嵌合蛋白1基因启动子两多态位点与阿尔茨海默病的相关性研究

目的探讨嵌合蛋白1(chimerin1,CHN1)基因启动子区多态性、载脂蛋白E(apolipoprotein,APOE)基因多态性和阿尔茨海默病(Alzheimer's disease,AD)的相关性。方法通过使用TaqMan-PCR法检测单核苷酸多态性方法,观察380例日本AD患者(包括327例迟发型AD与53例早发型AD)和380例非痴呆对照组CHN1基因启动子(rs3732315与rs1320875)及APOE基因的多态性分布,并分析与AD的相关性。结果CHN1基因启动子rs3732315上A/T多态位点与rs1320875上A/G多态位点分别与AD无明显相关性(P值分别为0.094,0.17)。进一步在LOAD,EOAD与对照组的比较中发现rs3732315AA基因型与rs1320875GG基因型与EOAD无明显相关(P值分别为0·055,0·065)。结论CHN1基因启动子区rs3732315与rs1320875多态位点与AD无明显相关性,但不能排除rs3732315AA基因型与rs1320875GG基因型微弱增加了EOAD的发病风险,其真正意义有待在大样本、多中心人群中进一步阐明。     

TM4SF5基因与阿尔茨海默病的相关性研究

目的 探讨跨膜蛋白4超级家族5 (transmembrane 4 superfamily member 5,TM4SF5)基因多态性、载脂蛋白E(ApoE)基因多态性和阿尔茨海黙病(AD)的相关性.方法 通过使用TaqMan-PCR法检测单核苷酸多态性(SNP)方法,在376例日本人AD患者,包括323例迟发型AD(LOAD)、53例早发型AD(EOAD)和377例非痴呆对照组中观察TM4SF5基因rs4790230(-791T/C)、rs746988(+1528T/C)、rs2302328(+11228C/A)及APOE基因的多态性分布,并分析与AD的相关性.结果 (1) TM4SF5基因rs4790230(-791T/C)C/C纯合子频率在EOAD中明显高于对照组(0.70比0.52,P值为0.017) ;rs2302328(+ 11228C/A)携带A等位基因者频率在总AD中略高于对照组(0.88比0.84,P值为0.05);(2)进一步在非APOE4携带者中分析显示rs4790230(-791T/C)C/C纯合子频率在EOAD中仍明显高于对照组(0.85比0.53,P＜0.001);(3)单倍型分析显示病例组C-C-A型与C-T-A型频率分别高于对照组(0.29比0.21;0.35比0.16;P＜0.001);病例组C-T-C型频率低于对照组(0.12比0.28;P＜0.001).结论 TM4SF5基因rs4790230(-791T/C)多态位点独立于APOE与EOAD存在相关性,三位点单倍型C-C-A型与C-T-A型增加了AD的发病风险.     

ApoE基因多态性与阿尔茨海默病的相关性研究

目的 探讨阿尔茨海默病（Alzheimer disease,AD）与载脂蛋白E（ApoE）基因多态性的关系.方法 采用PCR-RFL P方法,对68例晚发型AD（LOAD）、54例早发型AD（EOAD）和168例对照组进行ApoE基因型测定,对AD患者的ApoE基因多态性进行相关分析.结果 两组人群ε3/ε3基因型比例最大,未发现ε2/ε2基因型.APOEε4携带者的频率在LOAD组中是52.5%（43/80）,对照组16.1%（27/168）,其差别有显著性（χ^2=36.2,P＜0.000 1,RR=5.76,95%CI=3.17-10.47）;APOEε4携带者的频率与EOAD呈显著性相关（X^2=6.11,P=0.013 5,RR=2.40,95%CI=1.18-4.86）.结论 ε4等位基因与LOAD、EOAD呈显著性相关,是AD的危险因素之一.     

GRIN2B近似启动子区多态性与散发性阿尔茨海默病相关性分析

目的进一步探讨中国北方汉族人群N-甲基-D-天冬氨酸受体2B(N-methyl-D-aspartate receptor 2B,NR2B)基因GRIN2B近似启动子区(-2454bp至-1269 bp)变异与散发性阿尔茨海默病(sporadic Alzheimer's disease,SAD)的关系。方法利用聚合酶链反应-限制性片段长度多态性(polymerase chain reaction-restriction fragmentlength polymorphism,PCR-RFLP)的方法对中国北方汉族362例SAD患者和334例正常对照者进行GRIN2B近似启动子多态性及载脂蛋白E(apolipoprotein,APOE)分型。结果中国北方汉族人群中GRIN2B近似启动子区除之前发现的-1447T/C(ENS10557853)和-1497G/A(rs12368476)多态性位点外,还存在-1887A/G(rs10845866)和-2315A/G(rs10845867)两个多态性位点。-1887A/G和-2315A/G多态性在SAD和正常对照组中的基因型频率(P=0.841和P=0.298)无显著性差异,等位基因频率(P=0.605和P=0.409)也无显著性差异。无论是否携带APOEε4,-1887A/G和-2315A/G多态性的基因型频率及等位基因频率也均无显著性差异。结论近似启动子区(-2454bp至-1268bp)-1887A/G和-2315A/G变异与AD发病无明显相关性。     

淋巴细胞特异性酪氨酸蛋白激酶基因多态性与阿尔茨海默病的相关性研究

目的探讨淋巴细胞特并性酪氨酸蛋白激酶（LCK）基因多态性、载脂蛋白E（apoE）基因多态性和阿尔茨海默病（AD）的相关性。方法用TaqMan—PCR法检测单核苷酸多态性（SNP），对380例日本人AD患者[包括327例迟发型AD（LOAD）与53例早发型AD（EOAD）]和380例非痴呆对照纽中。观察LCK基因及apoE基因的多态性分布，并分析其与AD的相关性。结果（1）LCK基因＋6424A/G多态位点的G／G基因型息AD风险为非G／G型的1．41倍（95％CI=1．06～1．87），患LOAD风险为1．37倍（95％CI=1．02～1．85）；（2）apoEε4基因携带者患AD风险为非apoEε4基因携带者的5．11倍（95％CI=3．63～7．19）；（3）排除apoE基因型对AD风险的影响后，G／G基因型患AD风险为非G／G型的1．66倍（95％CI=1．16～2．38），患LOAD风险为1．64倍（95％CI=1．12～2．40），同时风险等位基因G与AD（P〈0．05）和LOAD（P〈0．05）具有相关性。结论LCK基因＋6424A／G多态位点与AD风险的增加呈正性相关性，apoEε4增加了AD的发病风险，LCK是独立于APOE基因的又一新的风险基因。     

IDE基因5''''-端侧翼微卫星重复序列的多态性与阿尔茨海默病的相关性研究

目的 研究人群中胰岛素降解酶基因（IDE）5’一端侧翼的微卫星重复序列多态性与阿尔茨海默病（AD）的相关性。方法采用病例一对照方法研究IDE基因5’—端侧翼的微卫星重复序列多态性、载脂蛋白E（ApoE）基因多态性与AD相关性。选择IDE基因5’端侧翼4个微卫星重复序列位点（CA）n、（AC）nC（GT）n、（CA）n（CT）n、（CA）n，按其基因图谱上的顺序分别给予A、B、D10S583、C为其编号；微卫星片段重复序列多态性的分型是用荧光标记引物PCR法，APOE的基因分型是PCR—RFLP法。结果本研究人群中IDE基因5’端侧翼的4个位点的微卫星片段重复序都有多态性；LOAD病例组和正常对照组中等位基因的分布频率有显著性差别；A208bp与EOAD显著性相关（P=0．0138）；APOEe4携带者的频率在LOAD组和对照组分别为52．5％、16．1％（x^2=36．2，P〈0．0001，RR=5．76，95％CI=3．17～10．47）；APOEe4携带者的频率与EOAD呈显著性相关（P=0．0135）；二项逻辑回归分析胰岛素降解酶基因的微卫星重复序列多态性与ApoE基因无显著性意义的相互作用。结论IDE基因5’—端侧翼的微卫星重复序列多态性与晚发型AD的呈显著性相关，支持在染色体10q23—25区域有LOAD候选相关基因的论点，对此区域进行深入研究很有价值。     

载脂蛋白E基因多态性与早发性阿尔茨海默病的相关性

目的：探讨载脂蛋白E（ApoE）基因多态性与早发性阿尔茨海默病（EOAD）的相关性。方法：用扩增抗拒突变系统法检测103例EOAD患者、159例迟发性阿尔茨海默病（LOAD）患者和118例认知功能正常对照（Nc）者的ApoE基因多态性,分析其与EOAD患病的相关性。结果：EOAD组ApoE等位基因和基因型分布频率与正常对照组差异有显著统计学意义,与LOAD组差异无统计学意义;Logisfc回归证实携带ApoEg4与EOAD有显著相关性;ε4等位基因拷贝数的增加,可显著提高EOAD的患病率,但不影响EOAD的发病年龄。结论：ApoEg4是EOAD的独立危险因素,可显著增加EOAD的患病率。     

miR146a基因多态性与早发型阿尔茨海默病的关联性研究

目的 探讨miR146a的基因多态性与早发型阿尔茨海默病（EOAD）的关系.方法 本研究共纳入103例EOAD患者和100名健康对照组人群,采用SnapShot分型技术检测miR146a基因的rs2910164和rs57095329的多态性.结果 病例组的rs57095329位点的基因型和等位基因频率与健康对照组比较,差异有统计学意义（基因型P=0.027 0,等位基因频率P=0.004 2）,而rs2910164的病例组和对照组基因型和基因频率差异无统计学意义（基因型P=0.595 7,等位基因频率P=0.322 6）.结论 miR146a基因的rs57095329多态位点与EOAD的发病风险具有相关性,rs57095329的G等位基因是EOAD的发病风险的保护因素.     

β-分泌酶基因编码区多态性与散发性阿尔茨海默病的关系

目的检测β-分泌酶(BACE1)基因编码区多态性位点与散发性阿尔茨海默病(AD)的相关性,探讨BACE1在AD发病中的作用。方法选择美国国家生物技术信息中心(NCBI)单核苷酸序列多态性数据库(SNPdatabase)中BACE1基因编码区的单核苷酸多态性(SNP)位点,利用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法检测99例散发性AD患者和140例正常人各多态性位点的基因型后,进行病例-对照相关分析。结果在所检的4个多态性位点中,其中3个位点的多态性(rs11216349,rs1061659,rs539765)均未在本研究的标本中检测到,而位于第5外显子的G/C多态性(rs608435),其等位基因的频率在病例组和对照组中分布差别有统计学意义(P=0.039),但基因型频率在两组的分布差别无统计学意义(P=0.095)。结论BACE1编码区上的3个多态性(rs11216349,rs1061659,rs539765)在我国汉人人群中没见到或不存在。外显子5上的G/C多态性(rs608435)的C等位基因可能通过某种途径增加了散发性AD的发病危险性。     

谷胱甘肽硫转移酶Pi基因多态性与Alzheimer病的关系

目的研究谷胱甘肽硫转移酶Pi(GSTPi)基因多态性与Alzheimer病(AD)的关系。方法 AD患者48例,按1:2匹配选择与AD患者同性别、同年龄、同文化程度、无血缘关系、认知功能正常、身体健康的96例老人作为正常对照,外周血提取基因组DNA,聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术检测GSTPi基因第5外显子rs1695位点和第6外显子rs1138272位点基因型。结果 rs1695位点存在A/A、A/G和G/G三种基因型;rs1138272位点存在C/C和C/T两种基因型,未发现T/T型。AD组和对照组rs1695位点基因型分布差异无统计学意义(P>0.05),但AD组等位基因G的频率(32.3%)明显高于对照组(21.9%)(P=0.05)。AD组和对照组rs1138272位点基因型分布及等位基因频率差异无统计学意义(P>0.05)。GSTPi基因染色体单体型G/T(即rs1695位点为等位基因G,rs1138272位点为等位基因T)的频率,AD组(9.1%)明显高于对照组(2.4%),差异无统计学意义(P=0.01)。结论 GSTPi基因rs1695位点等位基因G和rs1138272位点等位基因T可增加AD发生的危险,尤其rs1695位点等位基因G可能与AD发病关系更大。     

The alpha2-macroglobulin gene in AD: a population-based study and meta-analysis

BACKGROUND: Whereas several authors recently reported a positive association between the alpha2-macroglobulin gene (A2M) and late-onset AD (LOAD), others were unable to replicate these findings. Early-onset AD (EOAD) is defined as onset age <65 years. Virtually all patients with LOAD are >65 years of age. OBJECTIVE: To evaluate the role of A2M in AD, the authors conducted a population-based study of EOAD and LOAD as well as a meta-analysis of all studies conducted to date. METHODS: Patients with EOAD (n = 100) were derived from a population-based study in four northern provinces of the Netherlands and the area of metropolitan Rotterdam. Patients with LOAD (n = 344) were drawn from the Rotterdam Study, a population-based prospective study on residents aged 55 years and over of a Rotterdam suburb in the Netherlands. Two polymorphisms were studied, A2M-I/D and A2M-Ile1000Val, in relation to the APOE epsilon4 allele (APOE*4). RESULTS: No genotypic or allelic association was found for either polymorphism in the population-based series of patients with LOAD. In patients with EOAD without APOE*4, a significant increase of carriers of A2M-1000Val was found. The meta-analysis of available published case-control data on these polymorphisms in white and mixed ethnic populations yielded no significant differences between cases and controls. Pooling the Asian studies conducted to date showed a significant decrease in the frequency of A2M-D among patients. CONCLUSIONS: These results suggest that A2M is not genetically associated with LOAD in white patients or mixed populations as found in the United States. In these populations A2M does not have clinical relevance. From a scientific perspective, the findings on EOAD and Asian patients require replication and further research in the A2M region.     

Lymphocyte-specific protein tyrosine kinase is a novel risk gene for Alzheimer disease

Lymphocyte-specific protein tyrosine kinase (LCK) is a lymphoid-specific, Src family protein tyrosine kinase that is known to play a pivotal role in T-cell activation and interact with the T-cell coreceptors, CD4 and CD8. It has been shown to be significantly down-regulated in Alzheimer disease (AD) hippocampus compared with non-demented controls. Furthermore, it is located in a previously identified genetic linkage region (1p34-36) associated with AD. Therefore, we consider it to be a candidate gene for AD. We examined the relationship between AD and the LCK and apolipoprotein E (APOE) genes in 376 AD (including 323 late-onset AD (LOAD) cases and 53 early-onset AD (EOAD) cases) and 378 non-demented controls using a single nucleotide polymorphism (SNP). The polymorphism in intron 1 (+6424 A/G) was significantly associated with AD risk. The odds ratio (OR) for total AD associated with the GG genotype was 1.41 (95% CI=1.06-1.87) and that for LOAD was 1.37 (95%CI=1.02-1.85), while that for APOE-epsilon4 was 5.06 (95% CI=3.60-7.12). In the APOE-epsilon4 non-carrier subgroup, the GG genotype also showed significant association (OR=1.66; 95% CI=1.16-2.38). These results indicate that the LCK is a novel risk gene for AD regardless of the APOE genotype.     

GSK3B基因启动子区多态性与中国北方汉族人群阿尔茨海默病的相关分析

目的研究中国北方汉族人群中糖原合成酶激酶38基因（GSK3B）启动子区rs334558位点基因多态性与阿尔茨海默病（AD）易感性的相关性。方法采用直接测序的方法,对403例AD病例及369名对照外周血DNA的GSK3B基因多态位点rs334558进行基因分型。结果AD组与对照组rs334558位点等位基因和基因型分布相似,等位基因T的频率在AD组和对照组分别为38．8％和37．9％,差异无统计学意义（y。一0．130,P〉0．05）。按照性别或者是否携带AopF~4等位基因分别进行分层分析,发现AD组和对照组之间等位基因频率和基因型分布的差异无统计学意义（,分别为0．331,0．565;P〉0．05）。结论GSK3B基因启动子区多态性位点rs334558可能与中国汉族人群AD发病无关。     

Genetic Association of SLC2A14 Polymorphism with Alzheimer’s Disease in a Han Chinese Population

Glucose uptake and metabolism are impaired in Alzheimer's disease (AD) brain, which appear to be a cause, rather than a consequence of neurodegeneration. Recently, the gene of the 14th isoform of subfamily A of solute carrier family 2 (SLC2A14), encoding glucose transporter 14 (GLUT14), was identified for the association in vivo with AD pathology of Tau, and rs10845990 within SLC2A14 showed association with AD in Caucasians. In order to evaluate the involvement of the SLC2A14 polymorphism in the risk of developing late-onset Alzheimer's disease (LOAD) in Chinese, we performed an independent case-control association study in a Han Chinese population (597 LOAD cases and 605 healthy controls). There were significant differences in genotype and allele frequencies between LOAD cases and controls (genotype P?=?0.015, allele P?=?0.039). The G-carrying genotype (GT?+?GG) individuals showed a 1.41-fold increased risk compared with the TT genotype carriers (odds ratio (OR)?=?1.41, 95 % confidence interval (CI)?=?1.11-1.79, P?=?0.005, Power?=?83.6 %). After stratification by ApoE ε4-carrying status, rs10845990 polymorphism was only significantly associated with LOAD in non-ApoE ε4 allele carriers (P?相似文献   

Early-onset Alzheimer disease in families with late-onset Alzheimer disease: a potential important subtype of familial Alzheimer disease

BACKGROUND: Genetic influences on the development of late-onset Alzheimer disease (LOAD) are heterogeneous and ill defined. OBJECTIVE: To determine the genetic risk factors for LOAD. DESIGN: We asked the following questions: (1) Does early-onset Alzheimer disease (EOAD) occur in families with predominantly LOAD? and (2) Does the apolipoprotein E (APOE) genotype explain the wide differences in onset age in LOAD families? SETTING: University of Washington Alzheimer Disease Research Center, Seattle. PARTICIPANTS: A total of 136 kindreds and a separate group of 29 affected parent-child pairs. MAIN OUTCOME MEASURES: We evaluated the kindreds with familial LOAD for the occurrence of EOAD and the affected parent-child pairs with a 20-year or more difference in the age at onset. RESULTS: In the 136 kindreds with LOAD, 104 had only late-onset cases (men, 36%), whereas 32 families (24%) had a combination of LOAD and EOAD cases. The 44 EOAD cases in these families accounted for 20% of cases of AD in the 32 families and 6% in all 136 families. The early-onset cases had a mean +/- SD onset age of 56.1 +/- 3.2 years (range, 45-59 years; men, 50%). Seven (28%) of 25 individuals with EOAD sampled did not have an APOE epsilon4 allele, and 2 of the earliest-onset cases were epsilon3/epsilon3. In 29 parent-child pairs with a 20-year or more difference in age at onset, 7 (35%) of the 20 children sampled did not have an APOE epsilon4 allele. CONCLUSIONS: Many LOAD families (approximately 25%) have at least 1 individual with EOAD, and in these individuals, the ratio of men to women is nearly 50%, suggesting a possible subtype of familial AD. The APOE genotype plays an important role in these early-onset cases, but at least one fourth of the risk must represent the influence of other genetic and/or environmental factors. These LOAD families with early-onset cases represent an important resource for investigation of these factors.     

The APOE4 effect: structural brain differences in Alzheimer's disease according to the age at symptom onset

Background and purpose

How the APOE genotype can differentially affect cortical and subcortical memory structures in biomarker-confirmed early-onset (EOAD) and late-onset (LOAD) Alzheimer's disease (AD) was assessed.

Method

Eighty-seven cerebrospinal fluid (CSF) biomarker-confirmed AD patients were classified according to their APOE genotype and age at onset. 28 were EOAD APOE4 carriers (+EOAD), 21 EOAD APOE4 non-carriers (–EOAD), 23 LOAD APOE4 carriers (+LOAD) and 15 LOAD APOE4 non-carriers (–LOAD). Grey matter (GM) volume differences were analyzed using voxel-based morphometry in Papez circuit regions. Multiple regression analyses were performed to determine the relation between GM volume loss and cognition.

Results

Significantly more mammillary body atrophy in +EOAD compared to –EOAD is reported. The medial temporal and posterior cingulate cortex showed less GM in +LOAD compared to –LOAD. Medial temporal GM volume loss was also found in +EOAD compared to –LOAD. With an exception for +EOAD, medial temporal GM was strongly associated with episodic memory in the three groups, whilst posterior cingulate cortex GM volume was more related with visuospatial abilities. Visuospatial abilities and episodic memory were also associated with the anterior thalamic nucleus in –LOAD.

Conclusions

Our results show that the APOE genotype has a significant effect on GM integrity as a function of age of disease onset. Specifically, whilst LOAD APOE4 genotype is mostly associated with increased medial temporal and parietal atrophy compared to –LOAD, for EOAD APOE4 might have a more specific effect on subcortical (mammillary body) structures. The findings suggest that APOE genotype needs to be taken into account when classifying patients by age at onset.     

Analysis of UBQLN1 variants in a Polish Alzheimer's disease patient: control series

Late-onset Alzheimer's disease (LOAD) is the most common neurodegenerative disorder, and has a complex etiology. Recently an intronic polymorphism in the ubiquilin 1 gene (UBQLN1) and a particular haplotype was reported to be associated with LOAD. We investigated whether variants in UBQLN1 confer a risk for the disease in 407 Polish LOAD patients and 407 controls. We observed a weak association with the rs2781002 polymorphism, however, contrary to the initial reports, in our group the association was with the A allele. Risk estimation for AA versus GG genotypes showed that the AA genotype is a weak risk factor for AD (OR = 1.8, 95% CI = 1.1-3.1, p = 0.025). This effect was stronger in a group of LOAD patients without APOE4 allele. Haplotype analyses indicate that there is an increase of haplotypes with an A allele in the case group. Also, the specific haplotypes with the A allele that increase AD risk differ between the APOE4-positive and APOE4-negative pools. However, the association observed seems to be driven mostly by rare (<5%) haplotypes. Results suggest a need for additional association studies and in silico analysis of the UBQLN1 locus.     

Association of TOMM40 Polymorphisms with Late-Onset Alzheimer’s Disease in a Northern Han Chinese Population

Mitochondrial dysfunction is an early defect in the pathogenesis of late-onset Alzheimer’s disease (LOAD). One interesting candidate gene for mitochondrial dysfunction in LOAD is the translocase of outer mitochondrial membrane 40 homolog (TOMM40) gene. Several single nucleotide polymorphisms (SNPs) within TOMM40 have been shown to affect susceptibility to LOAD in Caucasians, while there are no studies on the association of the polymorphisms with LOAD risk in Han Chinese. Here, the association of TOMM40 polymorphisms in LOAD was investigated in a large Northern Han Chinese cohort consisting of 1,578 individuals. Both allelic and genotypic associations of three SNPs (rs157580, rs2075650, and rs11556505) with LOAD risk were observed in the total sample as well as in the non- APOE ε4 carriers. For rs1160985, the allele and genotype frequencies differed significantly only in APOE ε4 carriers. After adjustment for age, gender, and APOE ε4 status, the association remained statistically significant only for the rs157580 but not for rs2075650 and rs11556505. In contrast, the rs1160985 exhibited significant risk effect after adjustment. In addition, haplotype analysis confirmed that the haplotypes derived from SNPs in rs2075650, rs11556505, and rs1160985 were associated with either risk or protective effects. In summary, our findings suggest that the TOMM40 polymorphisms may play a role in the pathogenesis of LOAD in Han Chinese.