免疫性血小板减少症遗传易感性的初步研究
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摘要
研究背景及目的：非受体型蛋白酪氨酸磷酸酶22(protein tyrosine phosphatase, non-receptor type22, PTPN22)基因编码产物为淋巴酪氨酸磷酸酶(Lymphoid tyrosine phosphatase, LYP),该酶能够对T细胞活化信号转导起负向调控作用。近年的研究表明PTPN22多态性和多种自身免疫性疾病患病风险有关。免疫性血小板减少症(Immune Thrombocytopenia, ITP)是一种获得性器官特异性自身免疫性疾病,本研究的目的是探讨PTPN22基因多态性与ITP遗传易感性的关系。
研究方法：病例对照研究。采用聚合酶链反应-基质辅助激光解析电离飞行时间质谱技术(PCR-MALDI-TOF MS)对191例ITP患者和216例健康对照PTPN22基因-1123G>C(rs2488457)位点进行基因型鉴定分析。
结果：PTPN22-1123G>C位点优势等位基因为C,健康对照人群中C、G等位基因频率比70.6%：29.4%。ITP组-1123G>C位点等位基因G及GG基因型频率分布显著高于正常对照组(P=0.034；P=0.038)；G、GG、GC的优势比(OR)及95%置信区间(95%CI)分别为1.374(1.024～1.843),1.951(1.031-3.694),1.253(0.825～1.902)。分层分析结果：男性患者组G、GG频率显著高于同性别对照组(P=0.008, P=0.022), OR(95%CI)分别为1.849(1.174～2.911),3.152(1.143～8.692)。成人ITP组G、GG频率显著高于正常对照(P=0.042；P=0.048),OR(95%CI)分别为1.410(1.012-1.964),2.030(0.998～4.132)。慢性ITP组G、GG频率较对照组有升高趋势但无统计学意义(P=-0.082,P=0.081)。女性对照组-1123G的发生频率高于男性对照组,二者之间存在临界显著性差异(P=0.055)。
结论：研究证实PTPN22-1123G>C多态性和ITP遗传易感性相关,G为ITP患病的风险等位基因,并且患病风险的高低和G等位基因携带率呈剂量依赖关系；-1123G在各组ITP中起到的作用可能不同,我们的结果提示女性人群PTPN22-1123G的高水平分布可能是ITP在女性总体发病率较高的遗传学基础之一；目前至少可以肯定-1123G是男性ITP、成人ITP风险预测因素；-1123G可能对ITP病程的慢性转归具有一定预测价值,但该结论尚需进一步扩大样本量证实
研究背景和目的：干扰素(interferons, IFNs)是调节机体初始免疫应答和适应性免疫应答的重要因素,研究表明在系统性红斑狼疮、干燥综合症等自身免疫性疾病发病机制中,I型干扰素系统功能上调发挥至关重要的作用。干扰素调节因子5(interferon regulation factor5, IRF5)参与Ⅰ型干扰素分子的诱导生成及其效应阶段,是调控Ⅰ型干扰素分子和炎症因子表达的最重要的转录因子；信号转导子及转录激活子4(signal transducer and activator of transcription4, STAT4)介导淋巴细胞对Ⅰ型干扰素、白介素-12(IL-12)、白介素-23(IL-23)的信号转导过程,调控Th1、Th17分化；酪氨酸激酶2(tyrosine kinase2,TYK2)通过与JAK2(Janus kinase2)相互作用结合于Ⅰ型干扰素受体复合物,并启动JAK/STAT信号转导级联反应,调控干扰素相关基因的表达。IRF5、STAT4、TYK2三者均是!型干扰素系统的重要组分。免疫性血小板减少症(ITP)是一种器官特异性自身免疫性疾病,有报道指出,ITP患者IFN信号通路功能存在异常。本研究的目的是探讨IRF5、STAT4、TYK2基因多态性和ITP遗传易感性的关系。
研究方法：病例对照研究。采用聚合酶链反应-琼脂糖凝胶电泳分离方法检测IRF5基因3*/4*CGGGG、30bpIn/Del序列长度多态性位点基因型；采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法检测rs3821236、rs2304256位点基因型；采用聚合酶链反应-基质辅助激光解析电离飞行时间质谱技术(PCR-MALDI-TOF MS)检测rs10954231、rs7574865位点基因型。受试者共包括ITP患者159名,健康对照196名。
结果：1)30bpIn/De1、rs7574865、rs3821236及rs2304256位点的等位基因及基因型频率分布在ITP组和正常对照组之间存在显著性差异(P<0.05)；2)rs7574865、rs3821236之间存在连锁不平衡关系,产生的两种主要单元型在ITP及对照组间频率分布存在显著性差异[P=0.04, OR=1.413(1.013-1.971); P=0.02, OR=0.707(0.525-0.951)];3)将患者依据性别、起病年龄及病程因素分组进行分层分析,结果表明各位点与ITP发病风险的关联性并不局限于特定的分组；4)协同分析表明,各位点之间存在协同作用,同时携带多位点风险等位基因将提高ITP发病风险
结论：位于IRF5、STAT4、TYK2基因的多态性位点30bpIn/Del、rs7574865、 rs3821236及rs2304256和ITP的遗传易感性相关；且各位点之间能够以协同作用方式增加ITP的患病风险；IRF5、STAT4、TYK2基因是Ⅰ型干扰素系统的重要组分,推测Ⅰ型干扰素系统功能失调是ITP发病的重要机制
研究背景及目的：凝血因子Ⅴ、Ⅷ (FⅤ、FⅧ)联合缺乏症(F5F8D)是一种罕见的常染色体隐性遗传性出血性疾病。近年的研究发现该病病因在于基因lman1或mcfd2的突变。本研究的目的是对一个F5F8D先证者及其家系成员的lman1、mcfd2基因进行扩增、测序,以查找潜在的致病突变。
研究方法：我们采集了先证者及其父母的外周血样本,进行了凝血功能相关检查,包括活化部分凝血活酶时间(APTT)、凝血酶原时间(PT)、凝血酶时间(TT)、血浆纤维蛋白原(Fg)、FV促凝活性(FV:C)、FⅧ促凝活性(FVIII:C);并提取基因组DNA,通过PCR法对先证者lman1基因的13个外显子及侧翼序列、mcfd2基因的4个外显子及侧翼序列进行特异性扩增,产物经纯化后直接测序,以检测致病突变。根据先证者突变所在位点,选择性扩增其父、母的相应片段,纯化、测序,以便进行家系分析。
结果：先证者APTT82.2S, PT19.6S, TT18.6S, Fg2.9g/1, FV:C7.1%, FⅧ:C18.7%；先证者及其母亲lman1基因第8外显子区出现杂合性单碱基插入c.912_913insA,导致蛋白序列改变p.Glu305fsX20;先证者及其父亲lmanl基因11外显子区出现杂合性无义突变c.1366C>T,导致p.Arg456X。
结论：先证者lman1基因的复合杂合突变c.912_913insA、c.1366C>T是导致其发病的原因；前者继承自其母,后者继承自其父。这种复合杂合突变的组合方式尚未见报道。
Background and objective:Lymphoid tyrosine phosphatase (LYP) is a protein tyrosine phosphatase (PTP) encoded by the gene of protein tyrosine phosphatase nonreceptor22(PTPN22). LYP plays a negative role in T cell signaling. The polymorphisms of PTPN22gene have been reported to be associated with susceptibilities to numerous autoimmune diseases. Immune Thrombocytopenia (ITP) is an acquired organ-specific autoimmune disease. The purpose of this study was to investigate whether the PTPN22-1123C>G polymorphism contributes to risk of ITP.
Method:Genotyping of PTPN22-1123G>C (rs2488457) polymorphism was performed using polymerase chain reaction-matrix assisted laser desorption/ionization time-of-flight mass spectrometry (PCR-MALDI-TOF MS). Total subjects of191ITP patients and216healthy controls were enrolled in the case-control study.
Results:The major allele of the-1123site was C, with a frequency of70.6%vs.29.4%for allele G in normal controls. The allele and genotype distribution of-1123G>C was significantly skewed in ITP patients, who had significantly higher frequencies of G allele and GG genotype than normal control (P=0.034; P=0.038). Odds ratios (ORs) and95%confidence interval (95%CI) for G allele, GG and GC genotypes were1.374(1.024～1.843),1.951(1.031～3.694),1.253(0.825～1.902), respectively. Comparable observations were made in the stratified analysis. Both subgroups of male and adult-onset patients exhibited significantly elevated distribution of G allele and GG genotype accompanied with increased ORs for developing ITP when comparing with matched controls. Similar trend occurred in cohort of chronic patients, with a P value of almost0.08. The-1123G frequency is higher in female controls than in male ones, with a borderline P value of0.055.
Conclusion:Our results demonstrate that PTPN22-1123G is a susceptibility factor to developing ITP. And it works in a dose-dependent manner.-1123G>C polymorphism might play different roles in distinct ITP cohorts. Higher frequency of-1123G might be an important genetic risk factor for the increased incidence of ITP in female. It is confirmed at least that-1123G can be used as an independent predictor for male ITP and adult-onset ITP. Whether or not does-1123G contribute to chronic ITP needs to be further studied by larger samples.
Background and objective:Interferons (IFNs) are the most pleiotropic molecules which influence both the innate and adaptive immune responses. In the past decades, extensive studies revealed crucial roles for type Ⅰ IFN in pathogenesis of SLE and Sjogren's syndrome. Interferon regulatory factor5(IRF5) is a member of IRF family that plays an important role as a master transcription factor for genes of inflammatory cytokines and type Ⅰ interferon. The signal transducer and activator of transcription4(STAT4) could be activated by cytokines, including type Ⅰ IFN, interleukin-12and interleukin-23, then stimulates the differentiation of Thl and Th17. Tyrosine kinase2(TYK2) binds to the type Ⅰ IFN receptor complex with JAK1and initiates a JAK/STAT signaling cascade leading to the transcription of IFN signature genes. All of the three mentiend above are important components of the type Ⅰ IFN system. ITP is an organ-specific autoimmune disease. It was proposed that IFN system may involved in pathogenesis of ITP. The aim of the study was to determine the associations between polymorphisms of the three genes with ITP.
Method:Genotyping of length polymorphisms3*/4*CGGGG and30bpIn/Del in IRF5was performed using polymerase chain reaction followed by agarose gels electrophoresis. rs3821236and rs2304256were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay, while rs10954231and rs7574865by means of polymerase chain reaction-matrix assisted laser desorption/ionization time-of-flight mass spectrometry (PCR-MALDI-TOF MS). Total subjects of159ITP patients and196healthy controls were enrolled in the case-control study.
Result:Polymorphisms of IRF530bpIn/Del, TYK2rs2304256, STAT4rs7574865and rs3821236were shown to be associated with ITP (P=0.024,0.036,0.029,0.019, respectively). These associations were not restricted to a particular phenotype after the stratified analysis. We also investigated an addictive effect of the four polymorphisms on the risk for developing ITP.
Conclusion:Polymorphisms of30bpIn/Del, rs7574865, rs3821236and rs2304256correlated with susceptibility to Immune Thrombocytopenia. As all the polymorphisms located in genes related to type ⅠIFN system, we supposed that type Ⅰ IFN system dysfunction may be an important aspect of ITP pathogenesis.
Combined factor Ⅴ-factor Ⅷ deficiency (F5F8D) is a rare, autosomal recessive disorder caused by mutations in genes of either lmanl or mcfd2. To identify mutations of these two genes in a Chinese F5F8D family, samples of peripheral blood were collected from the proband and her parents. Coagulation tests were carried out including activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), fibrinogen(Fg) and coagulate activity of FⅤ, FⅧ (FⅤ:C, FⅧ:C). The genomic DNA was extracted, then, all the exons and intron/exon boundaries of these two genes were amplified by polymerase chain reaction (PCR). The products were finally analyzed by direct sequencing. According to the laboratory report, the proband's APTT, PT, TT, Fg, FⅤ:C and FⅧ：C were82.2S,19.6S,18.6S,2.9g/l,7.1%and18.7%respectively, while those of the parents' were all between the normal range. Two pathogenic mutations were identified in lmanl gene of the proband:one was the heterozygous c.912_913insA in exon8resulting in a frameshift of p.Glu305fsX20; the other was the heterozygous c.1366C>T in exon11resulting in p.Arg456X.The proband's father and mother were heterozygous for c.1366C>T and c.912_913insA respectively. So we drew a conclusion that F5F8D of the proband was caused by a novel compound heterozygosity of the lmanl gene, which had never been reported.
研究方法：病例对照研究。采用聚合酶链反应-基质辅助激光解析电离飞行时间质谱技术(PCR-MALDI-TOF MS)对191例ITP患者和216例健康对照PTPN22基因-1123G>C(rs2488457)位点进行基因型鉴定分析。
结果：PTPN22-1123G>C位点优势等位基因为C,健康对照人群中C、G等位基因频率比70.6%：29.4%。ITP组-1123G>C位点等位基因G及GG基因型频率分布显著高于正常对照组(P=0.034；P=0.038)；G、GG、GC的优势比(OR)及95%置信区间(95%CI)分别为1.374(1.024～1.843),1.951(1.031-3.694),1.253(0.825～1.902)。分层分析结果：男性患者组G、GG频率显著高于同性别对照组(P=0.008, P=0.022), OR(95%CI)分别为1.849(1.174～2.911),3.152(1.143～8.692)。成人ITP组G、GG频率显著高于正常对照(P=0.042；P=0.048),OR(95%CI)分别为1.410(1.012-1.964),2.030(0.998～4.132)。慢性ITP组G、GG频率较对照组有升高趋势但无统计学意义(P=-0.082,P=0.081)。女性对照组-1123G的发生频率高于男性对照组,二者之间存在临界显著性差异(P=0.055)。
结论：研究证实PTPN22-1123G>C多态性和ITP遗传易感性相关,G为ITP患病的风险等位基因,并且患病风险的高低和G等位基因携带率呈剂量依赖关系；-1123G在各组ITP中起到的作用可能不同,我们的结果提示女性人群PTPN22-1123G的高水平分布可能是ITP在女性总体发病率较高的遗传学基础之一；目前至少可以肯定-1123G是男性ITP、成人ITP风险预测因素；-1123G可能对ITP病程的慢性转归具有一定预测价值,但该结论尚需进一步扩大样本量证实
研究背景和目的：干扰素(interferons, IFNs)是调节机体初始免疫应答和适应性免疫应答的重要因素,研究表明在系统性红斑狼疮、干燥综合症等自身免疫性疾病发病机制中,I型干扰素系统功能上调发挥至关重要的作用。干扰素调节因子5(interferon regulation factor5, IRF5)参与Ⅰ型干扰素分子的诱导生成及其效应阶段,是调控Ⅰ型干扰素分子和炎症因子表达的最重要的转录因子；信号转导子及转录激活子4(signal transducer and activator of transcription4, STAT4)介导淋巴细胞对Ⅰ型干扰素、白介素-12(IL-12)、白介素-23(IL-23)的信号转导过程,调控Th1、Th17分化；酪氨酸激酶2(tyrosine kinase2,TYK2)通过与JAK2(Janus kinase2)相互作用结合于Ⅰ型干扰素受体复合物,并启动JAK/STAT信号转导级联反应,调控干扰素相关基因的表达。IRF5、STAT4、TYK2三者均是!型干扰素系统的重要组分。免疫性血小板减少症(ITP)是一种器官特异性自身免疫性疾病,有报道指出,ITP患者IFN信号通路功能存在异常。本研究的目的是探讨IRF5、STAT4、TYK2基因多态性和ITP遗传易感性的关系。
研究方法：病例对照研究。采用聚合酶链反应-琼脂糖凝胶电泳分离方法检测IRF5基因3*/4*CGGGG、30bpIn/Del序列长度多态性位点基因型；采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法检测rs3821236、rs2304256位点基因型；采用聚合酶链反应-基质辅助激光解析电离飞行时间质谱技术(PCR-MALDI-TOF MS)检测rs10954231、rs7574865位点基因型。受试者共包括ITP患者159名,健康对照196名。
结果：1)30bpIn/De1、rs7574865、rs3821236及rs2304256位点的等位基因及基因型频率分布在ITP组和正常对照组之间存在显著性差异(P<0.05)；2)rs7574865、rs3821236之间存在连锁不平衡关系,产生的两种主要单元型在ITP及对照组间频率分布存在显著性差异[P=0.04, OR=1.413(1.013-1.971); P=0.02, OR=0.707(0.525-0.951)];3)将患者依据性别、起病年龄及病程因素分组进行分层分析,结果表明各位点与ITP发病风险的关联性并不局限于特定的分组；4)协同分析表明,各位点之间存在协同作用,同时携带多位点风险等位基因将提高ITP发病风险
结论：位于IRF5、STAT4、TYK2基因的多态性位点30bpIn/Del、rs7574865、 rs3821236及rs2304256和ITP的遗传易感性相关；且各位点之间能够以协同作用方式增加ITP的患病风险；IRF5、STAT4、TYK2基因是Ⅰ型干扰素系统的重要组分,推测Ⅰ型干扰素系统功能失调是ITP发病的重要机制
研究背景及目的：凝血因子Ⅴ、Ⅷ (FⅤ、FⅧ)联合缺乏症(F5F8D)是一种罕见的常染色体隐性遗传性出血性疾病。近年的研究发现该病病因在于基因lman1或mcfd2的突变。本研究的目的是对一个F5F8D先证者及其家系成员的lman1、mcfd2基因进行扩增、测序,以查找潜在的致病突变。
研究方法：我们采集了先证者及其父母的外周血样本,进行了凝血功能相关检查,包括活化部分凝血活酶时间(APTT)、凝血酶原时间(PT)、凝血酶时间(TT)、血浆纤维蛋白原(Fg)、FV促凝活性(FV:C)、FⅧ促凝活性(FVIII:C);并提取基因组DNA,通过PCR法对先证者lman1基因的13个外显子及侧翼序列、mcfd2基因的4个外显子及侧翼序列进行特异性扩增,产物经纯化后直接测序,以检测致病突变。根据先证者突变所在位点,选择性扩增其父、母的相应片段,纯化、测序,以便进行家系分析。
结果：先证者APTT82.2S, PT19.6S, TT18.6S, Fg2.9g/1, FV:C7.1%, FⅧ:C18.7%；先证者及其母亲lman1基因第8外显子区出现杂合性单碱基插入c.912_913insA,导致蛋白序列改变p.Glu305fsX20;先证者及其父亲lmanl基因11外显子区出现杂合性无义突变c.1366C>T,导致p.Arg456X。
结论：先证者lman1基因的复合杂合突变c.912_913insA、c.1366C>T是导致其发病的原因；前者继承自其母,后者继承自其父。这种复合杂合突变的组合方式尚未见报道。
Background and objective:Lymphoid tyrosine phosphatase (LYP) is a protein tyrosine phosphatase (PTP) encoded by the gene of protein tyrosine phosphatase nonreceptor22(PTPN22). LYP plays a negative role in T cell signaling. The polymorphisms of PTPN22gene have been reported to be associated with susceptibilities to numerous autoimmune diseases. Immune Thrombocytopenia (ITP) is an acquired organ-specific autoimmune disease. The purpose of this study was to investigate whether the PTPN22-1123C>G polymorphism contributes to risk of ITP.
Method:Genotyping of PTPN22-1123G>C (rs2488457) polymorphism was performed using polymerase chain reaction-matrix assisted laser desorption/ionization time-of-flight mass spectrometry (PCR-MALDI-TOF MS). Total subjects of191ITP patients and216healthy controls were enrolled in the case-control study.
Results:The major allele of the-1123site was C, with a frequency of70.6%vs.29.4%for allele G in normal controls. The allele and genotype distribution of-1123G>C was significantly skewed in ITP patients, who had significantly higher frequencies of G allele and GG genotype than normal control (P=0.034; P=0.038). Odds ratios (ORs) and95%confidence interval (95%CI) for G allele, GG and GC genotypes were1.374(1.024～1.843),1.951(1.031～3.694),1.253(0.825～1.902), respectively. Comparable observations were made in the stratified analysis. Both subgroups of male and adult-onset patients exhibited significantly elevated distribution of G allele and GG genotype accompanied with increased ORs for developing ITP when comparing with matched controls. Similar trend occurred in cohort of chronic patients, with a P value of almost0.08. The-1123G frequency is higher in female controls than in male ones, with a borderline P value of0.055.
Conclusion:Our results demonstrate that PTPN22-1123G is a susceptibility factor to developing ITP. And it works in a dose-dependent manner.-1123G>C polymorphism might play different roles in distinct ITP cohorts. Higher frequency of-1123G might be an important genetic risk factor for the increased incidence of ITP in female. It is confirmed at least that-1123G can be used as an independent predictor for male ITP and adult-onset ITP. Whether or not does-1123G contribute to chronic ITP needs to be further studied by larger samples.
Background and objective:Interferons (IFNs) are the most pleiotropic molecules which influence both the innate and adaptive immune responses. In the past decades, extensive studies revealed crucial roles for type Ⅰ IFN in pathogenesis of SLE and Sjogren's syndrome. Interferon regulatory factor5(IRF5) is a member of IRF family that plays an important role as a master transcription factor for genes of inflammatory cytokines and type Ⅰ interferon. The signal transducer and activator of transcription4(STAT4) could be activated by cytokines, including type Ⅰ IFN, interleukin-12and interleukin-23, then stimulates the differentiation of Thl and Th17. Tyrosine kinase2(TYK2) binds to the type Ⅰ IFN receptor complex with JAK1and initiates a JAK/STAT signaling cascade leading to the transcription of IFN signature genes. All of the three mentiend above are important components of the type Ⅰ IFN system. ITP is an organ-specific autoimmune disease. It was proposed that IFN system may involved in pathogenesis of ITP. The aim of the study was to determine the associations between polymorphisms of the three genes with ITP.
Method:Genotyping of length polymorphisms3*/4*CGGGG and30bpIn/Del in IRF5was performed using polymerase chain reaction followed by agarose gels electrophoresis. rs3821236and rs2304256were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay, while rs10954231and rs7574865by means of polymerase chain reaction-matrix assisted laser desorption/ionization time-of-flight mass spectrometry (PCR-MALDI-TOF MS). Total subjects of159ITP patients and196healthy controls were enrolled in the case-control study.
Result:Polymorphisms of IRF530bpIn/Del, TYK2rs2304256, STAT4rs7574865and rs3821236were shown to be associated with ITP (P=0.024,0.036,0.029,0.019, respectively). These associations were not restricted to a particular phenotype after the stratified analysis. We also investigated an addictive effect of the four polymorphisms on the risk for developing ITP.
Conclusion:Polymorphisms of30bpIn/Del, rs7574865, rs3821236and rs2304256correlated with susceptibility to Immune Thrombocytopenia. As all the polymorphisms located in genes related to type ⅠIFN system, we supposed that type Ⅰ IFN system dysfunction may be an important aspect of ITP pathogenesis.
Combined factor Ⅴ-factor Ⅷ deficiency (F5F8D) is a rare, autosomal recessive disorder caused by mutations in genes of either lmanl or mcfd2. To identify mutations of these two genes in a Chinese F5F8D family, samples of peripheral blood were collected from the proband and her parents. Coagulation tests were carried out including activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), fibrinogen(Fg) and coagulate activity of FⅤ, FⅧ (FⅤ:C, FⅧ:C). The genomic DNA was extracted, then, all the exons and intron/exon boundaries of these two genes were amplified by polymerase chain reaction (PCR). The products were finally analyzed by direct sequencing. According to the laboratory report, the proband's APTT, PT, TT, Fg, FⅤ:C and FⅧ：C were82.2S,19.6S,18.6S,2.9g/l,7.1%and18.7%respectively, while those of the parents' were all between the normal range. Two pathogenic mutations were identified in lmanl gene of the proband:one was the heterozygous c.912_913insA in exon8resulting in a frameshift of p.Glu305fsX20; the other was the heterozygous c.1366C>T in exon11resulting in p.Arg456X.The proband's father and mother were heterozygous for c.1366C>T and c.912_913insA respectively. So we drew a conclusion that F5F8D of the proband was caused by a novel compound heterozygosity of the lmanl gene, which had never been reported.
引文
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