汉族人群中SLC26A4，线粒体转录因子A基因多态性与阿尔茨海默病的关联研究
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摘要
阿尔茨海默病（Alzheimer’s disease, AD）是一种与年龄相关的进行性神经系统变性病，是老年人发生认知功能减退及痴呆的最常见的病因。临床表现为进行性记忆力减退和严重的智能减退，神经系统病理改变主要有脑内β-淀粉样肽（Aβ）沉积、神经原纤维缠结和神经元缺失等。AD在世界范围内广泛发病，随着老年化时代的到来，AD以成为影响人类健康的最主要疾病之一。据统计到2010年，全世界已有3500万人罹患AD，并且随着年龄的增长,其发病风险每5年会成倍增加。AD的致残率和致死率给家庭和社会带来了沉重的负担。但目前AD的发病机制还不十分清晰，比较有影响的假说主要有“胆碱能学说”和“β-淀粉样蛋白学说”等。随着遗传分子生物学的发展，人类开始从基因层面来寻找AD的发病机制及治疗方法，目前全基因组关联研究(Genome-wide AssociationStudies，GWAS）已发现许多染色体区域很可能存在与AD有关的基因突变，如CLU、CRl、 PICALM、 PCDH11X、NEDD9以及一些神经营养因子等。目前只有载脂蛋白（ApoE）ε4等位基因在世界范围内得到了公认，但ApoEε4等位基因只占迟发型阿尔茨海默病（LOAD）患者遗传风险的42%。因此，寻找更多的候选基因，对将来AD的基因诊断和治疗至关重要。近期一项大规模的全基因关联研究发现SLC26A4基因rs2072064多态性位点与高加索人群迟发型阿尔茨海默病的发病风险相关联，然而目前在汉族人群中还没有关于上述基因位点多态性与LOAD的发病风险关系的研究报道。
1.SLC26A4基因rs2072064位点多态性与阿尔茨海默病的相关性研究：
近期一项大规模的全基因关联研究发现SLC26A4基因rs2072064多态性位点与高加索人群迟发型阿尔茨海默病（LOAD）的发病风险相关联，然而目前还没有关于该位点基因变异与亚洲人群LOAD的发病风险关系的研究报道。本研究旨在探讨SLC26A4基因rs2072064多态性位点与北方汉族人群迟发型阿尔茨海默病（LOAD）易感性的关系。采用病例-对照研究方法，选取599例LOAD患者和598例年龄和性别相匹配的健康对照作为研究对象，利用聚合酶链式反应—连接酶检测反应(PCR—LDR)技术进行基因分型。结果发现SLC26A4基因rs2072064多态性位点的基因频率和等位基因频率在病例组和对照组中有显著差异(P=0.001；P <0.001)，其中等位基因型A显著降低LOAD的发病风险(OR=0.792, P=0.007)。但是，经ApoEε4分层后，仅在ApoEε4非携带亚组中，SLC26A4基因型和等位基因型频率在AD组和对照组中存在显著差异（基因型p=0.001;等位基因型p=0.001）。此外，logistic回归分析发现，在校正性别、年龄和ApoEε4携带状态等因素后，该位点仍与LOAD的发病风险显著关联(显性模型: OR=0.787,95%CI=0.619-1.000, P=0.050;隐性模型: OR=0.655,95%CI=0.448-0.959,P=0.030;累加模型: OR=0.792,95%CI=0.661-0.950, P=0.012)。本研究支持SLC26A4基因为中国北方汉族人群LOAD的易感基因。
2.线粒体转录因子A基因遗传多态性与阿尔茨海默病发表风险的关联研究：
线粒体是ATP产生的主要场所，维持人体细胞的各种正常生理功能，对于能量需求量特别高的神经细胞来说其功能的完整性尤为重要。有研究表明慢性线粒体DNA的损伤和线粒体功能缺陷在阿尔茨海默病的发生和发展进程中发挥了重要的作用。线粒体转录因子A（TFAM）具有维持线粒体DNA结构和功能的完整性的作用。越来越多的研究表明TFAM与阿尔茨海默病发病风险有关。本实验采用大样本病例-对照的研究方法，应用生物质谱测序技术和等位基因特异性多重PCR技术（Multi-ARMS），检测394例临床确诊的迟发型阿尔茨海默病患者（发病年龄≥65岁）和390名健康对照者的TFAM受体基因多态性位点的等位基因型，基因型和单倍体型及载脂蛋白E基因多态性位点的等位基因型，基因型和单倍体型的分布特征情况，以探讨TFAM基因多态性、载脂蛋白E基因多态性以及TFAM基因与载脂蛋白E基因相互作用与迟发型阿尔茨海默病的关系。本研究采用SPSS11.5软件做统计学分析。两组间人群一般特征差异采用student-t检验或卡方检验，Hardy-Weinberg平衡定律采用卡方检验。同时比较AD组和对照组间基因型、等位基因型和单倍体型分布的差异，计算比值比（OR）及其95%可信区间（CI），确定相对风险度。采用多因素Logistic回归分析校正潜在的混淆因素。应用SHEsis软件做单倍体频率分析。所有统计学检验均为双侧概率检验，P﹤0.05为有统计学意义。结果显示，载脂蛋白E（ApoE）ε4与散发、晚发性阿尔茨海默病的发病风险高度相关（P＜0.001,OR=2.91),两组间rs1937基因型频率和等位基因频率差异有显著性（基因型p=0.03；等位基因型OR=0.76,95%CI=0.59-0.99,p=0.04）。位点rs2306604基因型和等位基因频率在AD组与对照组间均无显著差异（基因型p=0.76;等位基因型p=0.84）。按性别分层分析后，两位点基因型和等位基因型频率未见明显差异。多因素logistic分析表明ApoEε4与TFAM基因之间无交互作用，rs1937基因型频率差异在三种logistic模型中均有显著差异（显性模型：OR=0.71,95%CI=0.51-0.97, P=0.03;隐性模型：OR=0.25,95%CI=0.08-0.82, P=0.02;递加模型：0R=0.68,95%CI=0.51-0.91,P=0.01）。单倍体型分析发现单倍体型CC在AD的发病中有保护作用（OR=0.76,95%CI=0.59-0.99, P=0.038）。中国汉族人群线粒体转录因子A基因多态性与阿尔茨海默病相关，其中rs1937位点等位基因C和单倍体型CC在迟发型AD发病进程中起保护作用，该作用可能与TFAM基因点突变Ser12Thr可影响TFAM功能进而影响线粒体DNA的转录和线粒体结构和功能完整性等作用相关，TFAM有可作为阿尔茨海默病治疗新的靶标。
本论文的研究工作丰富了我国有关阿尔茨海默病的遗传风险的研究，发现了在中国北方汉族人群中SLC26A4基因rs2072064及TFAM基因rs1937位点多态性与迟发型阿尔茨海默病有密切相关性。不仅使人们进一步从基因多态性水平探索AD的病因及发病机制，而且为将来的基因诊断和治疗提供重要的资料。
Alzheimer's disease (AD) is a common age-associated progressiveneurodegenerative disorder. Although the etiology of AD remains poorlyunderstood, genetic factors explain about60-80%of the heritability ofAD. Several gene mutations, namely in β-amyloid precursor protein,presenilin1, and presenilin2, have been associated with the early-onsetfamilial form of Alzheimer's disease. In contrast to early-onset AD, thegenetic component of susceptibility to late-onset Alzheimer's disease(LOAD) seems to be more complex. Multiple genetic factors are believedto be involved in the pathogenesis and development of the disorder. Onlythe ε4allele of apolipoprotein E (APOE) gene is definitively associatedwith increased susceptibility to LOAD. However, about half the peoplecarrying at least one ε4allele do not develop LOAD and42%of patientswith LOAD do not possess an APOE ε4allele. Much effort has been madeto search for additional genes that confer LOAD-susceptibility.
1. association betweenSLC26A4gene polymorphism and late-onsetAlzheimer's disease：In a recent genome-wide association study, theSLC26A4gene rs2072064polymorphism was found to be associated withlate-onset Alzheimer's disease (LOAD) in Caucasians. Here, weinvestigated this association in a large Northern Han Chinese cohortconsisting of599sporadic LOAD patients and598healthy controls matchedfor sex and age in a Northern Han Chinese population from Qingdao, China.Genotyping by the polymerase chain reaction-ligase detection reactionrevealed that there were significant differences in the genotype (P=0.017) and allele (P=0.007) frequencies of the rs2072064polymorphismbetween LOAD patients and controls. The A allele of this polymorphism was significantly associated with a reduced risk of LOAD (odds ratio (OR)=0.792,95%confidence interval (CI)=0.670–0.937, P=0.007). When thedata were stratified by the apolipoprotein E (APOE) ε4status, there wasa significant difference only among APOE ε4non-carriers (genotypic P=0.001, allelic P=0.001). Furthermore, the association betweenrs2072064and LOAD remained significant by logistic regression analysisafter adjustment for age, gender, and the APOE ε4carrier status(dominant model: OR=0.787,95%CI=0.619–1.000, P=0.050; recessivemodel: OR=0.655,95%CI=0.448–0.959, P=0.030; additive model: OR=0.792,95%CI=0.661–0.950, P=0.012). These findings suggest thatSLC26A4is a susceptibility gene for LOAD in a Northern Han Chinesepopulation from the Qingdao area.
2. association betweenSLC26A4gene polymorphism and late-onsetAlzheimer's disease：been proved to contribute to the development ofAlzheimer's disease (AD).Mitochondrial transcription factor A (TFAM)plays an important role in the maintenance of mtDNA integrity. Recently,some studies suggested two single nucleotide polymorphisms (SNPs)(rs1937and rs2306604) in the TFAM gene are associated with sporadic late-onsetAD (LOAD) in Caucasians. To explore the correlation between TFAM gene andLOAD, we performed a case-control study in a large Chinese cohortconsisting of394patients and390healthy controls. The results showedthat there were significant differences in genotype (P=0.03) and allele(P=0.04) frequencies of the SNP rs1937between LOAD patients and controls.The minor C allele of rs1937acted as a moderate protective factor of LOAD(P=0.04, odds ratios/OR=0.76). The logistic regression analysis alsosuggested an association of LOAD with SNP rs1937(dominant model: P=0.03,OR=0.71; recessive model: P=0.02, OR=0.25; additive model: P=0.01,OR=0.68). No significant association was observed between rs2306604andLOAD. Haplotype analysis identified the haplotype CC as a protective factor of LOAD (P=0.038, OR=0.76). This study provides the evidence thatvariations in TFAM are involved in the pathogenesis of sporadic LOAD inthe Han Chinese population
This research work enriched the data between Alzheimer's disease andcandidate gene in China, and we discovered the association between SLC26A4gene rs2072064TFAM gene rs1937site polymorphism and late onsetAlzheimer's disease in the northern han people. Our study makes peopleto explore AD etiology and pathogenesis further more from genepolymorphism level, and provides important data for future geneticdiagnosis and treatment to.
1.SLC26A4基因rs2072064位点多态性与阿尔茨海默病的相关性研究：
近期一项大规模的全基因关联研究发现SLC26A4基因rs2072064多态性位点与高加索人群迟发型阿尔茨海默病（LOAD）的发病风险相关联，然而目前还没有关于该位点基因变异与亚洲人群LOAD的发病风险关系的研究报道。本研究旨在探讨SLC26A4基因rs2072064多态性位点与北方汉族人群迟发型阿尔茨海默病（LOAD）易感性的关系。采用病例-对照研究方法，选取599例LOAD患者和598例年龄和性别相匹配的健康对照作为研究对象，利用聚合酶链式反应—连接酶检测反应(PCR—LDR)技术进行基因分型。结果发现SLC26A4基因rs2072064多态性位点的基因频率和等位基因频率在病例组和对照组中有显著差异(P=0.001；P <0.001)，其中等位基因型A显著降低LOAD的发病风险(OR=0.792, P=0.007)。但是，经ApoEε4分层后，仅在ApoEε4非携带亚组中，SLC26A4基因型和等位基因型频率在AD组和对照组中存在显著差异（基因型p=0.001;等位基因型p=0.001）。此外，logistic回归分析发现，在校正性别、年龄和ApoEε4携带状态等因素后，该位点仍与LOAD的发病风险显著关联(显性模型: OR=0.787,95%CI=0.619-1.000, P=0.050;隐性模型: OR=0.655,95%CI=0.448-0.959,P=0.030;累加模型: OR=0.792,95%CI=0.661-0.950, P=0.012)。本研究支持SLC26A4基因为中国北方汉族人群LOAD的易感基因。
2.线粒体转录因子A基因遗传多态性与阿尔茨海默病发表风险的关联研究：
线粒体是ATP产生的主要场所，维持人体细胞的各种正常生理功能，对于能量需求量特别高的神经细胞来说其功能的完整性尤为重要。有研究表明慢性线粒体DNA的损伤和线粒体功能缺陷在阿尔茨海默病的发生和发展进程中发挥了重要的作用。线粒体转录因子A（TFAM）具有维持线粒体DNA结构和功能的完整性的作用。越来越多的研究表明TFAM与阿尔茨海默病发病风险有关。本实验采用大样本病例-对照的研究方法，应用生物质谱测序技术和等位基因特异性多重PCR技术（Multi-ARMS），检测394例临床确诊的迟发型阿尔茨海默病患者（发病年龄≥65岁）和390名健康对照者的TFAM受体基因多态性位点的等位基因型，基因型和单倍体型及载脂蛋白E基因多态性位点的等位基因型，基因型和单倍体型的分布特征情况，以探讨TFAM基因多态性、载脂蛋白E基因多态性以及TFAM基因与载脂蛋白E基因相互作用与迟发型阿尔茨海默病的关系。本研究采用SPSS11.5软件做统计学分析。两组间人群一般特征差异采用student-t检验或卡方检验，Hardy-Weinberg平衡定律采用卡方检验。同时比较AD组和对照组间基因型、等位基因型和单倍体型分布的差异，计算比值比（OR）及其95%可信区间（CI），确定相对风险度。采用多因素Logistic回归分析校正潜在的混淆因素。应用SHEsis软件做单倍体频率分析。所有统计学检验均为双侧概率检验，P﹤0.05为有统计学意义。结果显示，载脂蛋白E（ApoE）ε4与散发、晚发性阿尔茨海默病的发病风险高度相关（P＜0.001,OR=2.91),两组间rs1937基因型频率和等位基因频率差异有显著性（基因型p=0.03；等位基因型OR=0.76,95%CI=0.59-0.99,p=0.04）。位点rs2306604基因型和等位基因频率在AD组与对照组间均无显著差异（基因型p=0.76;等位基因型p=0.84）。按性别分层分析后，两位点基因型和等位基因型频率未见明显差异。多因素logistic分析表明ApoEε4与TFAM基因之间无交互作用，rs1937基因型频率差异在三种logistic模型中均有显著差异（显性模型：OR=0.71,95%CI=0.51-0.97, P=0.03;隐性模型：OR=0.25,95%CI=0.08-0.82, P=0.02;递加模型：0R=0.68,95%CI=0.51-0.91,P=0.01）。单倍体型分析发现单倍体型CC在AD的发病中有保护作用（OR=0.76,95%CI=0.59-0.99, P=0.038）。中国汉族人群线粒体转录因子A基因多态性与阿尔茨海默病相关，其中rs1937位点等位基因C和单倍体型CC在迟发型AD发病进程中起保护作用，该作用可能与TFAM基因点突变Ser12Thr可影响TFAM功能进而影响线粒体DNA的转录和线粒体结构和功能完整性等作用相关，TFAM有可作为阿尔茨海默病治疗新的靶标。
本论文的研究工作丰富了我国有关阿尔茨海默病的遗传风险的研究，发现了在中国北方汉族人群中SLC26A4基因rs2072064及TFAM基因rs1937位点多态性与迟发型阿尔茨海默病有密切相关性。不仅使人们进一步从基因多态性水平探索AD的病因及发病机制，而且为将来的基因诊断和治疗提供重要的资料。
Alzheimer's disease (AD) is a common age-associated progressiveneurodegenerative disorder. Although the etiology of AD remains poorlyunderstood, genetic factors explain about60-80%of the heritability ofAD. Several gene mutations, namely in β-amyloid precursor protein,presenilin1, and presenilin2, have been associated with the early-onsetfamilial form of Alzheimer's disease. In contrast to early-onset AD, thegenetic component of susceptibility to late-onset Alzheimer's disease(LOAD) seems to be more complex. Multiple genetic factors are believedto be involved in the pathogenesis and development of the disorder. Onlythe ε4allele of apolipoprotein E (APOE) gene is definitively associatedwith increased susceptibility to LOAD. However, about half the peoplecarrying at least one ε4allele do not develop LOAD and42%of patientswith LOAD do not possess an APOE ε4allele. Much effort has been madeto search for additional genes that confer LOAD-susceptibility.
1. association betweenSLC26A4gene polymorphism and late-onsetAlzheimer's disease：In a recent genome-wide association study, theSLC26A4gene rs2072064polymorphism was found to be associated withlate-onset Alzheimer's disease (LOAD) in Caucasians. Here, weinvestigated this association in a large Northern Han Chinese cohortconsisting of599sporadic LOAD patients and598healthy controls matchedfor sex and age in a Northern Han Chinese population from Qingdao, China.Genotyping by the polymerase chain reaction-ligase detection reactionrevealed that there were significant differences in the genotype (P=0.017) and allele (P=0.007) frequencies of the rs2072064polymorphismbetween LOAD patients and controls. The A allele of this polymorphism was significantly associated with a reduced risk of LOAD (odds ratio (OR)=0.792,95%confidence interval (CI)=0.670–0.937, P=0.007). When thedata were stratified by the apolipoprotein E (APOE) ε4status, there wasa significant difference only among APOE ε4non-carriers (genotypic P=0.001, allelic P=0.001). Furthermore, the association betweenrs2072064and LOAD remained significant by logistic regression analysisafter adjustment for age, gender, and the APOE ε4carrier status(dominant model: OR=0.787,95%CI=0.619–1.000, P=0.050; recessivemodel: OR=0.655,95%CI=0.448–0.959, P=0.030; additive model: OR=0.792,95%CI=0.661–0.950, P=0.012). These findings suggest thatSLC26A4is a susceptibility gene for LOAD in a Northern Han Chinesepopulation from the Qingdao area.
2. association betweenSLC26A4gene polymorphism and late-onsetAlzheimer's disease：been proved to contribute to the development ofAlzheimer's disease (AD).Mitochondrial transcription factor A (TFAM)plays an important role in the maintenance of mtDNA integrity. Recently,some studies suggested two single nucleotide polymorphisms (SNPs)(rs1937and rs2306604) in the TFAM gene are associated with sporadic late-onsetAD (LOAD) in Caucasians. To explore the correlation between TFAM gene andLOAD, we performed a case-control study in a large Chinese cohortconsisting of394patients and390healthy controls. The results showedthat there were significant differences in genotype (P=0.03) and allele(P=0.04) frequencies of the SNP rs1937between LOAD patients and controls.The minor C allele of rs1937acted as a moderate protective factor of LOAD(P=0.04, odds ratios/OR=0.76). The logistic regression analysis alsosuggested an association of LOAD with SNP rs1937(dominant model: P=0.03,OR=0.71; recessive model: P=0.02, OR=0.25; additive model: P=0.01,OR=0.68). No significant association was observed between rs2306604andLOAD. Haplotype analysis identified the haplotype CC as a protective factor of LOAD (P=0.038, OR=0.76). This study provides the evidence thatvariations in TFAM are involved in the pathogenesis of sporadic LOAD inthe Han Chinese population
This research work enriched the data between Alzheimer's disease andcandidate gene in China, and we discovered the association between SLC26A4gene rs2072064TFAM gene rs1937site polymorphism and late onsetAlzheimer's disease in the northern han people. Our study makes peopleto explore AD etiology and pathogenesis further more from genepolymorphism level, and provides important data for future geneticdiagnosis and treatment to.
引文
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