Association of alpha 2-macroglobulin polymorphisms and Alzheimer disease in Mainland Han Chinese

This study used case-control method to investigate roles of two α2-macroglobulin (A2M) polymorphisms, a 5-bp insertion/deletion (A2M-I/D) and an A→G substitution (A2M-A/G), in the development of sporadic Alzheimer disease (AD) in Mainland Han Chinese. Our results showed a trend of lower D-carrying genotype frequency in APOE-ε4 carrying AD patients than in corresponding control subjects (χ²=3.67, p=0.055). The ID/AA genotype frequency was lower in AD patients comparing with controls (χ²=4.04, p=0.044). In AD patients, the G-carrying genotype frequency was significantly higher in APOE-ε4 carrier subgroup than in APOE-ε4 non-carriers (χ²=7.38, OR=2.99, 95% CI: 1.33-6.71, p=0.007). These results indicated that A2M-D allele was probably a weak AD protective factor, and there was a possible interaction of APOE-ε4 and A2M-G alleles to increase AD risk in Mainland Han Chinese.     

No genetic association between the LRP receptor and sporadic or late-onset familial Alzheimer disease

The low-density lipoprotein receptor-related protein gene (LRP1) is often mentioned as a candidate gene for Alzheimer disease (AD) because of its role as a receptor for apolipoprotein E (apoE), a major genetic risk factor for late-onset familial and sporadic AD. A recent association study of a tetranucleotide repeat polymorphism located 5′ to the LRP1 gene detected an increase in the 87 base pair allele in AD cases compared to unaffected controls. Additionally, an independent study involving a genomic screen for genes associated with late-onset AD identified a region as a possible location of a late-onset AD gene on chromosome 12p between D12S373 and D12S390, about 10 cM proximal to LRP1. We examined 144 late-onset multiplex AD families, 436 sporadic AD cases, and 240 controls and found no evidence of linkage or association of LRP1 and AD. Our data indicate that genetic variation of the LRP1 gene is not a major risk factor in the etiology of AD. Received: June 16, 1997 / Accepted: August 10, 1997     

The role of low-density receptor-related protein 1 (LRP1) as a competitive substrate of the amyloid precursor protein (APP) for BACE1

Cleavage of APP by BACE1 is the first proteolytic step in the production of amyloid-beta (Aβ), which accumulates in senile plaques in Alzheimer's disease. Through its interaction with APP, the low-density receptor-related protein 1 (LRP1) enhances APP internalization. Recently, BACE1 has been shown to interact with and cleave the light chain (lc) of LRP1. Since LRP1 is known to compete with APP for cleavage by gamma-secretase, we tested the hypothesis that LRP1 also acts as a competitive substrate for β-secretase. We found that the increase in secreted APP (sAPP) mediated by over-expression of BACE1 in APP-transfected cells could be decreased by simultaneous LRP1 over-expression. Analysis by multi-spot ELISA revealed that this is due to a decrease in sAPPβ, but not sAPPα. Interaction between APP and BACE1, as measured by immunoprecipitation and fluorescence lifetime assays, was impaired by LRP1 over-expression. We also demonstrate that APP over-expression leads to decreased LRP1 association with and cleavage by BACE1. In conclusion, our data suggest that - in addition to its role in APP trafficking - LRP1 affects APP processing by competing for cleavage by BACE1.     

The role of the low-density lipoprotein receptor-related protein (LRP1) in Alzheimer's A beta generation: development of a cell-based model system

The clearance and degradation of extracellular Aβ is critical for regulating β-amyloid deposition, a major hallmark of brains of patients with Aβ in Alzheimer’s Disease. The low-density lipoprotein receptor-related protein, LRP1, is a large endocytic receptor that significantly contributes to the balance between degradation and production of Aβ. An extracellular portion of the LRP, known as the cluster II region can bind to the secreted form of APP (sAPP-KPI). We show here that a GST fusion protein containing the cluster II region of LRP can be used as a ‘mini-receptor’ that specifically binds to sAPP-KPI from conditioned cultured medium. The binding between the GST-LRP-cluster II fusion protein and sAPP-KPI can be inhibited with the strong binding ligand of LRP1, called receptor-associated protein (RAP). Furthermore, a cell-based in vitro assay system has been developed to monitor the production of total Aβ and Aβ_1–42 in the presence and absence of RAP in Chinese hamster ovary (CHO) cell lines both deficient in LRP and expressing LRP. A 3-day treatment of the L2 (CHO cells deficient in LRP and overexpressing APP751) and L3 (CHO cells expressing LRP and overexpressing APP751) cell lines with RAP showed a decrease in total Aβ and, interestingly, also a decrease in the ratio of Aβ₄₂/Aβ_total. This cell-based model system and LRP-cluster II mini-receptor will be very useful for screening novel compounds that can reduce Aβ accumulation by inhibiting binding of APP-KPI to LRP1.     

Role of LRP10 in Parkinson's disease in a Taiwanese cohort

IntroductionVariants in the low-density lipoprotein receptor–related protein 10 (LRP10), linked to inherited forms of α-synucleinopathies, have been reported. Nine variants of LRP10 were identified in the first such report, and subsequent studies have identified possible pathogenic variants in patients with sporadic Parkinson's disease (PD). Few studies have investigated the role of LRP10 in PD. We sought to validate the role of this gene in Taiwanese patients with PD.MethodsIn total, 1277 individuals were included in this study (669 had PD and 608 were controls). The entire LRP10 coding exons and exon–intron boundaries were sequenced in 103 probands with early-onset PD or familial PD. We then genotyped the newly identified variants from the 103 patients and previously reported potential pathogenic variants in our cohort. The frequencies of variants were analyzed.ResultsFive new and possibly pathogenic variants were identified initially. In total, 14 potentially pathogenic variants (including nine previously reported and five newly identified variants) were analyzed thereafter. We did not find any significant associations between any variant and the risk of PD. However, c.1424+5delG was identified in a patient with sporadic PD who was diagnosed as having PD and dementia and who had prominent psychiatric symptoms.ConclusionAlthough we identified a patient with sporadic PD and dementia carrying a c.1424+5delG variant, our data did not provide sufficient evidence to support the role of LRP10 in PD in Taiwanese adults.     

Association of neural cell adhesion molecule 1 gene polymorphisms with bipolar affective disorder in Japanese individuals.

BACKGROUND: Although the pathogenesis of mood disorders remains unclear, heritable factors have been shown to be involved. Neural cell adhesion molecule 1 (NCAM1) is known to play important roles in cell migration, neurite growth, axonal guidance, and synaptic plasticity. Disturbance of these neurodevelopmental processes is proposed as one etiology for mood disorder. We therefore undertook genetic analysis of NCAM1 in mood disorders. METHODS: We determined the complete genomic organization of human NCAM1 gene by comparing complementary deoxyribonucleic acid and genomic sequences; mutation screening detected 11 polymorphisms. The genotypic, allelic, and haplotype distributions of these variants were analyzed in unrelated control individuals (n = 357) and patients with bipolar disorder (n = 151) and unipolar disorder (n = 78), all from central Japan. RESULTS: Three single nucleotide polymorphisms, IVS6+32T>C, IVS7+11G>C and IVS12+21C>A, displayed significant associations with bipolar disorder (for allelic associations, nominal p =.04, p =.02, and p =.004, respectively, all p >.05 after Bonferroni corrections). Furthermore, the haplotype located in a linkage disequilibrium block was strongly associated with bipolar disorder (the p value of the most significant three-marker haplotype is .005). CONCLUSIONS: Our results suggest that genetic variations in NCAM1 or nearby genes could confer risks associated with bipolar affective disorder in Japanese individuals.     

A novel presenilin 1 mutation (L174 M) in a large Cuban family with early onset Alzheimer disease

We studied a Cuban family with presenile dementia (autosomal dominant) consisting of 281 members within six generations, the proband descended from a Spanish founder. Mean age at onset was 59 years of age. Memory impairment was the main symptom in all patients, additionally, ischemic episodes were described in 4 (n=18) patients. Neuropathological examination of brain material (1 patient) revealed neuronal loss, amyloid plaques, and neurofibrillary tangles. Thirty DNA samples were genotyped (regions on chromosome 1, 3, 10, 12, 14, 17, 19, 20, and 21). A maximum Lod score of 3.79 at θ=0 was obtained for marker D14S43, located in a 9-cM interval in which all patients shared the same haplotype. Sequencing of the PSEN1 gene revealed a heterozygous base substitution, C520A (exon 6), which is predicted to cause an amino acid change from leucine to methionine in the TMIII of the presenilin 1 protein. The mutation was found to co-segregate with the disease phenotype and the associated disease haplotype. The C→A change was not observed in 80 control chromosomes from the Cuban population. Leucine at position 174 is highly conserved among species and is identical in presenilin 1 and presenilin 2 proteins. We propose the L174 M mutation might lead to an abnormal N-terminal and probably C-terminal fragments and malfunction of the protein complex. In conclusion, we found a novel PSEN1 mutation in a large family with clinical and pathological diagnosis of early onset familial Alzheimer disease, which may be relevant for other Hispanic populations. Electronic Publication     

DISC1基因多态性与中国上海汉族人群阿尔茨海默病的关联研究

目的：探讨精神分裂症断裂基因(DISC1)rs821633,rs1000731单核苷酸多态性(SNP)与阿尔茨海默病(AD)的关系.方法提取中国上海汉族441例 AD 患者和749名健康对照组的 DNA,采用 Taqman 探针 SNP 基因分型技术测定 DISC1基因 SNP rs821633和 rs1000731位点的等位基因及基因型,检测两组受试者等位基因及基因型的频率分布差异.结果两组受试者中 rs821633不符合Hardy－Weinberg 平衡定律给予舍弃,rs1000731符合 Hardy－ Weinberg 平衡定律纳入,rs1000731位点的等位基因及基因型在两组受试者中分布比较,差异无统计学意义(P ＞0．05).结论 DISC1基因SNP rs1000731与 AD 无明显关联.     

中国汉族人群中LRP 766C/T多态性与阿尔茨海默病的关联性研究

目的 研究中国汉族人群中低密度脂蛋白受体相关蛋白766C／T（LRP 766C／T）多态性与阿尔茨海默病（AD）发病的关联性。方法 通过实时定量荧光聚合酶链反应（FQ-PCR）技术和GeneAmp 5700 SDS软件检测519例AD患者和549例非痴呆对照者LRP 766C／T的基因多态性，应用Logistic回归模型分析其与AD发病的相关性。结果 LRP的C／C、C／T和T／T基因型在AD组和对照组中分布差异存在统计学意义（P〈0．05），经条件Logistic回归模型调整年龄和性别的影响后，C等位基因为AD发病的危险因素，其OR值为1．66（P〈0．05）。结论 中国汉族人群中LRP的C等位基因可增加发生AD的危险性。     

丝裂酶原活化蛋白激酶1基因多态性与中国汉族阿尔茨海默病的关联研究

目的:研究探讨丝裂酶原活化蛋白激酶1(MAPK1)基因在中国汉族阿尔茨海默病(AD)发生过程中的作用。方法:根据《美国精神障碍诊断和统计手册》(DSM-IV)和美国国立神经病、语言功能紊乱和脑卒中研究所及AD和相关疾病协会临床诊断标准(NINCDS-ADRDA),收集中国东部和西南部人群AD患者715例和健康对照者760人。选取MAPK1基因3个标签多态性位点rs2276006、rs1063311和rs2006893。采用SNa Pshot SNP分型技术对这3个SNP位点进行分析。结果:中国东部和西南部人群AD组与对照组间MAPK1基因各位点基因多态性及等位基因分布频率差异无统计学意义(P0.05);东部及西南部人群合并后AD组与对照组间MAPK1基因各位点基因多态性及等位基因分布频率差异无统计学意义(P0.05),连锁不平衡检验显示各SNP位点之间存在强连锁(D'0.95),单体型分析结果显示病例组与对照组间单体型估计频率差异无统计学意义(P0.05)。结论:MAPK1基因可能不是中国汉族AD的主要致病基因。     

β-分泌酶2多态性位点rs2252576与散发性阿尔茨海默病的相关性分析

目的 研究β-分泌酶2（BACE2） rs2252576位点基因多态性与中国北方汉族人群散发性阿尔茨海默病（SAD）发病的相关性.方法 随机选取10例SAD患者和10名健康对照者进行BACE2外显子区测序.筛查出第5外显子上游10bp存在一多态性位点rs2252576C/T,随后对348例SAD患者和294名健康对照者进行多态性分型及统计学分析.结果 SAD患者和健康对照组的BACE2基因rs2252576多态性位点基因型和等位基因频率差异无统计学意义（P＞0.05）.根据是否携带ApoEε4等位基因进行进一步分层比较后,该位点差异仍无统计学意义（P＞0.05）.应用Logistic回归分析平衡了年龄、性别和ApoE分型的影响后,差异仍无统计学意义（P＞0.05）.结论 中国北方汉族人群中BACE2基因rs2252576 C/T位点的基因多态性与SAD的发病可能无关.     

精神分裂症和心境障碍混合家系MLC1基因多态性的关联研究

目的在中国汉族人群精神分裂症和心境障碍混合家系中探讨位于22q13的MLC1基因多态性(rs11568171、rs2076137及rs2235349)与精神分裂症、心境障碍的关系。方法在有精神分裂症和心境障碍混合遗传家族史的67个核心家系(包括44个完整的核心家系)中,采用聚合酶链式反应和限制性片断长度多态性(PCR-RFLP)方法,分析MLC1基因上述多态性的基因型及其单体型,进行传递不平衡检验(TDT)。结果患者组与父母组之间,MLC1基因rs11568171T/C、rs2076137T/C及rs2235349T/C多态性等位基因和基因型分布差异无统计学意义(P>0.05),且TDT结果示各多态性在精神分裂症或心境障碍组中父母与患者之间等位基因传递差异均无统计学意义(P>0.05)。单体型TDT显示,精神分裂症患者组中父母与患者之间单体型T-C-T明显传递过少(2=5.0,P<0.05),而单体型C-C-C明显传递过多(2=5.0,P<0.05)。结论在中国汉族人群中MLC1基因可能是精神分裂症的易感基因,但可能不是心境障碍的易感基因。     

新疆维吾尔族和汉族阿尔茨海默病患者载脂蛋白E基因的多态性研究

目的 探讨新疆维吾尔族(以下简称维族)与汉族阿尔茨海默病(AD)患者载脂蛋白E(apoE)基因型及等位基因频率的分布及其异同.方法 在流行病学调查基础上,采用美国神经病学会、语言障碍和卒中-老年性痴呆和相关疾病学会制定的标准,诊断为很可能AD的患者209例(汉族98例、维族111例)及正常对照220名(汉族103名、维族117名),应用聚合酶链反应-限制性片段长度多态分析方法,检测两组apoE基因多态性.结果 (1)AD组及对照组组内维、汉两民族受试者apoE基因型频率和等位基因频率整体分布的差异无统计学意义(P＞0.05);但AD组ε3/4基因型(28.2%)和84等位基因频率(14.8%)均高于对照组(分别为13.2%和8.0%,P＜0.05).(2)在维、汉两民族中,AD组ε3/4基因型频率(维族:30.6%;汉族:25.5%)和ε4等位基因频率(维族:15.8%;汉族:13.8%)均高于本民族对照组(ε3/4基因型频率分别为维族:14.5%,汉族:11.7%;ε4等位基因频率分别为维族:9.4%,汉族:6.3%;P均＜0.05).(3)AD组男性维族患者ε3/4基因型频率(31%)高于对照组男性维族受试者(11%);AD组女性维族患者(16%)和汉族患者ε4等位基因频率(14%),分别高于对照组女性维族受试者(8%)和汉族受试者(7%;P均＜0.05).结论 apoE基因型及等位基因频率在维、汉民族间的分布相似;apoEe4等位基因是AD的危险因素,在维、汉两民族女性AD的发病中起重要作用.     

Close association of water channel AQP1 with amyloid-β deposition in Alzheimer disease brains

Aquaporin-1 (AQP1), a membrane water channel protein, is expressed exclusively in the choroid plexus epithelium in the central nervous system under physiological conditions. However, AQP1 expression is enhanced in reactive astrocytes, accumulating in brain lesions of Creutzfeldt-Jakob disease and multiple sclerosis, suggesting a role of AQP1-expressing astrocytes in brain water homeostasis under pathological conditions. To clarify a pathological implication of AQP1 in Alzheimer disease (AD), we investigated the possible relationship between amyloid-beta (Abeta) deposition and astrocytic AQP1 expression in the motor cortex and hippocampus of 11 AD patients and 16 age-matched other neurological disease cases. In all cases, AQP1 was expressed exclusively in a subpopulation of multipolar fibrillary astrocytes. The great majority of AQP1-expressing astrocytes were located either on the top of or in close proximity to Abeta plaques in AD brains but not in non-AD cases, whereas those independent of Abeta deposition were found predominantly in non-AD brains. By Western blot, cultured human astrocytes constitutively expressed AQP1, and the levels of AQP1 protein expression were not affected by exposure to Abeta(1-42) peptide, but were elevated by hypertonic sodium chloride. By immunoprecipitation, the C-terminal fragment-beta (CTFbeta) of amyloid precursor protein interacted with the N-terminal half of AQP1 spanning the transmembrane helices H1, H2 and H3. These observations suggest the possible association of astrocytic AQP1 with Abeta deposition in AD brains.     

Genetic association of argyrophilic grain disease with polymorphisms in alpha-2 macroglobulin and low-density lipoprotein receptor-related protein genes

Argyrophilic grain disease (AGD) is a neurodegenerative disorder of the aged human brain associated with the formation of abnormal tau protein in specific neurones and macroglial cells. Previously, we reported the association between AGD and the epsilon2 allele of apolipoprotein E (ApoE). Here, the polymorphisms of the alpha-2 macroglobulin gene (A2M) and those of the low-density lipoprotein receptor-related protein gene (LRP) were assessed in 115 AGD cases and compared with 170 controls. The results reveal an association between AGD and the C766T polymorphism of LRP (P=0.001). In addition, the present study shows that the valine to isoleucine (Val1000Ile) polymorphism of A2M is linked with AGD (P=0.03). By comparison, no relationship between AGD and the intronic 5-bp deletion/insertion polymorphism of A2M is demonstrable (P=0.8). Finally, this report corroborates and extends our earlier finding in that the frequency of the epsilon2 allele of ApoE is higher in AGD cases than in controls (17.4% vs. 8.5%, P=0.003), whereas the epsilon4 allele frequency approximates that in control cases (13.9% vs. 13.2%, P=0.93). This association, however, is only apparent in the presence of the LRP CC genotype. In conclusion, the present study shows that AGD is associated with the LRP, A2M and ApoE genes.     

Lack of association of SLC1A1 variants with schizophrenia in Chinese Han population

In this study, we analyzed four single nucleotide polymorphisms (SNPs) (rs10491734, rs2228622, rs301430 and rs301443) of the solute carrier family 1 gene (SLC1A1) in a set of 616 schizophrenia patients and 638 matched healthy controls of Han Chinese descent. No significant differences of genotype or allele distribution were identified between the patients and controls. Our data suggest that SLC1A1 is unlikely to be a major susceptibility gene for schizophrenia in Han Chinese.     

Association of TLR9 polymorphisms with sporadic Parkinson's disease in Chinese Han population

Previous studies have acknowledged that inflammatory reaction has implicated in Parkinson's disease (PD) pathogenesis nowadays. Toll-like receptors (TLRs), as key players in the inflammatory reaction, play a pivotal role in the PD pathogenesis and accumulating evidences have shown that TLRs are increased in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of PD. Therefore, the present study aimed to identify the role of the polymorphisms of rs187084 and rs352140 in TLR9 gene with PD. The genotypes were detected by polymerase chain reaction and restriction fragment length polymorphism analysis in 380 PD patients and 380 healthy matched individuals in Chinese Han population. For rs352140, our data revealed a significant difference in allele distribution in female PD group and its healthy matched control (P = 0.040). Moreover, rs352140 T allele carriers of female group were associated with a reduced risk of PD (TT + TC vs. CC, P = 0.018). However, no significant differences in genotype and allele distribution were found between the age and gender subgroups for rs187084. Therefore, our studies indicate that the rs352140 gene polymorphism may be associated with the susceptibility of female PD in Chinese Han population.     

Family-based association studies of the TCP1 gene and schizophrenia in the Chinese Han population

Summary. A previous case-control study by Yang et al. indicated that the TCP1 gene in 6q25 was associated with schizophrenia in the Han population. To replicate this result, we selected eight SNPs (rs2273828, rs3818298, rs1547094, rs1547093, rs2295898, rs2295899, rs4832, rs15982) spanning the whole gene and performed a family-based study using 325 trios samples. Our transmission disequilibrium test showed neither allele nor haplotype association with schizophrenia, and suggests that the TCP1 locus is not associated with schizophrenia in the Chinese population. Since 6q25 has consistently been found to be a susceptible region for schizophrenia, we suggest that other genes within this region should be the focus of attention. The first and second authors contributed equally to this work