RESUMO
Late-onset Alzheimer's disease (LOAD) is the most common neurodegenerative disorder, and has a complex etiology. Recently an intronic polymorphism in the ubiquilin 1 gene (UBQLN1) and a particular haplotype was reported to be associated with LOAD. We investigated whether variants in UBQLN1 confer a risk for the disease in 407 Polish LOAD patients and 407 controls. We observed a weak association with the rs2781002 polymorphism, however, contrary to the initial reports, in our group the association was with the A allele. Risk estimation for AA versus GG genotypes showed that the AA genotype is a weak risk factor for AD (OR = 1.8, 95% CI = 1.1-3.1, p = 0.025). This effect was stronger in a group of LOAD patients without APOE4 allele. Haplotype analyses indicate that there is an increase of haplotypes with an A allele in the case group. Also, the specific haplotypes with the A allele that increase AD risk differ between the APOE4-positive and APOE4-negative pools. However, the association observed seems to be driven mostly by rare (<5%) haplotypes. Results suggest a need for additional association studies and in silico analysis of the UBQLN1 locus.
Assuntos
Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Proteínas de Transporte/genética , Proteínas de Ciclo Celular/genética , Polimorfismo de Nucleotídeo Único , Proteínas Adaptadoras de Transdução de Sinal , Idade de Início , Idoso , Apolipoproteína E4/genética , Proteínas Relacionadas à Autofagia , Feminino , Predisposição Genética para Doença/epidemiologia , Haplótipos , Humanos , Masculino , Polônia/epidemiologia , Fatores de RiscoRESUMO
The only well confirmed genetic risk factor for sporadic Alzheimer's disease (AD) is the possession of apolipoprotein E (APOE) epsilon4 allele. As it contributes to 40-70% of AD cases, a large proportion of genetic variance may be determined by additional loci. Our aim was to estimate how reported genetic factors (APOE, NOS3, MTHFR) interact to increase the risk for AD and combine them with environmental factors (homocysteine, vitamin B12, cholesterol). Genotyping was performed in 154 AD patients and 176 healthy controls. Levels of homocysteine, vitamin B12 and cholesterol were assessed in subgroups of 100 AD patients and 100 controls. We found a difference in APOE epsilon4 and NOS3 G/G distribution between groups (p<0.005). Plasma total homocysteine was increased and vitamin B12 decreased in AD patients (p<0.001). The influence of APOE epsilon4 and NOS3 G alleles on the risk of AD was independent of homocysteine, vitamin B12 levels and MTHFR status.
Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/genética , Predisposição Genética para Doença , Apolipoproteínas E/genética , Frequência do Gene , Homocisteína/sangue , Humanos , Hipercolesterolemia , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Óxido Nítrico Sintase Tipo III/genética , Fatores de Risco , Vitamina B 12/sangueRESUMO
As Alzheimer's disease (AD) is a complex disease, we decided to estimate how previously reported genetic polymorphisms interact to increase the risk for the disease. Five candidate genes were chosen: apolipoprotein E (APOE), alpha 2-macroglobulin, cathepsin D, myeloperoxidase and nitric oxide synthase. Genotyping was performed in 100 cases of late-onset AD and 100 healthy controls. We found a highly significant difference in APOE epsilon 4 distribution between groups (P<0.005). However, no evidence of association for other studied loci was found. Cumulative analysis of five genetic polymorphisms was performed, but it also failed to reveal any synergistic effect of candidate genes greater than that caused by APOE itself. Our results suggest that the APOE epsilon 4 allele is the only known genetic risk factor for late-onset, sporadic AD.