中国汉族人群多发性硬化关联基因的筛选及FCRL3基因多态与多发性硬化相关性的研究
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摘要
目的
多发性硬化(MS)与视神经脊髓炎(NMO)是常见的中枢神经系统脱髓鞘性疾病。目前全基因组关联研究(GWAS)，除人白细胞抗原(HLA)基因外，还发现许多非HLA基因与MS相关。本研究基于国外人群MS的GWAS结果，在中国汉族人群中筛选MS的非HLA关联基因。
方法
收集2007-2012年复旦大学附属华山医院和福建医科大学附属第一医院门诊及住院确诊的MS患者154例和NMO患者109例以及对照301例。采用基质辅助激光解吸电离飞行时间质谱技术(MALDI-TOF MS)，对病例组及对照组标本的71个单核苷酸多态性(SNPs)进行分型。
结果
1、MS组与对照组比较,仅有7个SNP位点的基因频率分布存在显著统计学差异：rs11129295/EOMES(P=0.008,OR=1.559),rs2293370/TMEM39A(P=0.018,OR=0.695),rs703842/CYP27B1(P=0.036,OR=1.354),rs7522061/FCRL3(P=0.0003,OR=0.593),rs3761959/FCRL3(P=0.0005,OR=0.601),rs7528684/FCRL3(P=0.0007,OR=0.616),rs10466829/CLECL1(P=0.026,OR=0.724)；
2、NMO组与对照组比较，仅有6个SNP位点的基因频率分布存在显著统计学差异：rs1800693/TNFRSF1A(P=0.032,OR=1.574),rs7522061/FCRL3(P=0.009,OR=0.658),rs3761959/FCRL3(P=0.014,OR=0.678),rs7528684/FCRL3(P=0.026,OR=0.701),rs6937876/ATG5(P=0.023,OR=1.449),rs763361/CD226(P=0.036,OR=1.404)。
结论
1、来自高加索人群MS的GWAS结果大部分不适用中国汉族人群MS；
2、FCRL3基因是中国汉族人群中与MS关联性最强的易感基因；
3、FCRL3基因与中国汉族人群MS和NMO均具有相关性。
目的
在前部分中，我们研究发现FCRL3基因与中国汉族人群MS和NMO相关联。在这部分，我们将进一步探讨FCRL3基因与MS和NMO表型的关系，特别是与寡克隆带(OCB)和AQP4抗体(AQP4-ab)两种抗体之间的关系；初步探讨FCRL3基因在MS发病过程中的可能机制。
方法
采用等电点聚焦技术检测OCB；采用免疫荧光技术检测AQP4-ab。收集MS患者34例和对照41例的外周血单核细胞RNA标本,采用实时定量PCR技术检测标本中FCRL3基因mRNA相对表达水平。
结果
1、FCRL3基因的4个SNP位点中，rs7528684位点与rs376195位点及rs7522061位点呈强连锁关系，而rs11264799位点与前述3个SNP位点呈弱连锁关系（平均R2=0.41）。
2、逻辑回归分析结果：在显性模型中，rs7528684位点的C等位基因为MS组的保护因素（CT+CC vs TT，p=0.002,OR=0.528），而rs11264799位点的A等位基因为NMO的保护因素(AG+AA vs GG，p=0.005,OR=0.492）。
3、TG单倍体型（rs7528684和rs11264799）为MS的风险因素(p=0.003,OR=1.534),而CG单倍体型为MS组的保护因素(p=0.012,OR=0.613）;TG单倍体型为NMO组的风险因素(p=0.012, OR=1.509),而CA单倍体型为NMO组的保护因素（p=0.015, OR=0.617）。
4、rs7528684位点和rs11264799位点与MS患者起病时间（AAO）和疾病严重程度（EDSS）无关，也与NMO患者起病时间（AAO）无关。
5、在MS组中，依据0CB状态分层，rs7528684位点的基因型在阴阳性组中存在明显的统计学差异（p=0.002），rs7528684位点的C等位基因与0CB的出现呈负相关（p=1.488×10~(-4), OR=0.354）；rs7528684位点的C等位基因为0CB阳性的MS患者保护因素（p=5.650×10-6，OR=0.392），而与0CB阴性的MS患者无相关性（p=0.636）。在NMO组中，依据AQP4-ab状态分层，rs11264799位点的基因型在阴阳性组中无明显的统计学差异（p=0.383）; rs11264799位点与AQP4-ab的出现无相关性（p=0.214）。
6、在对照组中，不同基因型FCRL3基因mRNA表达存在明显的统计学差异，CC基因型较其他基因型明显增高（CC vs TT,p=0.021; CC vs CT,p=0.025）；在MS组中，不同基因型FCRL3基因mRNA表达存在明显的统计学差异（CC vsTT,p=0.013; CC vs CT,p=0.045）。对于相同基因型CC，MS组的FCRL3基因mRNA表达明显高于对照组（p=2.481×10~(-4)）；对于相同基因型CT, MS组的FCRL3基因mRNA表达明显高于对照组（p=1.982×10~(-5)）；对于相同基因型TT，MS组的FCRL3基因mRNA表达明显高于对照组（p=0.029）。
结论
1、在中国汉族MS患者中，FCRL3基因rs7528684位点的C等位基因与OCB的出现呈负相关。在中国汉族NMO患者中，FCRL3基因rs11264799位点与AQP4-ab的出现无相关性。
2、FCRL3基因rs7528684位点影响外周血单个核细胞的FCRL3mRNA表达。外周血单个核细胞的FCRL3mRNA在MS复发期表达增高，推测可能是一种保护性反应，具体机制有待进一步研究。
Objective
Multiple sclerosis (MS) and neuromyelitis optica (NMO) are common inflammatorydemyelinating diseases of the central nervous system (CNS). Recently, a number ofMS susceptibility loci were identified by genome-wide association study (GWAS).We aimed to evaluate the association of these loci with MS and NMO in the HanChinese population.
Methods
Seventy-one single nucleotide polymorphisms (SNPs) were selected and genotypedby matrix-assisted laser desorption/ionization time of flight mass spectrometry(MALDI-TOF MS) in154MS patients,109NMO patients and301controls fromsoutheastern China.
Results
1. Among these71SNPs, only7SNPs were identified to be associated with MS asfollows:rs11129295/EOMES(P=0.008,OR=1.559),rs2293370/TMEM39A(P=0.018,OR=0.695),rs703842/CYP27B1(P=0.036,OR=1.354),rs7522061/FCRL3(P=0.0003,OR=0.593),rs3761959/FCRL3(P=0.0005,OR=0.601),rs7528684/FCRL3(P=0.0007,OR=0.616),rs10466829/CLECL1(P=0.026,OR=0.724).
2. Among these71SNPs, only6SNPs were identified to be associated with NMO asfollows:rs1800693/TNFRSF1A(P=0.032,OR=1.574),rs7522061/FCRL3(P=0.009,OR=0.658),rs3761959/FCRL3(P=0.014,OR=0.678),rs7528684/FCRL3(P=0.026,OR=0.701),rs6937876/ATG5(P=0.023,OR=1.449),rs763361/CD226(P=0.036,OR=1.404).
Conclusions
1. Most of MS susceptibility loci from GWAS in Caucasians are not associated withHan Chinese MS.
2. The greatest individual impact is from FCRL3gene on MS susceptibility in theHan Chinese.
3. The variants of FCRL3are associated with MS and NMO in the Han Chinese.
Objective
In the first part of study, we found that variants of Fc receptor-like3(FCRL3) areassociated with multiple sclerosis (MS) and neuromyelitis optica (NMO) in the HanChinese. The aim of this part of study is to test association of FCRL3variants withphenotype of MS and NMO in the Han Chinese, especially with the presence ofoligoclonal bands (OCB) and AQP4antibody (AQP4-ab) and to explore the role ofFCRL3in the pathogenesis of MS.
Methods
OCB were analyzed by isoelectric focusing and AQP4-ab was detected as with animmunofluorescence assay using HEK293cells transfected with recombinant humanAQP4gene. FCRL3mRNA levels of peripheral blood morphonuclear cells (PBMC)collected from34MS cases in the relapse and41controls were measured by real-timequantitative RT-PCR.
Results
1. The rs7528684was in high linkage disequilibrium (LD) with rs752206andrs3761959, while the rs11264799, another promoter SNP, showed relatively low LDwith the above three SNPs (mean R2=0.41).
2. The rs7528684was a protective factor for MS in the dominant model (CT+CC vsTT, P=0.002, OR=0.528) but not for NMO, while the rs11264799was a protectivefactor for NMO in the dominant model (AG+AA vs GG, P=0.005, OR=0.492) but notfor MS.
3. We found that the TG haplotype (rs7528684and rs11264799) was a risk factor forMS (p=0.003, OR=1.534) and the haplotype CG was a protective factor for MS(p=0.012, OR=0.613). In NMO group, the haplotype TG was a risk factor (p=0.012, OR=1.509), while the haplotype CA was a protective factor (p=0.015, OR=0.617).
4. In this cohort, no association was found between two SNPs rs7528684andrs11264799and age at onset (AAO) and Expanded Disability Status Scale (EDSS) inMS patients and there was no significant association between the two SNPs and AAOin NMO patients.
5. After stratification for OCB status, the allele C of rs7528684was significantlylower in OCB-positive MS than-negative MS, and was negatively associated withOCB positivity (p=1.488×10~(-4), OR=0.354). However, there was no significantdifference in the genotype distribution of rs11264799between AQP4-ab positiveand-negative NMO (p=0.383) and the allel A of rs11264799was not associated withAQP4-ab positivity (p=0.214).
6. PBMC from controls CC homozygotes expressd higher levels of FCRL3mRNAthan TT homozygotes and CT heterozygotes (CC vs TT: P=0.021, CC vs CT:P=0.025). The genotype effect on FCRL3mRNA levels was also significiant in MScases (CC vs TT: P=0.013, CC vs CT: P=0.045). Moreover, threre was significantdifference in expression of FCRL3between MS and controls with the same genotype(CC: p=2.481×10~(-4); CT: p=1.982×10~(-5); TT: p=0.029).
Conclusions
1.The variants of FCRL3are associated with MS and NMO, and the allel C ofrs7528684is negtive associated with the presence of OCB in Han Chinese MSpatients.
2. SNP rs7528684influences expression of FCRL3mRNA from PBMC. PBMC fromMS patients in the relapse phase express higher levels of FCRL3mRNA than controls,which suggests a protective response.
多发性硬化(MS)与视神经脊髓炎(NMO)是常见的中枢神经系统脱髓鞘性疾病。目前全基因组关联研究(GWAS)，除人白细胞抗原(HLA)基因外，还发现许多非HLA基因与MS相关。本研究基于国外人群MS的GWAS结果，在中国汉族人群中筛选MS的非HLA关联基因。
方法
收集2007-2012年复旦大学附属华山医院和福建医科大学附属第一医院门诊及住院确诊的MS患者154例和NMO患者109例以及对照301例。采用基质辅助激光解吸电离飞行时间质谱技术(MALDI-TOF MS)，对病例组及对照组标本的71个单核苷酸多态性(SNPs)进行分型。
结果
1、MS组与对照组比较,仅有7个SNP位点的基因频率分布存在显著统计学差异：rs11129295/EOMES(P=0.008,OR=1.559),rs2293370/TMEM39A(P=0.018,OR=0.695),rs703842/CYP27B1(P=0.036,OR=1.354),rs7522061/FCRL3(P=0.0003,OR=0.593),rs3761959/FCRL3(P=0.0005,OR=0.601),rs7528684/FCRL3(P=0.0007,OR=0.616),rs10466829/CLECL1(P=0.026,OR=0.724)；
2、NMO组与对照组比较，仅有6个SNP位点的基因频率分布存在显著统计学差异：rs1800693/TNFRSF1A(P=0.032,OR=1.574),rs7522061/FCRL3(P=0.009,OR=0.658),rs3761959/FCRL3(P=0.014,OR=0.678),rs7528684/FCRL3(P=0.026,OR=0.701),rs6937876/ATG5(P=0.023,OR=1.449),rs763361/CD226(P=0.036,OR=1.404)。
结论
1、来自高加索人群MS的GWAS结果大部分不适用中国汉族人群MS；
2、FCRL3基因是中国汉族人群中与MS关联性最强的易感基因；
3、FCRL3基因与中国汉族人群MS和NMO均具有相关性。
目的
在前部分中，我们研究发现FCRL3基因与中国汉族人群MS和NMO相关联。在这部分，我们将进一步探讨FCRL3基因与MS和NMO表型的关系，特别是与寡克隆带(OCB)和AQP4抗体(AQP4-ab)两种抗体之间的关系；初步探讨FCRL3基因在MS发病过程中的可能机制。
方法
采用等电点聚焦技术检测OCB；采用免疫荧光技术检测AQP4-ab。收集MS患者34例和对照41例的外周血单核细胞RNA标本,采用实时定量PCR技术检测标本中FCRL3基因mRNA相对表达水平。
结果
1、FCRL3基因的4个SNP位点中，rs7528684位点与rs376195位点及rs7522061位点呈强连锁关系，而rs11264799位点与前述3个SNP位点呈弱连锁关系（平均R2=0.41）。
2、逻辑回归分析结果：在显性模型中，rs7528684位点的C等位基因为MS组的保护因素（CT+CC vs TT，p=0.002,OR=0.528），而rs11264799位点的A等位基因为NMO的保护因素(AG+AA vs GG，p=0.005,OR=0.492）。
3、TG单倍体型（rs7528684和rs11264799）为MS的风险因素(p=0.003,OR=1.534),而CG单倍体型为MS组的保护因素(p=0.012,OR=0.613）;TG单倍体型为NMO组的风险因素(p=0.012, OR=1.509),而CA单倍体型为NMO组的保护因素（p=0.015, OR=0.617）。
4、rs7528684位点和rs11264799位点与MS患者起病时间（AAO）和疾病严重程度（EDSS）无关，也与NMO患者起病时间（AAO）无关。
5、在MS组中，依据0CB状态分层，rs7528684位点的基因型在阴阳性组中存在明显的统计学差异（p=0.002），rs7528684位点的C等位基因与0CB的出现呈负相关（p=1.488×10~(-4), OR=0.354）；rs7528684位点的C等位基因为0CB阳性的MS患者保护因素（p=5.650×10-6，OR=0.392），而与0CB阴性的MS患者无相关性（p=0.636）。在NMO组中，依据AQP4-ab状态分层，rs11264799位点的基因型在阴阳性组中无明显的统计学差异（p=0.383）; rs11264799位点与AQP4-ab的出现无相关性（p=0.214）。
6、在对照组中，不同基因型FCRL3基因mRNA表达存在明显的统计学差异，CC基因型较其他基因型明显增高（CC vs TT,p=0.021; CC vs CT,p=0.025）；在MS组中，不同基因型FCRL3基因mRNA表达存在明显的统计学差异（CC vsTT,p=0.013; CC vs CT,p=0.045）。对于相同基因型CC，MS组的FCRL3基因mRNA表达明显高于对照组（p=2.481×10~(-4)）；对于相同基因型CT, MS组的FCRL3基因mRNA表达明显高于对照组（p=1.982×10~(-5)）；对于相同基因型TT，MS组的FCRL3基因mRNA表达明显高于对照组（p=0.029）。
结论
1、在中国汉族MS患者中，FCRL3基因rs7528684位点的C等位基因与OCB的出现呈负相关。在中国汉族NMO患者中，FCRL3基因rs11264799位点与AQP4-ab的出现无相关性。
2、FCRL3基因rs7528684位点影响外周血单个核细胞的FCRL3mRNA表达。外周血单个核细胞的FCRL3mRNA在MS复发期表达增高，推测可能是一种保护性反应，具体机制有待进一步研究。
Objective
Multiple sclerosis (MS) and neuromyelitis optica (NMO) are common inflammatorydemyelinating diseases of the central nervous system (CNS). Recently, a number ofMS susceptibility loci were identified by genome-wide association study (GWAS).We aimed to evaluate the association of these loci with MS and NMO in the HanChinese population.
Methods
Seventy-one single nucleotide polymorphisms (SNPs) were selected and genotypedby matrix-assisted laser desorption/ionization time of flight mass spectrometry(MALDI-TOF MS) in154MS patients,109NMO patients and301controls fromsoutheastern China.
Results
1. Among these71SNPs, only7SNPs were identified to be associated with MS asfollows:rs11129295/EOMES(P=0.008,OR=1.559),rs2293370/TMEM39A(P=0.018,OR=0.695),rs703842/CYP27B1(P=0.036,OR=1.354),rs7522061/FCRL3(P=0.0003,OR=0.593),rs3761959/FCRL3(P=0.0005,OR=0.601),rs7528684/FCRL3(P=0.0007,OR=0.616),rs10466829/CLECL1(P=0.026,OR=0.724).
2. Among these71SNPs, only6SNPs were identified to be associated with NMO asfollows:rs1800693/TNFRSF1A(P=0.032,OR=1.574),rs7522061/FCRL3(P=0.009,OR=0.658),rs3761959/FCRL3(P=0.014,OR=0.678),rs7528684/FCRL3(P=0.026,OR=0.701),rs6937876/ATG5(P=0.023,OR=1.449),rs763361/CD226(P=0.036,OR=1.404).
Conclusions
1. Most of MS susceptibility loci from GWAS in Caucasians are not associated withHan Chinese MS.
2. The greatest individual impact is from FCRL3gene on MS susceptibility in theHan Chinese.
3. The variants of FCRL3are associated with MS and NMO in the Han Chinese.
Objective
In the first part of study, we found that variants of Fc receptor-like3(FCRL3) areassociated with multiple sclerosis (MS) and neuromyelitis optica (NMO) in the HanChinese. The aim of this part of study is to test association of FCRL3variants withphenotype of MS and NMO in the Han Chinese, especially with the presence ofoligoclonal bands (OCB) and AQP4antibody (AQP4-ab) and to explore the role ofFCRL3in the pathogenesis of MS.
Methods
OCB were analyzed by isoelectric focusing and AQP4-ab was detected as with animmunofluorescence assay using HEK293cells transfected with recombinant humanAQP4gene. FCRL3mRNA levels of peripheral blood morphonuclear cells (PBMC)collected from34MS cases in the relapse and41controls were measured by real-timequantitative RT-PCR.
Results
1. The rs7528684was in high linkage disequilibrium (LD) with rs752206andrs3761959, while the rs11264799, another promoter SNP, showed relatively low LDwith the above three SNPs (mean R2=0.41).
2. The rs7528684was a protective factor for MS in the dominant model (CT+CC vsTT, P=0.002, OR=0.528) but not for NMO, while the rs11264799was a protectivefactor for NMO in the dominant model (AG+AA vs GG, P=0.005, OR=0.492) but notfor MS.
3. We found that the TG haplotype (rs7528684and rs11264799) was a risk factor forMS (p=0.003, OR=1.534) and the haplotype CG was a protective factor for MS(p=0.012, OR=0.613). In NMO group, the haplotype TG was a risk factor (p=0.012, OR=1.509), while the haplotype CA was a protective factor (p=0.015, OR=0.617).
4. In this cohort, no association was found between two SNPs rs7528684andrs11264799and age at onset (AAO) and Expanded Disability Status Scale (EDSS) inMS patients and there was no significant association between the two SNPs and AAOin NMO patients.
5. After stratification for OCB status, the allele C of rs7528684was significantlylower in OCB-positive MS than-negative MS, and was negatively associated withOCB positivity (p=1.488×10~(-4), OR=0.354). However, there was no significantdifference in the genotype distribution of rs11264799between AQP4-ab positiveand-negative NMO (p=0.383) and the allel A of rs11264799was not associated withAQP4-ab positivity (p=0.214).
6. PBMC from controls CC homozygotes expressd higher levels of FCRL3mRNAthan TT homozygotes and CT heterozygotes (CC vs TT: P=0.021, CC vs CT:P=0.025). The genotype effect on FCRL3mRNA levels was also significiant in MScases (CC vs TT: P=0.013, CC vs CT: P=0.045). Moreover, threre was significantdifference in expression of FCRL3between MS and controls with the same genotype(CC: p=2.481×10~(-4); CT: p=1.982×10~(-5); TT: p=0.029).
Conclusions
1.The variants of FCRL3are associated with MS and NMO, and the allel C ofrs7528684is negtive associated with the presence of OCB in Han Chinese MSpatients.
2. SNP rs7528684influences expression of FCRL3mRNA from PBMC. PBMC fromMS patients in the relapse phase express higher levels of FCRL3mRNA than controls,which suggests a protective response.
引文
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