RESUMO
In our search for genetic factors related to the development of Alzheimer's disease, we have genotyped 332 pedigrees for three coding polymorphisms in the ABCA1 gene, two of which are known to alter plasma cholesterol levels, as well as a non-coding polymorphism within the promoter. We show an apparent weak association of rs2230806 (p-value=0.01) with the disease in a sibpair series of Alzheimer's disease that had shown previously evidence for linkage to the chromosome 9 locus where ABCA1 maps.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Doença de Alzheimer/genética , Predisposição Genética para Doença/genética , Transportador 1 de Cassete de Ligação de ATP , Idoso , Feminino , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Linhagem , Polimorfismo de Fragmento de Restrição , Fatores de RiscoRESUMO
Genetic linkage studies have provided evidence for a late-onset Alzheimer's disease (AD) susceptibility locus on chromosome 21q. We have tested, in a two-stage association study, whether allelic or haplotype variation of the beta-amyloid cleaving enzyme-2 (BACE2) locus on chromosome 21q affects the risk of late-onset AD. In stage-1, an unselected population-based sample of Finns aged 85 years or over (n=515) was analysed. Neuropathologic examination including beta-amyloid load quantification was possible in over 50% (n=264) of these subjects. AD patients (n=100) and controls (n=48) were defined by modified neuropathological NIA-RI criteria. Positive associations were taken as a hypothesis, and tested in stage-2 using 483 AD families from the USA. Four single nucleotide polymorphisms (SNPs) of BACE2 gene were tested in stage-1. A SNP close to exon-6 was associated with neuropathologically verified AD (p=0.02) and also with beta-amyloid load in non-selected autopsied subjects after conditioning with APOE genotype (p=0.001). In haplotype analysis a specific, relatively common haplotype (H5) was found to associate with AD (p=0.004) and a second haplotype (H7) showed a weaker association with protection against AD (p=0.04). In stage-2, the SNP association was not replicated, whereas the haplotype H5 association was replicated (p=0.004) and a trend to association was found with the putative protective haplotype H7 (two-sided p=0.08). BACE2 haplotype association with AD in two independent datasets provides further evidence for an AD susceptibility locus on chromosome 21q within or close to BACE2.
Assuntos
Doença de Alzheimer/genética , Ácido Aspártico Endopeptidases/genética , Cromossomos Humanos Par 21 , Predisposição Genética para Doença , Idoso , Idoso de 80 Anos ou mais , Secretases da Proteína Precursora do Amiloide , Apolipoproteínas E/genética , Distribuição de Qui-Quadrado , Bases de Dados como Assunto , Éxons , Feminino , Haplótipos , Humanos , Masculino , Exame Neurológico/métodos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
We performed an affected sib-pair (ASP) linkage analysis to test for the effects of age at onset (AAO), rate of decline (ROD), and Apolipoprotein E (APOE) genotype on linkage to late-onset Alzheimer's disease (AD) in a sample comprising 428 sib-pairs. We observed linkage of mean AAO to chromosome 21 in the whole sample (max LOD = 2.57). This came entirely from the NIMH sample (max LOD = 3.62), and was strongest in pairs with high mean AAO (>80). A similar effect was observed on chromosome 2q in the NIMH sample (max LOD = 2.73); this region was not typed in the IADC/UK sample. Suggestive evidence was observed in the combined sample of linkage of AAO difference to chromosome 19q (max LOD = 2.33) in the vicinity of APOE and 12p (max LOD = 2.22), with linkage strongest in sib-pairs with similar AAO. Mean ROD showed suggestive evidence of linkage to chromosome 9q in the whole sample (max LOD = 2.29), with the effect strongest in the NIMH sample (max LOD = 3.58), and in pairs with high mean ROD. Additional suggestive evidence was also observed in the NIMH sample with AAO difference on chromosome 6p (max LOD = 2.44) and 15p (max LOD = 1.87), with linkage strongest in pairs with similar AAO, and in the UK sample with mean ROD on chromosome 1p (max LOD = 2.73, linkage strongest in pairs with high mean ROD). We also observed suggestive evidence of increased identical by descent (IBD) in APOE epsilon4 homozygotes on chromosome 1 (max LOD = 3.08) and chromosome 9 (max LOD = 3.34). The previously reported genome-wide linkage of AD to chromosome 10 was not influenced by any of the covariates studied.
Assuntos
Doença de Alzheimer/genética , Predisposição Genética para Doença/genética , Genoma Humano , Idade de Início , Apolipoproteínas E/genética , Mapeamento Cromossômico , Ligação Genética , Genótipo , Humanos , Escore Lod , IrmãosRESUMO
The gene encoding alpha-T-catenin, CTNNA3, is positioned within a region on chromosome 10, showing strong evidence of linkage to Alzheimer's disease (AD), and is therefore a good positional candidate gene for this disorder. We have demonstrated that alpha-T-catenin is expressed in human brain, and like other alpha-catenins, it inhibits Wnt signaling and is therefore also a functional candidate. We initially genotyped two single-nucleotide polymorphisms (SNPs) in the gene, in four independent samples comprising over 1200 cases and controls but failed to detect an association with either SNP. Similarly, we found no evidence for association between CTNNA3 and AD in a sample of subjects showing linkage to chromosome 10, nor were these SNPs associated with Abeta deposition in brain. To comprehensively screen the gene, we genotyped 30 additional SNPs in a subset of the cases and controls (n > 700). None of these SNPs was associated with disease. Although an excellent candidate, we conclude that CTNNA3 is unlikely to account for the AD susceptibility locus on chromosome 10.
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Cromossomos Humanos Par 10/genética , Proteínas do Citoesqueleto/metabolismo , Ligação Genética/genética , Proteínas Proto-Oncogênicas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Processamento Alternativo/genética , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/fisiopatologia , Química Encefálica/genética , Estudos de Casos e Controles , Linhagem Celular , Mapeamento Cromossômico , Análise Mutacional de DNA , Feminino , Expressão Gênica/genética , Frequência do Gene/genética , Testes Genéticos , Genótipo , Humanos , Masculino , Camundongos , Polimorfismo Genético/genética , Transdução de Sinais/genética , Proteínas Wnt , alfa CateninaRESUMO
Linkage studies indicate that the same region of chromosome 10 contains a risk locus for late onset Alzheimer disease (LOAD) and a QTL for plasma Abeta42 levels suggesting that a single locus may influence risk for AD by elevating plasma Abeta42 [Ertekin-Taner et al., 2000; Myers et al., 2000]. A strong positional and biological candidate is the urokinase-plasminogen activator (PLAU) gene. Eight polymorphisms spanning the entire gene were examined using case control (CC) and family-based association methods. No association was observed by any method making it unlikely that variation in PLAU explains our linkage data.
Assuntos
Doença de Alzheimer/genética , Cromossomos Humanos Par 10/genética , Ativador de Plasminogênio Tipo Uroquinase/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença de Alzheimer/patologia , Estudos de Casos e Controles , Feminino , Frequência do Gene , Ligação Genética , Genótipo , Haplótipos , Humanos , Masculino , Polimorfismo GenéticoRESUMO
Apolipoprotein(a) (Apo(a)) is a glycoprotein that is linked by a disulfide bond to apolipoprotein B on low density lipoprotein particles to form lipoprotein(a) (Lp(a)). High plasma levels of Lp(a) are thought to contribute directly to the development of atherosclerosis. We tested a variant (T3888P) located in the Kringle-IV region of Apo(a) in a case-control series. Overall, there were no differences between case and controls. However, in the apoE2 positive subgroup, we noticed that the mutant allele is over-represented in the cases (P=0.005). We suggest that this polymorphism and others at the Apo(a) locus be further studied in relation to Alzheimer's disease.
Assuntos
Doença de Alzheimer/genética , Apolipoproteínas E/genética , Apolipoproteínas/genética , Variação Genética , Lipoproteína(a)/genética , Apolipoproteína E2 , Apoproteína(a) , Estudos de Casos e Controles , Genótipo , Humanos , Kringles/genética , Mutação PuntualRESUMO
Results from various genetic association studies of the lipoprotein lipase (LPL) S447X polymorphism and Alzheimer's disease (AD), range from a statistically significant negative association of clinically examined patients to a non-significant but consistent trend for under-representation of the X447 allele in neuropathologically confirmed subjects. In this report we have compared the distribution of the above polymorphism in an independent group of clinically diagnosed AD patients, including a subgroup where the disease was pathologically confirmed, and a spousal control group. No statistically significant differences emerged from this comparison. We conclude that LPL cannot be a major factor in pathogenesis of AD.
Assuntos
Doença de Alzheimer/enzimologia , Doença de Alzheimer/genética , Lipase Lipoproteica/genética , Idoso , Alelos , Doença de Alzheimer/patologia , Apolipoproteínas E/genética , Feminino , Marcadores Genéticos , Genótipo , Humanos , Masculino , Polimorfismo Genético/genéticaRESUMO
We performed a two-stage genome screen to search for novel risk factors for late-onset Alzheimer disease (AD). The first stage involved genotyping 292 affected sibling pairs using 237 markers spaced at approximately 20 cM intervals throughout the genome. In the second stage, we genotyped 451 affected sibling pairs (ASPs) with an additional 91 markers, in the 16 regions where the multipoint LOD score was greater than 1 in stage I. Ten regions maintained LOD scores in excess of 1 in stage II, on chromosomes 1 (peak B), 5, 6, 9 (peaks A and B), 10, 12, 19, 21, and X. Our strongest evidence for linkage was on chromosome 10, where we obtained a peak multipoint LOD score (MLS) of 3.9. The linked region on chromosome 10 spans approximately 44 cM from D10S1426 (59 cM) to D10S2327 (103 cM). To narrow this region, we tested for linkage disequilibrium with several of the stage II microsatellite markers. Of the seven markers we tested in family-based and case control samples, the only nominally positive association we found was with the 167 bp allele of marker D10S1217 (chi-square=7.11, P=0.045, df=1).
