender and the Han nationality. PUMC classification,curve pattern,cobb's angle of main curve of AIS patients were recorded.Genomic DNA was extracted from peripheral blood leukocytes of each subject who had signed informed consent with QIAamp DNA Blood Mini Kit.Based on genotype data from the international HapMap project,14 single nucleotide polymorphisms(SNPs) in calmodulin 1(CALM1) gene were initially choosed by Haploview 4.0 software.Genotyping of all selected SNPs was done by SNPstream technolofy(Beckman Coulter SNPstream).However,2 SNPs failed in composition of premier and were abandoned.All the data of 12 SNPs with polymorphism were analysed by the association analysis based on alleles and phenotypes of SNPs.Odds ratio(ORs) and 95%confidence intervals(CIs) were computed by the unconditional logistic regression to estimate the relative risk for the single locus genotypes by online software—SNPstats.Haplotype frequencies were estimated and difference in haplotype distributions between cases and controls were assessed by Haploview 4.0 software.
Results
1.Epidemiologic data analysis:there were no significant difference of age distribution and sex proportion between case group and control group.
2.We failed in composing premier of two SNPs(rs12885713,rs5871) and abandoned them in this study.The remained 12 SNPs were genotyped and all polymorphisms were in Hardy-Weinberg equilibrium between case group and contrl group.
3.SNP Allele-AIS:the allele frequency distributions of rs2300496,rs2300500 and rs3213718 were statistically different between case group and control group(P=0.0079,0.0079,0.0257 respectively).
4.SNP genotype-AIS
(1)The genotypes distributions of rs2300496,rs2300500 and rs3213718 were statistically different between caseg roup and control group(P=0.0196, 0.0196,0.0378 respectively).In the unconditional logistic regression analysis,after adjustment for age and gender,rs2300496 and rs2300500 both showed significant difference in Codominant model(OR=0.12,95%, CI=0.01-0.99,p=0.015,AIC=402.4),Dominant model(OR=0.56,95Z%,CI= 0.34-0.92,p=0.022,AIC=403.6) and Log-additive model(OR=0.54, 95%CI=0.35-0.86,p=0.0073,AIC=401.6).The Log-additive model was accepted as the best inheritance model because of the smallest AIC (Akaikeinformation) value.rs3213718 showed significant difference in Log-additive model(OR=0.60,95%CI=0.39-0.93,p=0.022,AIC=403.5).
(2)Haplotype-AIS:we got 1 positive haplotype:SNP8C-SNP1A-SNP13C-SNP14C-SNP2C-SNP3T-SNP4G-SNP5T-SNP11C.
(3)The genotypes distributions of rs2300496 and rs2300500 were statistically different between PUMCⅡAIS group and control group(P=0.0470,0.0470 respectively).
(4)The genotypes distributions of rs2300496,rs2300500 and rs3213718 were statistically different between thoracic curve group and control group(P=0.0180,0.0180,0.0402 respectively).
(5)There was no statistical difference between main curve severity and genotypes distributions of all of 12 SNPs.
Conclusion
1.Genetic variants of CALM1 gene are associated with AIS and may play an important role in the development of AIS.
2.The development of PUMCⅡAIS might be related to genotype polymorphisms of rs2300496 and rs2300500.The development of thoracic curve AIS might be related to genotype polymorphisms of rs2300496,rs2300500 and rs3213718.
3.The different clinical phenotype of AIS might be related to the different SNP site.It was preliminarily suggested that PUMC classification of AIS is not only the criterion of treatment,but also the logical combination of genetic mechanism and phenotype.
4.There was no statistically different between main curve severity and genotypes distributions of all of 12 SNPs in CALM1 gene.
5.Although it's too early to draw a conclusion,it was suggested that different clinical phenotype of AIS might be related to different SNP loci.It's the first time to research the association of genetic mechanism of AIS with to clinical classificiation.
特发性脊柱侧凸(Idiopathic scoliosis,IS)是最常见的脊柱畸形,发病率约1%～3%,其中,青少年特发性脊柱侧凸(Adolescent idiopathic scoliosis,AIS)约占80%。虽然AIS的病因还不明确,但随着分子生物学和遗传学水平的发展,AIS的遗传病因学研究逐渐深入。目前,人们普遍认为它是一种多因素作用的遗传性疾病,且有学者采用全基因扫描法将AIS相关基因定位于有限的几个染色体位点。
对于研究复杂多基因相关疾病,候选基因法、关联分析、单倍体型分析法具有先进和准确的特点,如今它们已成为群体遗传学研究和疾病相关基因检测的重要手段,能够直接、简便、准确地阐述疾病相关基因的关联性和作用机制。
另外,AIS作为一种临床表型复杂的疾病,目前尚无从不同的临床表型角度如PUMC分型,分组分层对AIS不同临床表型的遗传病因学机制进行研究的相关报道。
【研究目的】
1.通过对钙调蛋白1基因(Calmodulin 1,CALM1基因)与AIS之间的关联分析,明确其在AIS发病机制中发挥的效应。
2.通过对CALM1基因SNPs位点等位基因/基因型与AIS临床表型的关联分析,在基因水平上探索CALM1基因与AIS不同临床表型之间的关系,从遗传学上丰富AIS临床表型的内容。
3.根据研究结果提出可能的AIS病因学假说。
【研究方法】本实验采用以医院为基础的“病例-对照”研究。
1.研究对象:根据入选和排除标准选取2005年10月至2008年2月期间北京协和医院骨科收治并已确诊的汉族青少年特发性脊柱侧凸患者,共146例,其中男性24例,女性122例,平均年龄14.89岁(10～20岁)。对照组则为同期北京协和医院收治的感染或创伤患者、健康查体者等汉族患者,共146例,男性24例,女性122例,平均年龄15.18岁(10～20岁)。
2.研究方法
(1)QIAamp(?) DNA Blood Mini Kit试剂盒提取DNA;
(2)根据国际人类基因组单倍体型图计划(http://www.hapmap.org/)提供的基因型数据,应用Haploview 4.0软件选取CALM1基因的SNPs位点,优先选取杂合度高于10%,位于外显子区域或有错义突变的SNPs和位于3'-、5'-调控区的SNPs作为遗传标记、共选取14个SNPs;
(3)分别按照侧凸顶点所在位置(主弯)、PUMC分型对病例组进行分组;
(4)在所有146例AIS患者和146例对照组中应用超高通量的SNP分型系统——SNPstream UHT Genotyping System对所选SNPs进行基因型鉴定;
(5)拟合优度x2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;
(6)基于基因型/等位基因频率的“病例-对照”关联分析及病例组不同临床表型之间的关联分析;
(7)在基因型/等位基因频率关联分析基础上,应用在线软件(SNPstats)进行非条件Logistic回归模型评估单位点基因型与AIS发生风险的相关程度,并计算优势比(OR)及95%可信区间(CIs);
(8)连锁不平衡和单倍体型分析:应用Haploview 4.0软件计算CALM1基因所有单倍体型在病例组和对照组之间的分布差异。
【研究结果】
1.流行病学资料分析:病例组和对照组之间年龄、性别分布无统计学差异。
2.因rs12885713、rs5871引物设计失败,故研究中放弃这两个位点,最终对CALM1基因的12个SNPs位点进行统计分析,这12个SNPs位点均具有多态性,其等位基因和基因型在病例组和对照组中均符合Hardy-Weinberg平衡。
3.SNPs等位基因多态性—AIS:rs2300496、rs2300500和rs3213718等位基因在病例组和对照组中的分布频率统计学上存在显著差异(P值分别为0.0079,0.0079,0.0257),进一步分析得知rs2300496位点等位基因C、rs2300500位点等位基因G和rs3213718位点等位基因C与AIS的易感性升高有关。
4.基因型多态性—AIS
(1)rs2300496、rs2300500和rs3213718基因型在病例组和对照组中的分布频率统计学上存在显著差异(P值分别为0.0196,0.0196,0.0378),进一步分析得知rs2300496基因型C/C、rs2300500基因型G/G和rs3213718基因型C/C与AIS的易感性升高有关。在非条件Logistic回归分析中,经年龄和性别校正后,rs2300496和rs2300500基因型分布符合Codominant遗传模型(OR=0.12,95%CI=0.01-0.99,p=0.015,AIC=402.4)、Dominant遗传模型(OR=0.56,95%CI=0.34-0.92,p=0.022,AIC=403.6)和Log-additive遗传模型(OR=0.54,95%CI=0.35-0.86,p=0.0073,AIC=401.6),后者最佳(AIC值较小);rs3213718基因型分布符合Log-additive遗传模型(OR=0.60,95%CI=0.39-0.93,p=0.022,AIC=403.5)。
(2)单倍体-AIS:在多位点单倍体型分析中,发现1种阳性单倍体型:SNP8C-SNP1A-SNP13C-SNP14C-SNP2C-SNP3T-SNP4G-SNP5T-SNP11C。
(3)结合PUMC分型,rs2300496和rs2300500基因型在PUMCⅡ型和对照组中的分布频率统计学上存在显著差异(P值分别为0.0470,0.0470),进一步分析得知rs2300496基因型C/C、rs2300500基因型G/G与PUMCⅡ型的发生有关。
(4)结合AIS主弯顶点分析,rs2300496、rs2300500和rs3213718基因型在胸弯和对照组中的分布频率统计学上存在显著差异(P值分别为0.0180,0.0180,0.0402),进一步分析得知rs2300496基因型C/C、rs2300500基因型G/G和rs3213718基因型C/C与胸弯的发生有关。
(5)12个SNPs位点基因型与病例组主侧弯Cobb's角度数之间无统计学差异。
【结论】
1.CALM1基因遗传变异可能与青少年特发性脊柱侧凸(AIS)发生相关,有可能是影响AIS易感性的重要因素。
2.PUMCⅡ型AIS的发生可能与rs2300496和rs2300500基因型多态性有关;胸弯AIS的发生可能和rs2300496、rs2300500和rs3213718基因型多态性有关。
3.AIS不同的临床表型可能和不同的SNP位点多态性有关,初步显示AIS的PUMC分型可能和不同的SNP位点多态性有关,提示PUMC分型不仅是指导临床治疗的可靠标准,而且可能是符合遗传病因学机制的合理分型。
Background
Idiopathic scoliosis is the most common pediatric spinal deformity affecting 1%to 3%of the population,and adolescent idiopathic scoliosis(AIS) accounts for approximately 80%of these cases.The etiology of AIS is still uncertain,but with the rapid development of genetics and molecular biology in recent years,genetics researches of AIS are brought into focus gradually.Nowadays,AIS is widely believed a multifactorial inheritance disease.Recent linkage studies on familial idiopathic scoliosis revealed multiple putative predisposition loci.
As for investigating complicated multigenetic disease,candidate gene analysis, association analysis and haplotype analysis are advanced and exact methods,and they are direct and effective means of elucidating the mechanism of disease-related gene.
In addition,AIS has complex clinical phenotypes,such as PUMC classification classification,yet there are no report about the association of genetic mechanism with different clinical classifications.
Objects
1.To identify the relationship between CALM1 gene and AIS,and to investigate the major effect of CALM1 Gene in AIS patients,
2.To identify the relationship between the genotypes of SNPs and the clinical phenotypes of AIS.
3.To explore possible etiologic hypothesis contributed to the development of AIS and the different clinical phenotypes of AIS at gene level.
Methods
A hospital-based case-ontrol design was applied in this study.A total of 146 patients(24 boys,122 girls,mean age 14.89 y/o) diagnosed with adolescent idiopathic scoliosis admitted in Peking Union Medical College(PUMC) hospital were enrolled in this study according to inclusion and exclusion criteria between October 2005 and February 2008.The control group also comprised 146 patients(24 boys,122 girls,mean age 15.18 y/o) and consisted of infection(64),inflammatory disease(53),trauma(11),hypersensitive disease(6)and others(12) at PUMC hospital during the same period.All the control subjects were frequency-matched to the cases on age(±3 years),gender and the Han nationality. PUMC classification,curve pattern,cobb's angle of main curve of AIS patients were recorded.Genomic DNA was extracted from peripheral blood leukocytes of each subject who had signed informed consent with QIAamp DNA Blood Mini Kit.Based on genotype data from the international HapMap project,14 single nucleotide polymorphisms(SNPs) in calmodulin 1(CALM1) gene were initially choosed by Haploview 4.0 software.Genotyping of all selected SNPs was done by SNPstream technolofy(Beckman Coulter SNPstream).However,2 SNPs failed in composition of premier and were abandoned.All the data of 12 SNPs with polymorphism were analysed by the association analysis based on alleles and phenotypes of SNPs.Odds ratio(ORs) and 95%confidence intervals(CIs) were computed by the unconditional logistic regression to estimate the relative risk for the single locus genotypes by online software—SNPstats.Haplotype frequencies were estimated and difference in haplotype distributions between cases and controls were assessed by Haploview 4.0 software.
Results
1.Epidemiologic data analysis:there were no significant difference of age distribution and sex proportion between case group and control group.
2.We failed in composing premier of two SNPs(rs12885713,rs5871) and abandoned them in this study.The remained 12 SNPs were genotyped and all polymorphisms were in Hardy-Weinberg equilibrium between case group and contrl group.
3.SNP Allele-AIS:the allele frequency distributions of rs2300496,rs2300500 and rs3213718 were statistically different between case group and control group(P=0.0079,0.0079,0.0257 respectively).
4.SNP genotype-AIS
(1)The genotypes distributions of rs2300496,rs2300500 and rs3213718 were statistically different between caseg roup and control group(P=0.0196, 0.0196,0.0378 respectively).In the unconditional logistic regression analysis,after adjustment for age and gender,rs2300496 and rs2300500 both showed significant difference in Codominant model(OR=0.12,95%, CI=0.01-0.99,p=0.015,AIC=402.4),Dominant model(OR=0.56,95Z%,CI= 0.34-0.92,p=0.022,AIC=403.6) and Log-additive model(OR=0.54, 95%CI=0.35-0.86,p=0.0073,AIC=401.6).The Log-additive model was accepted as the best inheritance model because of the smallest AIC (Akaikeinformation) value.rs3213718 showed significant difference in Log-additive model(OR=0.60,95%CI=0.39-0.93,p=0.022,AIC=403.5).
(2)Haplotype-AIS:we got 1 positive haplotype:SNP8C-SNP1A-SNP13C-SNP14C-SNP2C-SNP3T-SNP4G-SNP5T-SNP11C.
(3)The genotypes distributions of rs2300496 and rs2300500 were statistically different between PUMCⅡAIS group and control group(P=0.0470,0.0470 respectively).
(4)The genotypes distributions of rs2300496,rs2300500 and rs3213718 were statistically different between thoracic curve group and control group(P=0.0180,0.0180,0.0402 respectively).
(5)There was no statistical difference between main curve severity and genotypes distributions of all of 12 SNPs.
Conclusion
1.Genetic variants of CALM1 gene are associated with AIS and may play an important role in the development of AIS.
2.The development of PUMCⅡAIS might be related to genotype polymorphisms of rs2300496 and rs2300500.The development of thoracic curve AIS might be related to genotype polymorphisms of rs2300496,rs2300500 and rs3213718.
3.The different clinical phenotype of AIS might be related to the different SNP site.It was preliminarily suggested that PUMC classification of AIS is not only the criterion of treatment,but also the logical combination of genetic mechanism and phenotype.
4.There was no statistically different between main curve severity and genotypes distributions of all of 12 SNPs in CALM1 gene.
5.Although it's too early to draw a conclusion,it was suggested that different clinical phenotype of AIS might be related to different SNP loci.It's the first time to research the association of genetic mechanism of AIS with to clinical classificiation.
引文
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39.Mototani H,Mabuchi A,Saito S,et al.A functional single nucleotide polymorphism in the core promoter region of CALM1 is associated with hip osteoarthritis in Japanese.Hum Mol Genet.2005,14(8):1009-17.
40.邱贵兴,仉建国,王以朋,等。特发性脊柱侧凸的PUMC(协和)分型系统。中华骨科杂志。2003,23(1):1-9。
2.Rogala EJ,Gurr J.Scoliosis:incidence and natural history.A prospective epidemiological study.J Bone Joint Surg Am,1978,60:173-176.
3.Daruwalla JS,Chay SO.Idiopathic scoliosis:prevalence and ethnic distribution in Singapore school children.J Bone Joint Surg Br,1985,67:182-184.
4.ShohatM,NitzanM.Growth and ethnicity in scoliosis.Acta Orthop Scand,1988,59:310-313.
5.Lonstein JE.Adolescent idiopathic scoliosis.Lancet,1994,344:1407-1412.
6.Soucacos PN,Soucacos PK.School-screening for scoliosis:a prospective epidemiological study in northwestern and central Greece.J Bone Joint Surg Am,1997,79:1498-1503.
7.邱贵兴,庄乾宇。青少年特发性脊柱侧凸的流行病学研究进展。中华医学杂志。2006,86(11):790-792。
8.Ratahi ED,Barnes MJ.Ethnic variance in the epidemiology of scoliosis in New Zealand.J Pediatr Orthop,2002,22:784-787.
9.Harrington PR.The etiology of idiopathic scoliosis.Clin Orthop,1977,126:17.
10.Wynne R.A genetic survey of idiopathic scoliosis in Boston,Massachusetts.J Bone Joint Surg Am,1973,55:974-982.
11.Kesling KL,Reinker KA.Scoliosis in twins:a meta-analysis of the literature and report of six cases.Spine,1997,22:2009.
12.Carr AJ.Adolescent idiopathic scoliosis in identical twins.J Bone Joint Surg Br,1990,72:1077.
13.Gaertner RL.Idiopathic scoliosis in identical(mono-zygotic) twins.SouthMed J,1979,72:231.
14.Machida M.Cause of idiopathic scoliosis.Spine.1999 24(24):2576-83.
15.Bouhoute A,Leclercq G.Calmodulin decreases the estrogen binding capacity of the estrogen receptor.Biochem Biophys Res Commun 1996;227:651-7.
16.Yamada K,Yamamoto H,Nakagawa Y,et al.Etiology of idiopathic scoliosis[J].Clin Orthop,1984,(184):50-57.
17.Sahlstrand T,Petruson B,Ortengren R.Vestibulospinal reflex activity in patients with adolescent idiopathic scoliosis.Postural effects during caloric labyrinthine stimulation recorded by stabilometry[J].Acta Orthop Scand,1979,50(3):275-281.
18.KeessenW,Crowe A,HearnM.Proprioceptive accuracy in idiopathic scoliosis[J].Spine,1992,17(2):149-155.
19.潘少川。青年型特发性脊柱侧弯(一)[J]。临床小儿外科杂志,2004,3(1):42-47。
20.邱勇,朱丽华,宋知非,等。脊柱侧凸病因学的临床分类研究[J]。中华骨科杂志,2000,20:265。
21.Riseborough EJ,Wynne-Davies R.A genetic survey of idiopathic scoliosis in Boston,Massachusetts[J].J Bone Joint Surg(Am),1973,55(5):974-982.
22.Damborg F,Engell V.The Genetics of AIS:A Twin Study[C].Proceedings of the 39th Annal SRS & Course,California.2004.
23.Wynne-Davies R.Familial(idiopathic) scoliosis:a family survey[J].J Bone Joint Surg(Br),1968,50(1):24-30.
24.袁元杏,刘尚礼,符丹。特发性脊柱侧弯2例的家谱分析[J]。中山医科大学学报,1998,19(增刊),封3。
25.Ogilvie JW,Braun J,Argyle V,et al.The search for idiopathic scoliosis genes.Spine.2006,15;31(6):679-81.
26.Cowell HR,Hall JN,MacEwen GD.Genetic aspects of idiopathic scoliosis[J].Clin Orthop,1972,86:121-131.
27.Miller NH,Schwab D,Sponseller P,et al.Genomic Search for X-Linkage in Familial Adolescent Idiopathic Scoliosis[C].Proceedings of the 10th International Philip Zorab Symposium,Oxford.1998.
28. Berven S,Fairbank J. C. T, Carr A. J, et al. On the genetics of spinal asymmetry and adolescent idiopathic scoliosis patients of deformity and heredity. J Bone Joint Surg(Br), 1997, 79-B(4S), P:452.
29. Bonaiti C, Feingold J, Briard ML, et al. Genetics of idiopathic scoliosis[J].Helv Paediatr Acta, 1976, 31(3): 229- 240.
30. Axenovich TI, Zaidman AM, Zorkoltseva IV, et al. Segregation analysis of idiopathic scoliosis: demonstration of a major gene effect[J].Am J Med Genet,1999, 86(4): 389-394.
31. Wise CA, Barnes R, Gillum J, et al.Localization of susceptibility to familial idiopathic scoliosis [J].Spine, 2000, 25 (18) : 2372- 2380.
32. Salehi LB, Mangino M, Serio SD, et al. Assignment of a locus for autosomal dominant idiopathic scoliosis (IS) to human chromosome 17p11[J]. Hum Genet,2002, 111(4): 401-404.
33. Chan V, Fong CY, Luk DK, et al.A Genetic locus for adolescent idiopathic scoliosis linked to chromosome 19p13.3 [J]. Am J Hum Genet, 2002, 71 (2): 401-406.
34. Justice CM, Miller NH, Marosy B, et al. Familial idiopathic scoliosis - evidence of an X- Linked susceptibility locus [J]. Spine, 2003, 28( 6): 589- 594.
35. Alden KJ, Marosy B, Nzegwu N, et al. Idiopathic scoliosis: identification of candidate regions on chromosome 19p13. Spine. 2006 Jul 15;31(16):1815-9
36. Miller NH, Justice CM, Marosy B, et al. Identification of candidate regions for familial idiopathic scoliosis. Spine. 2005 May 15;30(10):1181-7.
37. Hanley RM, Shenolikar S, Pollack J, et al. Identification of calcium-calmodulin multifunctional protein kinase II in rabbit kidney. Kidney Int. 1990,38(1):63-6.
38. Yarom R,Robin GC.Studies on spinal and peripheral muscles from patients with scoliosis. [J]. Spine, 1979, 4(1): 12-21.
39. Machida M, Dubousset J, Imamura Y, et al. An experimental study in chickens for the pathogenesis of idiopathic scoliosis. [J]. Spine, 1993,18( 12): 1609-15.
40. Cohen DS,Solomons CS, Lowe TG Altered platelet calmodulin activity in idiopathic scoliosis. Orthop Trans, 1985, 9:106.
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