α2-巨球蛋白基因多态性与Alzheimer病的关联研究

目的　观察α2-巨球蛋白基因(α2-macroglobulin, A2M)内含子17一种五核苷酸缺失突变在广州地区汉族老年人中的分布，探讨其与晚发Alzheimer病(AD)的相关性。方法　以97例晚发AD患者和111名健康老年人为对照进行病例-对照研究。用聚合酶链反应-限制性片段长度多态性方法分析A2M缺失／插入多态性和载脂蛋白E(apolipoprotein E， apoE)基因多态性。结果　(1)A2M基因缺失突变在晚发AD患者中的频率为2.6%，在正常老年人中的频率为2.7%，在所有受试者中未检测到A2M突变纯合体，晚发AD患者和健康老年人之间不存在A2M等位基因和基因型分布的差异，A2M基因多态性与晚发AD无关联。(2)晚发AD患者中apoE等位基因ε4频率显著升高(Z=3.32，P＜0.01)。晚发AD与ε3／ε4基因型正关联(RR=2.62，χ2=6.89，P＜0.01)，和等位基因ε4正关联(RR=2.67，χ2=10.71，P＜0.01)。(3)晚发AD无论是否伴有apoE-ε4均与A2M不存在相关性。结论　广州汉族人群中A2M基因缺失突变多态性与晚发AD不具有关联。     

α3—巨球蛋白基因多态性与Alzheimer病的关联研究

目的：观察α2-巨球蛋白基因（α2-macroglobulin,A2M) 内含子17一种五核苷酸缺失突变在广州地区汉族老年人中的分布,探讨其与晚发Alzheimer病（AD）的相关性。方法：以97例晚发AD患者和111名健康老年人为对照进行病例－对照研究。用聚合酶链反应－限制性片段长度多态性方法分析A2M缺失／插入多态性和载脂蛋白E（apolipoproteinE,apoE)基因多态性。结果：（1）A2M基因缺失突变在晚发AD患者中的频率为2．6％,在正常老年人中的频率为2．7％,在所有受试者中未检测到A2M突变纯合体,晚发AD患者和健康老年人之间不存在A2M等位基因和基因型分布的差异,A2M基因多态性与晚发AD无关联。（2）晚发AD患者中apoE等位基因ε4频率显著升高（Z＝3．32,P＜0．01）。晚发AD与ε3／ε4基因型正关联（RR＝2．62,χ^2=6.89,P＜0．01）,和等位基因ε4正关联（RR＝2．67,χ^2=10.71,P＜0．01）。（3）晚发AD无论是否伴有apoE-ε4均与A2M不存在相关性。结论：广州汉族人群中A2M基因缺失突变多态性与晚发AD不具有关联。     

CYP1A1基因多态性与妊娠期肝内胆汁淤积症相关性研究

目的 探讨参与雌激素代谢的细胞色素P4501A1(cytochrome P450 1A1,CYPlA1)基因多态性与成都地区妊娠期肝内胆汁淤积症(intrahepatic cholestasis of pregnancy,ICP)的关系.方法 分别应用聚合酶链反应.限制性片段长度多态性技术和等位基因特异性PCR技术,对100例ICP患者和100名正常对照孕妇CYP1A1基因Msp I位点和Ile/Val位点多态性进行分析.结果 Msp I位点多态性在ICP组和对照组中的分布差异无统计学意义(P》0.05),而ICP组含Val等位基因的Ile/Val和Val/Val基因型增加ICP的发病风险(P=0.047,OR=1.768).结论 CYP1A1基因第7外显子的Ile/Val基因多态性可能与成都地区ICP易感性有关;而Msp I位点多态性与ICP的发生无相关性.     

阿尔茨海默病与载脂蛋白E基因-427C/T多态性的关联研究

目的 探讨上海地区汉族人群载脂蛋白E(apolipoprotein E，apoE)基因启动子区—427C／T多态性与Alzheimer病(Alzheimer's disease，AD)发病风险的关系。方法 采用聚合酶链反应和限制性片段长度多态性方法，在104例AD患者和110名正常人中检测了apoE基因—427C／T各基因型及基因频率的分布。按比值比(odds ratio，0R)作疾病关联分析。结果 (1)AD患者与正常对照人群之间不存在—427C／T各等位基因和基因型频率分布的差异(P＞0．05)；(2)按apoE ε4基因分层后，无论是ε4型人群还是非ε4人群都不存在AD患者与正常老人间多态分布的差异(P＞0．05)；(3)在—427C／T 3种基因型中，仅T／T型AD与apoE ε4等位基因呈正关联(OR＝3．94，95％CI：2．206—7．038，x^2＝21．48，P＜0．05)。结论 上海地区汉族人群中，apo E基因—427C／T多态不是AD的疾病易感因子。     

HER-2基因Ile655Val多态性与结直肠癌易感性分析

目的 探讨HER-2原癌基因Ile655Val多态性与结直肠癌易感性的相关性,及其在自然人群中的分布频率.方法 应用病例对照研究,对浙江省嘉善县292例结直肠癌患者和842名健康对照者采用聚合酶链反应-限制性片段长度多态性方法检测HER-2基因密码子655基因型.结果 结直肠癌组HER-2基因Ile/Val+Val/Val基因型频率(25.34%)和Val等位基因频率(13.36%)均显著高于对照组(18.41%和9.74%)(P<0.05).与Ile/lie基因型携带者相比,Ile/Val+Val/Val基因型携带者患结直肠癌的风险增加(OR=1.54,95%CI:1.11～2.14).HER-2基因多态性与吸烟、饮酒的交互作用OR值分别为1.43(95%CI:0.88～2.30)和1.29(95%CI:0.73～2.29).结论 HER-2基因Ile655Val多态性与结直肠癌易感性相关,但是这种多态性与吸烟、饮酒在结直肠癌发生中不存在交互作用.     

GSTM1、GSTT1缺失和GSTP1基因多态性与原发无精症的相关性研究

目的 探讨谷胱甘肽硫转移酶(glutathione S-transferase,GST)基因家族中GSTM1、GSTT1缺失和GSTP1多态性与汉族人群原发性无精子症的相关性.方法 采用病例对照研究的方法,应用多重PCR及PCR-限制性片段长度多态性技术检测236例汉族原发无精症患者和142名正常生育男性的GSTM1、GSTT1基因缺失和GSTP1基因(Ile/Val)多态性.结果 M1(-/-)和P1(Ile/Val或Val/Val)联合基因型在对照组中分布为24.65％(35/142),高于病例组的15.68％(37/236),差异有统计学意义(P=0.031)；M1(-/-),T1(+/+)和P1(Ile/Val或Val/Val)联合基因型在对照组中分布为12.68％ (18/142),高于病例组的5.51％(13/236),差异有统计学意义(P=0.014).结论 M1(-/-)和P1(Ile/Val或Val/Val)联合基因型以及M1(-/-),T1(+/+)和P1(Ile/Val或Val/Val)联合基因型可能降低男性患无精症的风险.     

HER-2基因Ile655Val多态性与结直肠癌易感性分析

目的 探讨HER-2原癌基因Ile655Val多态性与结直肠癌易感性的相关性,及其在自然人群中的分布频率.方法 应用病例对照研究,对浙江省嘉善县292例结直肠癌患者和842名健康对照者采用聚合酶链反应-限制性片段长度多态性方法检测HER-2基因密码子655基因型.结果 结直肠癌组HER-2基因Ile/Val+Val/Val基因型频率(25.34%)和Val等位基因频率(13.36%)均显著高于对照组(18.41%和9.74%)(P<0.05).与Ile/lie基因型携带者相比,Ile/Val+Val/Val基因型携带者患结直肠癌的风险增加(OR=1.54,95%CI:1.11～2.14).HER-2基因多态性与吸烟、饮酒的交互作用OR值分别为1.43(95%CI:0.88～2.30)和1.29(95%CI:0.73～2.29).结论 HER-2基因Ile655Val多态性与结直肠癌易感性相关,但是这种多态性与吸烟、饮酒在结直肠癌发生中不存在交互作用.     

HER-2基因Ile655Val多态性与结直肠癌易感性分析

目的 探讨HER-2原癌基因Ile655Val多态性与结直肠癌易感性的相关性,及其在自然人群中的分布频率.方法 应用病例对照研究,对浙江省嘉善县292例结直肠癌患者和842名健康对照者采用聚合酶链反应-限制性片段长度多态性方法检测HER-2基因密码子655基因型.结果 结直肠癌组HER-2基因Ile/Val+Val/Val基因型频率(25.34%)和Val等位基因频率(13.36%)均显著高于对照组(18.41%和9.74%)(P<0.05).与Ile/lie基因型携带者相比,Ile/Val+Val/Val基因型携带者患结直肠癌的风险增加(OR=1.54,95%CI:1.11～2.14).HER-2基因多态性与吸烟、饮酒的交互作用OR值分别为1.43(95%CI:0.88～2.30)和1.29(95%CI:0.73～2.29).结论 HER-2基因Ile655Val多态性与结直肠癌易感性相关,但是这种多态性与吸烟、饮酒在结直肠癌发生中不存在交互作用.     

HER-2基因Ile655Val多态性与结直肠癌易感性分析

目的 探讨HER-2原癌基因Ile655Val多态性与结直肠癌易感性的相关性,及其在自然人群中的分布频率.方法 应用病例对照研究,对浙江省嘉善县292例结直肠癌患者和842名健康对照者采用聚合酶链反应-限制性片段长度多态性方法检测HER-2基因密码子655基因型.结果 结直肠癌组HER-2基因Ile/Val+Val/Val基因型频率(25.34%)和Val等位基因频率(13.36%)均显著高于对照组(18.41%和9.74%)(P<0.05).与Ile/lie基因型携带者相比,Ile/Val+Val/Val基因型携带者患结直肠癌的风险增加(OR=1.54,95%CI:1.11～2.14).HER-2基因多态性与吸烟、饮酒的交互作用OR值分别为1.43(95%CI:0.88～2.30)和1.29(95%CI:0.73～2.29).结论 HER-2基因Ile655Val多态性与结直肠癌易感性相关,但是这种多态性与吸烟、饮酒在结直肠癌发生中不存在交互作用.     

HER-2基因Ile655Val多态性与结直肠癌易感性分析

目的 探讨HER-2原癌基因Ile655Val多态性与结直肠癌易感性的相关性,及其在自然人群中的分布频率.方法 应用病例对照研究,对浙江省嘉善县292例结直肠癌患者和842名健康对照者采用聚合酶链反应-限制性片段长度多态性方法检测HER-2基因密码子655基因型.结果 结直肠癌组HER-2基因Ile/Val+Val/Val基因型频率(25.34%)和Val等位基因频率(13.36%)均显著高于对照组(18.41%和9.74%)(P<0.05).与Ile/lie基因型携带者相比,Ile/Val+Val/Val基因型携带者患结直肠癌的风险增加(OR=1.54,95%CI:1.11～2.14).HER-2基因多态性与吸烟、饮酒的交互作用OR值分别为1.43(95%CI:0.88～2.30)和1.29(95%CI:0.73～2.29).结论 HER-2基因Ile655Val多态性与结直肠癌易感性相关,但是这种多态性与吸烟、饮酒在结直肠癌发生中不存在交互作用.     

No genetic association between alpha-2 macroglobulin I1000V polymorphism and Japanese sporadic Alzheimer's disease

Alpha-2 macroglobulin (A2M) is a serum pan-protease inhibitor that is related with the pathogenesis of Alzheimer's disease (AD) through its ability to mediate amyloid beta degradation. Recently, it has been reported that the I1000V polymorphism in A2M gene might increase the risk of AD. In the present study, we investigated this mutation in 95 healthy controls and in 111 sporadic AD cases by polymerase chain reaction-restriction fragment length polymorphism method in order to study this hypothesis in the Japanese AD population. Allelic frequencies with the I1000V polymorphism in the gene were 7.4 and 6.8% in the control and AD groups, respectively. Our results failed to demonstrate an association between this polymorphism and Japanese sporadic AD, and the A2M I1000V mutation does not seem to be a risk factor per se for sporadic AD.     

载脂蛋白E基因多态性与散发性老年性痴呆病的关系

目的:探讨载脂蛋白E(apoE)外显子4和增强子元件基因多态性与散发性Alzheimer病(AD)的关系。方法:应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术分别检测apoE外显子4和内含子1内增强子元件(IE1)基因型。结果:(1)ApoE外显子4基因多态性:AD组ε3/4基因型频率(0.381)和ε4等位基因频率(0.226)显著高于对照组(P＜0.05)。(2)ApoEIE1基因多态性AD组G/G基因型频率(0.595)显著高于对照组(P＜0.05)。(3)有apoEε4个体患AD风险为无ε4个体的3倍,比值比为2.932,95%可信区间1.379~6.226;G/G基因型个体患AD风险为G/C、C/C个体的2倍,比值比为2.223,95%可信区间1.075~4.599;经统计分析发现apoEε4与IE1G/G呈非常显著性正相关(P＜0.01);排除apoEε4后发现IE1G/G与AD发病风险无关。结论:ApoEε4等位基因是个体发生AD的危险因素,IE1G/G增加AD发病风险是因其与ε4相关所致。     

Activation of gonadotropin-releasing hormone receptors induces a long-term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus

Besides apolipoprotein E (APOE) polymorphism, whose association with Alzheimer's disease (AD) has been confirmed in most of the numerous population samples studied, other markers have been investigated. In most cases the association firstly described was not confirmed in subsequent works. Since it is important to examine these associations in as many populations as possible, we investigated APOE, APOC1, APOC2, alpha-1 antichymotrypsin (ACT) and presenilin-1 (PS-1) polymorphisms in a series of elderly patients with late-onset sporadic AD from Northern Italy and in a sex and age-matched control group. We could not confirm the significantly higher frequency of the ACT*A allele among carriers of APOE e*4 allele described elsewhere, although a similar trend was observed. The APOC2 and the PS-1 distributions were similar between patients and controls. However, we observed a significant difference in the genotype and allele frequencies of APOE and APOC1: patients had higher e*4 and C1*2 allele frequencies. This finding confirms the important role for APOE in AD occurrence. In addition, APOC1 seems to be an interesting marker because, though in strict linkage disequilibrium with APOE, it seems to play an independent role in AD risk. In contrast to previously reported data, plasma apoE concentrations were similar in patients and in controls. An interaction between APOE and APOC1 polymorphisms and apoE levels was observed in patients: subjects carrying the APOE E3/E2 or the APOC1 2-2 genotype have higher apoE concentrations than those who do not.     

Alpha-2 macroglobulin I1000 V polymorphism in Chinese sporadic Alzheimer's disease and Parkinson's disease

Several lines of evidence have revealed some overlapping pathologies in Alzheimer's disease (AD) and Parkinson's disease (PD). Although the alpha-2 macroglobulin gene (A2M) might be a risk factor of these two neurodegenerative diseases, conclusions from different studies have remained conflicting. Here we studied the role of A2M I1000 V polymorphism in both AD and PD in a Chinese Han population. We found that the A2M I/V genotype is associated with both AD (odds ratio (OR)=2.55, 95% confidential interval (95% CI): 1.20-5.43, attributable fraction (AF)=13.65%) and PD (OR=3.03, 95% CI: 1.30-7.02, AF=16.51%). After classifying according to the age of onset, this association is only detected in early-onset AD patients (OR=3.96, 95% CI: 1.28-12.26) and late-onset PD patients (OR=2.61, 95% CI: 0.97-7.09). Therefore, we conclude that in our samples, the A2M I/V genotype might be a susceptibility variant, even with minor effect, for both sporadic AD and PD.     

Alpha2-macroglobulin, lipoprotein receptor-related protein and lipoprotein receptor-associated protein and the genetic risk for developing Alzheimer's disease

2-Macroglobulin (2M) as well as its receptor, the low-density lipoprotein receptor-related (LRP) and the receptor-associated protein (RAP) are involved in the clearance of cerebral Aβ. Current evidence suggests that polymorphisms in the genes of 2M, LRP and RAP may have functional effects on the proteins. Two independent association samples of 271 AD patients and 280 representative controls were investigated whether the risk for developing AD is altered in carriers of polymorphisms in the 2M-gene (Va1000Ile), in the LRP-gene (Ala216Val) and in the RAP-gene (Val311Met). Genotypes were determined by standard PCR and restriction fragment length polymorphism. The results were adjusted for age, gender and apolipoprotein E-4 (APOE) polymorphism. Inheritance of 2M conferred a small increased risk for sporadic AD with an estimated Mantel–Haenszel odds ratio of 1.47. There was no age- or gender-dependent increase in 2M Val1000Ile allele frequencies in AD patients compared to controls. There was no significant difference in the allele frequencies among control and AD subjects for the LRP and RAP polymorphisms. We found no evidence of an interaction between the 2M and RAP or LRP with regard to conferred risk. Our data suggest that the 2M Val1000Ile polymorphism is weakly associated with AD. Although LRP as well as RAP seem to play an essential role in the metabolism of 2M and APOE, there is no increase in the genetic risk for AD in patients carrying the investigated polymorphisms.     

Alpha2-macroglobulin exon 24 (Val-1000-Ile) polymorphism is not associated with late-onset sporadic Alzheimer's dementia in the Hungarian population

Several lines of biochemical evidence support a role of alpha2-macroglobulin (A2M) in the pathogenesis of Alzheimer's dementia (AD). A2M participates in the general defence mechanism against proteinases and it is supposed to be involved in the degradation of beta-amyloid peptide (betaAP). Furthermore, A2M has been shown to reduce betaAP fibril formation, and it is upregulated in the acute-phase inflammatory response like the process occurring in the AD brain. The exon 18 splice acceptor deletion polymorphism and the exon 24 (Val-1000-Ile) GG genotype were reported to be associated with AD, but the results are contradictory. Since the Hungarian population is genetically distinct from the other European ethnic groups, we examined whether the risk for developing AD is increased in the A2M GG carriers. The interaction of apolipoprotein E (apoE) and A2M polymorphisms was also examined. The distribution of A2M genotypes and alleles in the entire data set was consistent with the previous negative observations in which A and G allelic frequencies were comparable in both groups (72% and 28% in the AD population, and 72% and 28% in the control population, respectively). The GG genotype was over-represented (14%) only in the apoE epsilon4 non-carrier subgroup of AD probands (7% in the control group), but the difference was not significant. Our data suggest that, although A2M has an important role in the AD-specific neurodegenerative process, its exon 24 Val-1000-Ile polymorphism is not likely to be associated with late-onset sporadic AD in the Hungarian population.     

Genetic association between alpha-2 macroglobulin and Japanese sporadic Alzheimer's disease.

Alpha-2 macroglobulin (encoded by the gene A2M) is a serum pan-protease inhibitor that may be related with the pathogenesis of Alzheimer's disease (AD) because of its ability to mediate amyloid beta degradation. Recently, several groups have reported that the five-nucleotides deletion in A2M gene at the 5' splice site of exon 18 might increase risk for AD. In the present study, therefore, this mutation was studied in 69 healthy controls and 55 sporadic AD cases by polymerase chain reaction- restriction fragment length polymorphism method. The allelic frequencies with the deletion (A2M-2) are 9.4 and 6.4% in the control and AD groups, respectively. There is no significant difference in the A2M-2 frequencies between the controls and sporadic AD cases. This is the first report to study the frequencies of A2M-2 in Japanese AD cases, suggesting its no genetic association with sporadic AD.     

Regional European differences in allele and genotype frequencies of low density lipoprotein receptor-related protein 1 polymorphism in Alzheimer's disease.

The low density lipoprotein receptor-related protein 1 (LRP1 gene) is a candidate gene for Alzheimer's disease (AD), because it is a ligand for proteins involved in AD pathogenesis, such as apolipoprotein E (APOE), alpha2-macroglobulin (A2M), amyloid precursor protein (APP), and is located on chromosome 12, within a region linked with AD. An association between a silent polymorphism (C/T) in exon 3 and late onset AD has been reported, with an increased frequency of the C allele, although with conflicting results. We examined this polymorphism in a cohort of 166 sporadic AD patients and 225 sex- and age-matched nondemented controls from Southern Italy. No statistically significant differences were found in LRP1 genotype and allele frequencies between the whole AD sample and controls, nor in early- and late-onset subsets of AD patients. No statistically significant differences in frequencies between LRP1 alleles and AD among APOE allele, age, or gender strata were found. Finally, comparing our results with the findings from other European populations, the LRP1 C allele frequency showed a statistically significant decreasing trend from Northern to Southern regions of Europe, with a concomitant increase in LRP1 T allele frequency, but in AD patients only. Finally, in the AD sample, a decreasing geographical trend from North to South of Europe was found for LRP1 CC genotype, and an inverse trend for LRP1 CT genotype frequency. We suggest that these regional variations in LRP1 genotype and allele frequencies in AD could be related to the different patterns of association between this polymorphism and the disease in various European studies.     

Alpha2-macroglobulin polymorphisms in Italian sporadic and familial Alzheimer's disease

A 5-bp deletion and a Val1000 polymorphism at the alpha(2)-macroglobulin (A2M) gene have recently been reported to be associated with late onset Alzheimer's disease (AD). As recently it has been suggested that the effect of the A2M gene on AD susceptibility may be limited to certain populations or families, we analyzed the segregation of A2M and apolipoprotein E polymorphisms in Italian sporadic and familial AD. We analyzed the two polymorphisms in a total of 346 subjects including 98 controls by polymerase chain reaction-restriction fragment length polymorphism method. Our data do not confirm these associations, in particular we found a significant decrease of the deletion allele in AD with respect to controls. Our data do not support a role for the A2M gene as genetic risk factor for AD.     

The alpha-2 macroglobulin gene is not associated with Alzheimer''s disease in a case-control sample

Genetic association has recently been reported between alleles in the alpha-2-macroglobulin (A2M) gene and the occurrence of Alzheimer's disease (AD) in familial and sporadic samples. We have investigated the A2M intronic deletion polymorphism in a case-control study of 295 unrelated clinic and community-based AD cases, and compared these to a sample of 113 unrelated control individuals recruited as part of an epidemiological study. Our results show no association between A2M and AD in either case sample. Furthermore, A2M is not predictive of AD in an interactive fashion when considering APOE, race or gender. In a subset of our larger sample we have also investigated the A2M Val1000Ile polymorphism, and again find no evidence for association. We conclude that there is no genetic association between A2M and AD in our case-control sample.