Genetic variation in APOE, GRN, and TP53 are phenotype modifiers in frontotemporal dementia
Por:
Rosas, I, Martinez, C, Coto, E, Clarimon, J, Lleo, A, Illan-Gala, I, Dols-Icardo, O, Borroni, B, Almeida, MR, van der Zee, J, Van Broeckhoven, C, Bruni, AC, Anfossi, M, Bernardi, L, Maletta, R, Serpente, M, Galimberti, D, Scarpini, E, Rossi, G, Caroppo, P, Benussi, L, Ghidoni, R, Binetti, G, Nacmias, B, Sorbi, S, Piaceri, I, Bagnoli, S, Antonell, A, Sanchez-Valle, R, De la Casa-Fages, B, Grandas, F, Diez-Fairen, M, Pastor, P, Ferrari, R, Queimalinos-Perez, D, Perez-Oliveira, S, Alvarez, V, Menendez-Gonzalez, M, EU EOD Consortium, IFGC
Publicada:
1 mar 2021
Ahead of Print:
2 sep 2020
Resumen:
Frontotemporal dementia (FTD) is a clinical, genetic, and pathologic heterogeneous group of neurodegenerative diseases. In this study, we investigated the role of APO epsilon 4, rs5848 in GRN, and rs1042522 in TP53 gene as disease risk factors and/or phenotype modifiers in 440 FTD patients, including 175 C9orf72 expansion carriers. We found that the C9orf72 expansion carriers showing an earlier age at onset (p < 0.001). Among the clinical groups, the FTD-MND (motoneuron disease) showed the lowest survival (hazard ratio [HR] = 4.12), and the progressive nonfluent aphasia group showed the highest onset age (p = 0.03). In our cohort, the rs1042522 in TP53 was associated with disease onset (p = 0.02) and survival (HR = 1.73) and rs5848 GRN with a significantly shorter survival in CC homozygous patients (HR = 1.98). The frequency of APO epsilon 4 carriers was significantly increased in the C9orf72 noncarriers (p = 0.022). Although validation of our findings is necessary, our results suggest that TP53, GRN, and APOE genes may act as phenotype modifiers in FTD and should be considered in future clinical trials. (C) 2020 Elsevier Inc. All rights reserved.
|