TY  - JOUR
AU  - Meyer, Charlotte Clara
AU  - de Mattos, Eduardo Preusser
AU  - Burger, Rahel Maria
AU  - Blumenstock, Gunnar
AU  - Pereira Sena, Priscila
AU  - Gordon, Carlos
AU  - Zaltzman, Roy
AU  - França, Marcondes Cavalcante
AU  - Saraiva-Pereira, Maria-Luiza
AU  - Cornejo-Olivas, Mario R
AU  - Bauer, Peter
AU  - Schöls, Ludger
AU  - van de Warrenburg, Bart P
AU  - Durr, Alexandra
AU  - Brice, Alexis
AU  - Klockgether, Thomas
AU  - Jardim, Laura Bannach
AU  - Riess, Olaf
AU  - Schmidt, Thorsten
TI  - Association of rare apolipoprotein E ε4 homozygosity with an earlier age at onset in spinocerebellar ataxia type 3.
JO  - Human molecular genetics
VL  - 35
IS  - 5
SN  - 0964-6906
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DZNE-2026-00288
SP  - ddag016
PY  - 2026
AB  - Spinocerebellar Ataxia Type 3 (SCA3) is an autosomal dominant neurodegenerative Polyglutamine (polyQ) disease, caused by a cytosine-adenine-guanine (CAG) repeat expansion in the ATXN3 gene, resulting in an expanded polyQ tract in the Ataxin-3 protein. Although the principal genetic determinant of the age at onset (AAO) in polyQ diseases is the expanded CAG repeat length, variability in AAO has been explained only partly, suggesting the existence of additional genetic modifiers. Apolipoprotein E (APOE) haplotypes are associated with the risk of numerous, especially degenerative, diseases. Investigations of a potential role of APOE haplotypes in AAO variability of SCA3 have resulted in partly conflicting outcomes, with current evidence lacking power and patient diversity. To further clarify a potential modifying effect of APOE haplotypes on the AAO in SCA3, over 800 SCA3 patients from different origins were enrolled in the present study. While we did not find an association of common APOE haplotypes or singular APOE alleles with AAO in SCA3, rare ε4 homozygosity was linked to an earlier AAO in individuals from Brazil, with a mean disease onset six years earlier than carriers of other APOE haplotypes. Our study thus provides initial evidence for a relevant impact of ε4 homozygosity on disease onset in SCA3 and provides evidence supporting an allele-dosage effect of APOE ε4 in polyQ diseases.
KW  - Humans
KW  - Age of Onset
KW  - Female
KW  - Male
KW  - Machado-Joseph Disease: genetics
KW  - Machado-Joseph Disease: epidemiology
KW  - Middle Aged
KW  - Homozygote
KW  - Adult
KW  - Haplotypes
KW  - Apolipoprotein E4: genetics
KW  - Aged
KW  - Ataxin-3
KW  - Alleles
KW  - Repressor Proteins
KW  - Spinocerebellar Ataxia 3 (Other)
KW  - genetic modifier (Other)
KW  - genetic risk factor (Other)
KW  - neurodegeneration (Other)
KW  - neurogenetics (Other)
KW  - Apolipoprotein E4 (NLM Chemicals)
KW  - Ataxin-3 (NLM Chemicals)
KW  - ATXN3 protein, human (NLM Chemicals)
KW  - Repressor Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41854058
DO  - DOI:10.1093/hmg/ddag016
UR  - https://pub.dzne.de/record/285731
ER  -