RESUMO
The apolipoprotein E (APOE, gene; apoE, protein) isoforms are associated with differential risk of Alzheimer's disease (AD). An additional involvement of APOE promoter polymorphisms in AD risk has recently been suggested by several studies. Indeed, three polymorphisms of the APOE regulatory region (-219 G/T, -427 C/T and -491 A/T) have been found associated with AD even after adjustment on the apoE status. We analysed these three promoter region polymorphisms in a large French case-control study (388 AD cases and 386 controls). We found that the -427 T and -491 A alleles were associated with an increased risk of developing AD, but not the -219 G/T alleles. However, a strong linkage disequilibrium was observed between the alleles of these promoter region polymorphisms and the APOE coding region alleles. We therefore retested association after adjustment on apoE status and found that the sole association which remained significant was the association with the -427 T allele. The alpha level was equal to 0.03 (0.09 after Bonferroni correction for multiple comparisons). Analysis of promoter haplotypes also yielded non-significant results. Thus our study does not reinforce the hypothesis of an independent involvement of the APOE promoter region polymorphisms in AD risk.
Assuntos
Doença de Alzheimer/genética , Apolipoproteínas E/genética , Polimorfismo Genético/genética , Regiões Promotoras Genéticas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/epidemiologia , Feminino , França/epidemiologia , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Penetrância , Fatores de RiscoAssuntos
Doença de Alzheimer/genética , Substituição de Aminoácidos/genética , Genes Dominantes/genética , Proteínas de Membrana/genética , Mutação de Sentido Incorreto/genética , Adulto , Doença de Alzheimer/epidemiologia , Feminino , França/epidemiologia , Humanos , Leucina/genética , Masculino , Presenilina-1 , Valina/genéticaRESUMO
Autosomal dominant cerebellar ataxias (ADCA) of type I, a group of clinically heterogeneous neurodegenerative disorders, are known to be genetically heterogeneous since a second locus for ADCA type I (SCA2) has been identified on the long arm of chromosome 12. Linkage analysis was performed in 7 French ADCA type I families in order to estimate its frequency. We analysed 121 individuals, 39 of whom were affected. In 6 families, the SCA2 candidate interval, spanning 12.8 cM, was excluded by bi- and multipoint analysis. In one family (SAL-315), however, the maximal positive lod score reached 2.03 at the D12S79 locus. A posterior probability of 94% in favor of linkage to SCA2 was calculated by homogeneity analysis. The clinical profile of this family was similar to that of previously described SCA1 and non-SCA1 families, except that dementia was observed in 2 out of 6 patients. This may be a clinical idiosyncrasy in this family and was insufficient for a genotype-phenotype correlation.