RESUMO
Several studies have reported evidence for linkage of late-onset Alzheimer's disease (LOAD) to chromosome 9. Recently, an intronic polymorphism affecting alternative splicing of exon 8 of ubiquilin 1 (UBQLN1) was reported to be associated with LOAD. We attempted to replicate this observation by genotyping this polymorphism, rs12344615 (also known as UBQ-8i), in a large sample of 1,544 LOAD cases and 1,642 nondemented controls. We did not find any evidence that this single nucleotide polymorphism, or any of six others tested in UBQLN1, increases risk for LOAD.
Assuntos
Doença de Alzheimer/genética , Proteínas de Transporte/genética , Proteínas de Ciclo Celular/genética , Polimorfismo Genético , Proteínas Adaptadoras de Transdução de Sinal , Doença de Alzheimer/metabolismo , Proteínas Relacionadas à Autofagia , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular/metabolismo , Feminino , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
UNLABELLED: Recent studies suggest vasovagal syncope (VVS) has a significant heritable component (crude estimate sibling relative risk (lambda(s)): 1080) indicating that at least some forms of VVS may have a genetic cause. Here we present the first study examining a potential genetic abnormality in VVS. METHODS: DNA was collected from consecutive patients attending our unit with head up tilt confirmed VVS (n=165). One hundred and fourteen affected and unaffected first-degree relatives of those with a definitive diagnosis of VVS and positive family history also provided DNA. RESULTS: DNA from 165 VVS index cases was genotyped for the ACE insertion/deletion polymorphism. Mean+/-SD age of cases was 56+/-19 years (103 (62%) females). There was no significant difference in distribution of ACE insertion or deletion gene frequencies in cases compared with a large (>6000 subjects) national control population. No preferential transmission of alleles in families was identified using tests of association (P=0.1789) CONCLUSION: We have shown using both a case control and a small family based association study that polymorphisms of ACE alone are not associated with increased risk of VVS. Further studies are planned to clarify the genotype/phenotype relationship in VVS and examine other candidate genes.
Assuntos
Elementos de DNA Transponíveis/genética , Deleção de Genes , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Síncope Vasovagal/genética , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Linkage studies have suggested there is a susceptibility gene for late onset Alzheimer's disease (LOAD) in a broad region of chromosome 10. A strong positional and biological candidate is the gene encoding the insulin-degrading enzyme (IDE), a protease involved in the catabolism of Abeta. However, previous association studies have produced inconsistent results. To systematically evaluate the role of variation in IDE in the risk for LOAD, we genotyped 18 SNPs spanning a 276 kb region in and around IDE, including three "tagging" SNPs identified in an earlier study. We used four case-control series with a total of 1,217 cases and 1,257 controls. One SNP (IDE_7) showed association in two samples (P-value = 0.0066, and P = 0.026, respectively), but this result was not replicated in the other two series. None of the other SNPs showed association with LOAD in any of the tested samples. Haplotypes, constructed from the three tagging SNPs, showed no globally significant association. In the UK2 series, the CTA haplotype was over-represented in cases (P = 0.046), and in the combined data set, the CCG haplotype was more frequent in controls (P = 0.015). However, these weak associations observed in our series were in the opposite direction to the results in previous studies. Although our results are not universally negative, we were unable to replicate the results of previous studies and conclude that common variants or haplotypes of these variants in IDE are not major risk factors for LOAD.
Assuntos
Doença de Alzheimer/genética , Insulisina/genética , Polimorfismo de Nucleotídeo Único , Alelos , Doença de Alzheimer/enzimologia , Apolipoproteínas E/genética , Estudos de Casos e Controles , Feminino , Frequência do Gene , Marcadores Genéticos/genética , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Fatores de RiscoRESUMO
Genetic analysis of early onset Parkinson's disease (PD) has indicated that the mutation DJ-1 gene is one cause of autosomal recessive PD. Its role in the development of late onset PD and other Lewy body associated disorders such as dementia with Lewy bodies (DLB) is however unknown. We have therefore determined the influence of a common polymorphism in the DJ-1 gene that shows strong linkage disequilibrium with other DJ-1 polymorphisms, in late onset PD and DLB. No alteration in the frequency of the intron 1 deletion allele was seen in PD or DLB, nor were DJ-1 genotypes altered by disease. Stratification of the cases according to the apolipoprotein E epsilon4 allele additionally failed to show any significant association. The DJ-1 gene does not appear to be a significant risk factor for late onset Lewy body disease in this population.
