Author(s):
Bettencourt, C. 
; Raposo, Mafalda ; Kazachkova, Nadiya ; Cymbron, Teresa ; Santos, Cristina ; Kay, Teresa ; Vasconcelos, João ; Maciel, P. ; Donis, Karina ; Pereira, M. L. ; Jardim, Laura ; Sequeiros, Jorge ; Lima, M.
Date: 2011
Persistent ID: http://hdl.handle.net/1822/18852
Origin: RepositóriUM - Universidade do Minho
Description
Background. Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder of late onset, caused by a (CAG)n expansion at the ATXN3 gene (14q32.1). Variation in age-at-onset is partially explained by the size of the (CAG)n tract in expanded alleles. The remaining variation should be the product of other factors, namely modifier genes. The genotype at the APOE locus has been described as a possible modifier in different neurological disorders, namely Parkinson (PD) and Huntington disease (HD). In the CNS, apolipoprotein E constitutes an important mediator of cholesterol transport/metabolism, which is essential for synaptic integrity and neuronal function.
Objective. To investigate a modulating effect of the APOE polymorphism on age-at-onset of MJD.
Design and Subjects. The APOE polymorphism was typed in a series of 192 MJD patients.
Results. Cases with the ε2/ε3 genotype presented an earlier onset, when compared with those with ε3/ε3 or ε3/ε4. In this series of patients, the presence of an APOE ε2 allele implies a decrease of nearly 5 years in the age-at-onset. When combining, in a general linear model, several other predictors, namely the presence/absence of the APOE ε2 allele, with the size of the (CAG)n in expanded alleles, the model was significantly improved and the explanation of onset variance was raised from 59.8% to 66.5%. Furthermore, the presence of the ε2 allele was associated with an onset below 39 years (OR=5.00; 95% CI: 1.18-21.14).
Conclusions. These findings indicate that the polymorphism at the APOE gene plays a role as a genetic modifier of MJD phenotype.
