SLE相关候选基因FCRL3，SLAM的SNP分析及其功能研究
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摘要
随着人类基因组计划的完成,有关个体遗传变异与疾病的关系日益受到重视,单核苷酸多态性(SNP)是人类基因组中遗传学变异最常见的一种类型,也是决定不同个体临床表型多样性的重要因素。因此对复杂性疾病进行SNP研究对于临床上早期诊断、预防和治疗这类疾病有重要意义。
SLE是一种典型的自身免疫疾病,其主要病理生理学过程为大量自身抗体产生,补体激活,免疫复合物的沉积从而导致组织和器官的损伤。尽管SLE的发病机制目前并不十分清楚,但是现已达成共识:SLE是遗传因素和环境因素共同作用的结果,其遗传学模式非常复杂,多个基因参与其发病机制。目前已有研究表明Fc受体样基因3(FCRL3)及信号转导淋巴细胞激活分子(SLAM)基因参与了SLE的发病机制。然而,这两个基因多态性位点与中国人群SLE的易感性尚未有研究。我们选择上述两个基因作为候选基因,拟在中国SLE人群中筛查其SNP分布及频率,并对阳性关联SNP位点的生物学意义进行初步实验研究。本研究收集了248名SLE患者及278名正常对照,采用PCR-限制性片段长度多态性(RFLP)在中国SLE人群对FCRL3基因4个SNPs (-169A/G, -110C/T, +358C/G及+1381C/T)及SLAM基因4个SNPs (-262A/T, -188A/G, -112C/T及+116A/C)进行了病例-对照研究。等位基因频率直接由基因型计算,Hardy-Weinberg平衡由χ2检验检测,以p>0.05为符合Hardy-Weinberg平衡,两组间的差异由列联表χ2检测,通过LDA软件检测连锁不平衡,PHASE软件分析单倍型。对发现的与SLE相关的SLAM基因5’非翻译区两种单倍型(-262A-188G,-262T-188A)进行了初步的功能研究,即通过荧光素酶报告基因实验分析不同单倍型转录调控功能是否具有差异,电泳迁移率实验(EMSA)体外分析不同等位的寡核苷酸结合核蛋白的能力,并通过在不同基因型SLE患者中检测SLAM基因mRNA及蛋白的表达,分析SLAM基因启动子区不同单倍型对SLAM基因转录及表达的影响。
研究主要结果如下:
1. FCLR3基因4个SNP位点(-169A/G, -110C/T, +358C/G和+1381C/T)在病例组和对照组中的基因型频率分布无明显差异(p值分别为0.227,0.444,0.412,0.167),ACCC、GTGT、GCGT这三种主要的单倍型在正常对照及SLE患者中分布无显著差异(p值分别为0.943,0.084,0.387),FCRL3基因4个SNP位点等位基因分布频率与SLE患者ANA无相关性(p>0.05)。
2.在248名SLE患者及278名正常对照采用PCR-RFLP对SLAM基因4个SNP位点(-262A/T,-188A/G,-112C/T,+116A/C)进行分型,结果发现-262A/T,-188A/G等位频率分布在SLE患者及正常对照中存在显著差异(p值分别为0.0003,0.002),对-262A/T及-188A/G进行连锁不平衡分析提示,两个位点存在连锁(D’=0.6443)。非条件Logistic回归分析显示-262A-188G及-262T-188A在SLE病例组及正常对照中分布有显著性差异(p值分别为0.002,0.003),这两种单倍型可能与系统性红斑狼疮的发病相关,且-262A-188G单倍型发生SLE的危险性显著增加(OR=1.478, 95%CI=1.152-1.897)。3.通过定点突变的方法成功构建了含有四种不同单倍型的pGL3-Basic重组质粒,采用双荧光素酶报告系统对荧光素酶表达量进行检测。与pGL3-Basic空载体相比,这四种单倍型片段重组pGL3-Basic载体荧光素酶活性明显增强,提示-415到+4这个片段具有启动子功能。但不同单倍型片段启动子活性存在差异,在HeLa细胞中及Jurkat细胞中,单倍型-262A-188G荧光素酶表达量显著高于单倍型-262T-188A、单倍型-262T-188G及单倍型-262A-188A。
4.分别合成含-262A,-262T及-188A,-188G等位的探针进行EMSA实验。结果显示-262A,-262T等位探针与核蛋白均产生一条结合带,且结合量无明显差异。-188G、-188A等位寡核苷酸与Jurkat细胞及PBMC核蛋白能形成一条结合带,但-188G等位与核蛋白的结合量高于-188A等位(约2.55倍),说明这两个等位探针与核蛋白结合的能力存在差异,-188G等位与核蛋白的结合能力强于-188A等位,推测-188G等位的变异可能增加了该等位核酸序列与转录因子的结合能力。
5. PHA体外刺激后,不同基因型的SLE患者SLAM基因mRNA及蛋白表达量存在差异,与疾病关联的单倍型-262AA-188GG SLE患者SLAM基因mRNA表达显著高于其余单倍型SLE患者(p<0.01),而蛋白表达高于单倍型为-262A/T-188A/G的SLE患者(p<0.05),提示不同单倍型可能影响SLE患者SLAM基因mRNA及蛋白表达,而与疾病关联的单倍型-262A-188G可能增加了SLE患者SLAM基因mRNA及蛋白的表达。
综上所述:本研究通过在中国SLE人群进行病例-对照研究,发现FCRL3基因多态性与中国汉族人群SLE无相关性。SLAM基因-262A/T,-188A/G多态性与中国人群SLE发病相关,这两位位点存在连锁,单倍型-262A-188G能显著增强启动子功能,单倍型为-262AA-188GG的SLE患者SLAM基因mRNA及蛋白表达的显著增加,-188G等位变异可能增强了与转录因子结合的能力,这可能是-262A-188G单倍型转录活性增强的活性的原因之一。因此,SLAM基因单倍型-262A-188G可能通过上调SLAM基因的表达增加了SLE发病的危险因素。
With the completion of the human genome project, attention is now rapidly shifting towards the study of individual genetic variation. The most abundant source of genetic variation in the human genome is represented by single nucleotide polymorphisms (SNPs), which can account for heritable inter-individual differences in complex phenotypes. Identification of SNPs that contribute to susceptibility to comples diseases will provide highly accurate diagnostic information that will facilitate early diagnosis, prevention, and treatment of human diseases.
Systemic lupus erythematosus(SLE) is a prototypic systemic autoimmune disease characterized by a diverse array of autoantibody production, complement activation, immune complex deposition, and tissue and organ damage. Although the etiopathogenesis of SLE remains unclear, SLE has long been appreciated to be a complex interlay of genetic and environmental factors. The complex patterns of inheritance in SLE suggest that multiple genes contribute to the etiology. Several studies have shown that the Fc receptor-like 3 (FCRL3) and signaling lymphocytic activation molecule (SLAM) genes play important role in the pathogenesis of SLE. However, the importance between their genetic polymorphisms and SLE has not been studied in Chinese population. In this study, we investigated the occurrence of polymorphisms within the FCRL3 and SLAM gene, and further validated the biological functions of positive associated SNP loci.
We analyzed four SNPs (-169A/G, -110C/T, +358C/G and +1381C/T) of FCRL3 gene and four SNPs (-262A/T, -188A/G, -112C/T and +116A/C) of SLAM gene in a case–control cohort composed of 248 SLE patients and 278 healthy controls using the PCR-RFLP assay. The case-control association studies were analyzed usingχ2 tests for Hardy–Weinberg equilibrium. And 2×2 and 2×3 contingency tables for allele and genotype frequencies were conducted respectively. For the haplotype analysis, pairwise linkage disequilibrium measures were investigated by using linkage disequilibrium analyzer(LDA), haplotype frequencies were estimated and calculated using the PHASE package. To further validate the biological functions of positive associated SNP loci, the functions of the haplotypes(-262A-188T,-262T-188A) in the 5’untranslated region of the SLAM gene in patients with SLE were studied. The promoter activities of the haplotypes on the SLAM gene were evaluated with the dual-luciferase reporter system. EMSA was used for identify nulear protein binding ability between the alleles of -262A/T and -188A/G in SLAM gene.
The mRNA and protein expression of SLAM on the peripheral blood monocyte cells of SLE patients with different genotypes were determined by real-time PCR and flow cytometry respectively.
The main results and conclusions were summarized as follows:
1. Analysis of allelic frequencies revealed no significant difference between SLE patients and control subjects for the FCRL3 gene polymorphisms. We also inferred three common haplotypes (ACCC、GTGT、GCGT) and found no significant difference of haplotype frequencies between SLE patients and controls. The associations of FCRL3 with SLE patients with antinuclear antibody(ANA) were examined, we did not detect any association of FCRL3 genotype with ANA in the SLE patients. These results suggested that genetic variations in FCRL3 were not associated with SLE in Chinese population.
2. We evaluated the -262A/T,-188A/G,-112C/T and +116A/C polymorphisms of SLAM gene for associations with SLE in a case-control study. The -262A/T and -188A/G polymorphisms were associated with susceptibility of SLE(p=0.0003,0.002), analysis showed that the two SNPs were in linkage disequilibrium(D’=0.6443). The -262A-188G and -262T-188A haplotypes were associated with SLE(p=0.002,0.003), the -262A-188G haplotype might increase the risk for developing SLE(OR=1.478, 95%CI=1.152-1.897).
3. The four different haplotype DNA of SLAM gene were cloned into a luciferase expression plasmid(pGL3-Basic) respectively, then the different vectors were transfected into HeLa cells and Jurkat cells, the reporter activities were measured by using dual luciferase reporter assay. The results showed increased luciferase expression of the four haplotypes, however, the luciferase expression of the -262A-188G haplotype was significant greater than the other three haplotype. This suggested that -262A-188G can significantly increase the expression level of the reporter gene.
4. EMSA showed that there were no different abilities of nuclear protein binding between the two alleles of -262A/T. However, the intensity of binding band was higher for the -188G allele than for the -188A allele. The -188A/G polymorphism altered the binding affinity of nuclear protein.
5. In response to phytohemagglutinin(PHA) stimulation, the SLAM mRNA expressions on PBMC of SLE patients were significantly higher in -262AA-188GG homozygous genotype compared with individuals heterozygous and homozygous with other genotypes(p<0.01). The SLAM protein expressions on T cells of SLE patients were significantly higher in -262AA-188GG homozygous genotypes compared with -262A/T-188A/G heterozygous(p<0.05).
In conclusion: we find that FCRL3 polymorphisms are not associated with susceptibility to SLE in Chinese population. The -262A/T and -188A/G polymorphisms of SLAM gene are associated with susceptibility of SLE. The haplotype -262A-188G can significantly increase the expression level of the reporter gene. The expression level of mRNA and protein expression of SLAM is significantly higher in SLE patients with -262AA-188GG haplotype. The -188A/G polymorphism alters the binding affinity of nuclear protein. These findings suggest that the -262A-188G haplotype in the SLAM gene promoter contributes to risk of the occurrence SLE by increasing expression of SLAM.
SLE是一种典型的自身免疫疾病,其主要病理生理学过程为大量自身抗体产生,补体激活,免疫复合物的沉积从而导致组织和器官的损伤。尽管SLE的发病机制目前并不十分清楚,但是现已达成共识:SLE是遗传因素和环境因素共同作用的结果,其遗传学模式非常复杂,多个基因参与其发病机制。目前已有研究表明Fc受体样基因3(FCRL3)及信号转导淋巴细胞激活分子(SLAM)基因参与了SLE的发病机制。然而,这两个基因多态性位点与中国人群SLE的易感性尚未有研究。我们选择上述两个基因作为候选基因,拟在中国SLE人群中筛查其SNP分布及频率,并对阳性关联SNP位点的生物学意义进行初步实验研究。本研究收集了248名SLE患者及278名正常对照,采用PCR-限制性片段长度多态性(RFLP)在中国SLE人群对FCRL3基因4个SNPs (-169A/G, -110C/T, +358C/G及+1381C/T)及SLAM基因4个SNPs (-262A/T, -188A/G, -112C/T及+116A/C)进行了病例-对照研究。等位基因频率直接由基因型计算,Hardy-Weinberg平衡由χ2检验检测,以p>0.05为符合Hardy-Weinberg平衡,两组间的差异由列联表χ2检测,通过LDA软件检测连锁不平衡,PHASE软件分析单倍型。对发现的与SLE相关的SLAM基因5’非翻译区两种单倍型(-262A-188G,-262T-188A)进行了初步的功能研究,即通过荧光素酶报告基因实验分析不同单倍型转录调控功能是否具有差异,电泳迁移率实验(EMSA)体外分析不同等位的寡核苷酸结合核蛋白的能力,并通过在不同基因型SLE患者中检测SLAM基因mRNA及蛋白的表达,分析SLAM基因启动子区不同单倍型对SLAM基因转录及表达的影响。
研究主要结果如下:
1. FCLR3基因4个SNP位点(-169A/G, -110C/T, +358C/G和+1381C/T)在病例组和对照组中的基因型频率分布无明显差异(p值分别为0.227,0.444,0.412,0.167),ACCC、GTGT、GCGT这三种主要的单倍型在正常对照及SLE患者中分布无显著差异(p值分别为0.943,0.084,0.387),FCRL3基因4个SNP位点等位基因分布频率与SLE患者ANA无相关性(p>0.05)。
2.在248名SLE患者及278名正常对照采用PCR-RFLP对SLAM基因4个SNP位点(-262A/T,-188A/G,-112C/T,+116A/C)进行分型,结果发现-262A/T,-188A/G等位频率分布在SLE患者及正常对照中存在显著差异(p值分别为0.0003,0.002),对-262A/T及-188A/G进行连锁不平衡分析提示,两个位点存在连锁(D’=0.6443)。非条件Logistic回归分析显示-262A-188G及-262T-188A在SLE病例组及正常对照中分布有显著性差异(p值分别为0.002,0.003),这两种单倍型可能与系统性红斑狼疮的发病相关,且-262A-188G单倍型发生SLE的危险性显著增加(OR=1.478, 95%CI=1.152-1.897)。3.通过定点突变的方法成功构建了含有四种不同单倍型的pGL3-Basic重组质粒,采用双荧光素酶报告系统对荧光素酶表达量进行检测。与pGL3-Basic空载体相比,这四种单倍型片段重组pGL3-Basic载体荧光素酶活性明显增强,提示-415到+4这个片段具有启动子功能。但不同单倍型片段启动子活性存在差异,在HeLa细胞中及Jurkat细胞中,单倍型-262A-188G荧光素酶表达量显著高于单倍型-262T-188A、单倍型-262T-188G及单倍型-262A-188A。
4.分别合成含-262A,-262T及-188A,-188G等位的探针进行EMSA实验。结果显示-262A,-262T等位探针与核蛋白均产生一条结合带,且结合量无明显差异。-188G、-188A等位寡核苷酸与Jurkat细胞及PBMC核蛋白能形成一条结合带,但-188G等位与核蛋白的结合量高于-188A等位(约2.55倍),说明这两个等位探针与核蛋白结合的能力存在差异,-188G等位与核蛋白的结合能力强于-188A等位,推测-188G等位的变异可能增加了该等位核酸序列与转录因子的结合能力。
5. PHA体外刺激后,不同基因型的SLE患者SLAM基因mRNA及蛋白表达量存在差异,与疾病关联的单倍型-262AA-188GG SLE患者SLAM基因mRNA表达显著高于其余单倍型SLE患者(p<0.01),而蛋白表达高于单倍型为-262A/T-188A/G的SLE患者(p<0.05),提示不同单倍型可能影响SLE患者SLAM基因mRNA及蛋白表达,而与疾病关联的单倍型-262A-188G可能增加了SLE患者SLAM基因mRNA及蛋白的表达。
综上所述:本研究通过在中国SLE人群进行病例-对照研究,发现FCRL3基因多态性与中国汉族人群SLE无相关性。SLAM基因-262A/T,-188A/G多态性与中国人群SLE发病相关,这两位位点存在连锁,单倍型-262A-188G能显著增强启动子功能,单倍型为-262AA-188GG的SLE患者SLAM基因mRNA及蛋白表达的显著增加,-188G等位变异可能增强了与转录因子结合的能力,这可能是-262A-188G单倍型转录活性增强的活性的原因之一。因此,SLAM基因单倍型-262A-188G可能通过上调SLAM基因的表达增加了SLE发病的危险因素。
With the completion of the human genome project, attention is now rapidly shifting towards the study of individual genetic variation. The most abundant source of genetic variation in the human genome is represented by single nucleotide polymorphisms (SNPs), which can account for heritable inter-individual differences in complex phenotypes. Identification of SNPs that contribute to susceptibility to comples diseases will provide highly accurate diagnostic information that will facilitate early diagnosis, prevention, and treatment of human diseases.
Systemic lupus erythematosus(SLE) is a prototypic systemic autoimmune disease characterized by a diverse array of autoantibody production, complement activation, immune complex deposition, and tissue and organ damage. Although the etiopathogenesis of SLE remains unclear, SLE has long been appreciated to be a complex interlay of genetic and environmental factors. The complex patterns of inheritance in SLE suggest that multiple genes contribute to the etiology. Several studies have shown that the Fc receptor-like 3 (FCRL3) and signaling lymphocytic activation molecule (SLAM) genes play important role in the pathogenesis of SLE. However, the importance between their genetic polymorphisms and SLE has not been studied in Chinese population. In this study, we investigated the occurrence of polymorphisms within the FCRL3 and SLAM gene, and further validated the biological functions of positive associated SNP loci.
We analyzed four SNPs (-169A/G, -110C/T, +358C/G and +1381C/T) of FCRL3 gene and four SNPs (-262A/T, -188A/G, -112C/T and +116A/C) of SLAM gene in a case–control cohort composed of 248 SLE patients and 278 healthy controls using the PCR-RFLP assay. The case-control association studies were analyzed usingχ2 tests for Hardy–Weinberg equilibrium. And 2×2 and 2×3 contingency tables for allele and genotype frequencies were conducted respectively. For the haplotype analysis, pairwise linkage disequilibrium measures were investigated by using linkage disequilibrium analyzer(LDA), haplotype frequencies were estimated and calculated using the PHASE package. To further validate the biological functions of positive associated SNP loci, the functions of the haplotypes(-262A-188T,-262T-188A) in the 5’untranslated region of the SLAM gene in patients with SLE were studied. The promoter activities of the haplotypes on the SLAM gene were evaluated with the dual-luciferase reporter system. EMSA was used for identify nulear protein binding ability between the alleles of -262A/T and -188A/G in SLAM gene.
The mRNA and protein expression of SLAM on the peripheral blood monocyte cells of SLE patients with different genotypes were determined by real-time PCR and flow cytometry respectively.
The main results and conclusions were summarized as follows:
1. Analysis of allelic frequencies revealed no significant difference between SLE patients and control subjects for the FCRL3 gene polymorphisms. We also inferred three common haplotypes (ACCC、GTGT、GCGT) and found no significant difference of haplotype frequencies between SLE patients and controls. The associations of FCRL3 with SLE patients with antinuclear antibody(ANA) were examined, we did not detect any association of FCRL3 genotype with ANA in the SLE patients. These results suggested that genetic variations in FCRL3 were not associated with SLE in Chinese population.
2. We evaluated the -262A/T,-188A/G,-112C/T and +116A/C polymorphisms of SLAM gene for associations with SLE in a case-control study. The -262A/T and -188A/G polymorphisms were associated with susceptibility of SLE(p=0.0003,0.002), analysis showed that the two SNPs were in linkage disequilibrium(D’=0.6443). The -262A-188G and -262T-188A haplotypes were associated with SLE(p=0.002,0.003), the -262A-188G haplotype might increase the risk for developing SLE(OR=1.478, 95%CI=1.152-1.897).
3. The four different haplotype DNA of SLAM gene were cloned into a luciferase expression plasmid(pGL3-Basic) respectively, then the different vectors were transfected into HeLa cells and Jurkat cells, the reporter activities were measured by using dual luciferase reporter assay. The results showed increased luciferase expression of the four haplotypes, however, the luciferase expression of the -262A-188G haplotype was significant greater than the other three haplotype. This suggested that -262A-188G can significantly increase the expression level of the reporter gene.
4. EMSA showed that there were no different abilities of nuclear protein binding between the two alleles of -262A/T. However, the intensity of binding band was higher for the -188G allele than for the -188A allele. The -188A/G polymorphism altered the binding affinity of nuclear protein.
5. In response to phytohemagglutinin(PHA) stimulation, the SLAM mRNA expressions on PBMC of SLE patients were significantly higher in -262AA-188GG homozygous genotype compared with individuals heterozygous and homozygous with other genotypes(p<0.01). The SLAM protein expressions on T cells of SLE patients were significantly higher in -262AA-188GG homozygous genotypes compared with -262A/T-188A/G heterozygous(p<0.05).
In conclusion: we find that FCRL3 polymorphisms are not associated with susceptibility to SLE in Chinese population. The -262A/T and -188A/G polymorphisms of SLAM gene are associated with susceptibility of SLE. The haplotype -262A-188G can significantly increase the expression level of the reporter gene. The expression level of mRNA and protein expression of SLAM is significantly higher in SLE patients with -262AA-188GG haplotype. The -188A/G polymorphism alters the binding affinity of nuclear protein. These findings suggest that the -262A-188G haplotype in the SLAM gene promoter contributes to risk of the occurrence SLE by increasing expression of SLAM.
引文
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