RESUMO
Insulin degrading enzyme, encoded by IDE, plays a primary role in the degradation of amyloid beta-protein (A beta), the deposition of which in senile plaques is one of the defining hallmarks of Alzheimer's disease (AD). We recently identified haplotypes in a broad linkage disequilibrium (LD) block encompassing IDE that associate with several AD-related quantitative traits. Here, by examining 32 polymorphic markers extending across IDE and testing quantitative measures of plaque density and cognitive function in three independent Swedish AD samples, we have refined the probable position of pathogenic sequences to a 3' region of IDE, with local maximum effects in the proximity of marker rs1887922. To replicate these findings, a subset of variants were examined against measures of brain A beta load in an independent English AD sample, whereby maximum effects were again observed for rs1887922. For both Swedish and English autopsy materials, variation at rs1887922 explained approximately 10% of the total variance in the respective histopathology traits. However, across all clinical materials studied to date, this variant site does not appear to associate directly with disease, suggesting that IDE may affect AD severity rather than risk. Results indicate that alleles of IDE contribute to variability in A beta deposition in the AD brain and suggest that this relationship may have relevance for the degree of cognitive dysfunction in AD patients.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Mapeamento Cromossômico/métodos , Insulisina/genética , Insulisina/metabolismo , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Sequência de Aminoácidos , Análise Mutacional de DNA/métodos , Inglaterra/epidemiologia , Marcadores Genéticos/genética , Predisposição Genética para Doença/epidemiologia , Variação Genética , Humanos , Desequilíbrio de Ligação/genética , Dados de Sequência Molecular , Mutação , Locos de Características Quantitativas/genética , Estatística como Assunto , Suécia/epidemiologiaRESUMO
Linkage studies have implicated a broad region on chromosome 10q in Alzheimer's disease (AD). A recent genetic association study has provided evidence that polymorphism in the gene encoding alpha-3 catenin (CTNNA3, referred to previously as VR22 and also known as alpha-T catenin) may underlie linkage signals. Here, to investigate this finding, markers that previously exhibited maximum evidence of association have been tested in Swedish and Scottish AD case-control samples. Across models of disease risk and in relation to multiple quantitative indices of AD pathology (CSF A beta 42 and tau levels, age-at-onset, MMSE scores, and measures of senile plaque density) no evidence was found supporting a role for these particular variants in AD. More detailed studies of regional linkage disequilibrium structure around CTNNA3 will likely be required to determine whether sequence variation in this region impacts AD.
Assuntos
Doença de Alzheimer/genética , Cromossomos Humanos Par 10/genética , Proteínas do Citoesqueleto/genética , Marcadores Genéticos/genética , Variação Genética/genética , Idade de Início , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Feminino , Predisposição Genética para Doença/genética , Humanos , Desequilíbrio de Ligação/genética , Masculino , Fragmentos de Peptídeos/líquido cefalorraquidiano , Placa Amiloide/genética , Placa Amiloide/metabolismo , Polimorfismo Genético/genética , alfa Catenina , Proteínas tauRESUMO
Most genetic sequence variants that contribute to variability in complex human traits will have small effects that are not readily detectable with population samples typically used in genetic association studies. A potentially valuable tool in the gene discovery process is meta-analysis of the accumulated published data, but in order to be valid these require a sample of studies representative of the true genetic effect and thus hypothetically should include some positive and an abundance of negative reports. A survey of the literature on association studies for Alzheimer disease (AD) from January 2004-April 2005, identified 138 studies, 86 of which reported positive findings other than for apolipoprotein E (APOE), strongly indicative of publication bias. We report here an analysis of 62 genetic markers, tested for association with AD risk as well as for possible effects upon quantitative indices of AD severity (mini-mental state examination scores, age-at-onset, and cerebrospinal fluid (CSF) beta-amyloid (Abeta) and CSF tau proteins). Within this set, only modest signals were present that, with the exception of APOE are easily lost when corrections for multiple hypotheses are applied. In isolation, results are thus broadly negative. Genes studied encompass both novel candidates as well as several recently claimed to be associated with AD (e.g. urokinase plasminogen activator (PLAU) and acetyl-coenzyme A acetyltransferase 1 (ACAT1)). By reporting these data we hope to encourage the publication of gene compendia to guide further studies and aid future meta-analyses aimed at resolving the involvement of genes in complex human traits.
Assuntos
Doença de Alzheimer/genética , Predisposição Genética para Doença/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Análise de Variância , Apolipoproteínas E/genética , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Peptidil Dipeptidase A/genética , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Proteínas tau/líquido cefalorraquidianoRESUMO
We recently reported that a linkage disequilibrium (LD) block on chromosome 10q encompassing the gene encoding insulin-degrading enzyme ( IDE) harbors sequence variants that associate with Alzheimer disease (AD). Evidence also indicated effects upon a number of quantitative indices of AD severity, including age-at-onset (AAO). Since linkage of this immediate region to AAO has been shown in both AD and Parkinson disease (PD), we have explored the possibility that polymorphism within this LD block might also influence PD. Utilizing single nucleotide polymorphisms that delineate common haplotypes from this region, we observed significant evidence of association with AAO in an Australian PD case-control sample. Analyses were complemented with AAO data from two independent Swedish AD case samples, for which previously reported findings were replicated. Results were consistent between AD and PD, suggesting the presence of equivalent detrimental and protective alleles. These data highlight a genomic region in the proximity of IDE that may contribute to AD and PD in a similar manner.