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.
Filiaciones:
Rosas, I:
Hosp Univ Cent Asturias, Lab Genet, Ave Roma S-N, Oviedo 33011, Spain
Martinez, C:
Hosp Univ Cabuenes, Serv Neurol, Gijon, Spain
Inst Invest Sanitaria Principado Asturias ISPA, Oviedo, Spain
Coto, E:
Hosp Univ Cent Asturias, Lab Genet, Ave Roma S-N, Oviedo 33011, Spain
Inst Invest Sanitaria Principado Asturias ISPA, Oviedo, Spain
Clarimon, J:
Univ Autonoma Barcelona, IIB St Pau, Dept Neurol, Hosp Santa Creu & St Pau, Barcelona, Spain
Ctr Networker Biomed Res Neurodegenerat Dis CIBER, Barcelona, Spain
Lleo, A:
Univ Autonoma Barcelona, IIB St Pau, Dept Neurol, Hosp Santa Creu & St Pau, Barcelona, Spain
Ctr Networker Biomed Res Neurodegenerat Dis CIBER, Barcelona, Spain
Illan-Gala, I:
Univ Autonoma Barcelona, IIB St Pau, Dept Neurol, Hosp Santa Creu & St Pau, Barcelona, Spain
Ctr Networker Biomed Res Neurodegenerat Dis CIBER, Barcelona, Spain
Dols-Icardo, O:
Univ Autonoma Barcelona, IIB St Pau, Dept Neurol, Hosp Santa Creu & St Pau, Barcelona, Spain
Ctr Networker Biomed Res Neurodegenerat Dis CIBER, Barcelona, Spain
Borroni, B:
Univ Brescia, Ctr Neurodegenerat Disorders, Dept Clin & Expt Sci, Brescia, Italy
Almeida, MR:
Univ Coimbra, Ctr Neurosci & Cell Biol, Coimbra, Portugal
van der Zee, J:
VIB, Ctr Mol Neurol, Neurodegenerat Brain Dis Grp, Antwerp, Belgium
Univ Antwerp, Inst Born Bunge, Lab Neurogenet, Antwerp, Belgium
Van Broeckhoven, C:
VIB, Ctr Mol Neurol, Neurodegenerat Brain Dis Grp, Antwerp, Belgium
Univ Antwerp, Inst Born Bunge, Lab Neurogenet, Antwerp, Belgium
Bruni, AC:
ASP CZ, Reg Neurogenet Ctr, Catanzaro, Italy
Anfossi, M:
ASP CZ, Reg Neurogenet Ctr, Catanzaro, Italy
Bernardi, L:
ASP CZ, Reg Neurogenet Ctr, Catanzaro, Italy
Maletta, R:
ASP CZ, Reg Neurogenet Ctr, Catanzaro, Italy
Serpente, M:
Univ Milan, Dino Ferrari Ctr, Dept Pathophysiol & Transplantat, Milan, Italy
Fdn IRCCS Ca Granda, Osped Policlin, Neurodegenerat Dis Unit, Milan, Italy
Galimberti, D:
Fdn IRCCS Ca Granda, Osped Policlin, Neurodegenerat Dis Unit, Milan, Italy
Univ Milan, Dino Ferrari Ctr, Dept Biomed Surg & Dent Sci, Milan, Italy
Scarpini, E:
Fdn IRCCS Ca Granda, Osped Policlin, Neurodegenerat Dis Unit, Milan, Italy
Univ Milan, Dino Ferrari Ctr, Dept Biomed Surg & Dent Sci, Milan, Italy
Rossi, G:
Fdn IRCCS Ist Neurol Carlo Besta, Neurol & Neuropathol Unit, Milan, Italy
Caroppo, P:
Fdn IRCCS Ist Neurol Carlo Besta, Neurol & Neuropathol Unit, Milan, Italy
Benussi, L:
IRCCS Ist Ctr San Giovanni Dio Fatebenefratelli, Mol Markers Lab, Brescia, Italy
Ghidoni, R:
IRCCS Ist Ctr San Giovanni Dio Fatebenefratelli, Mol Markers Lab, Brescia, Italy
Binetti, G:
IRCCS Ist Ctr San Giovanni Dio Fatebenefratelli, Mol Markers Lab, Brescia, Italy
IRCCS Ist Ctr San Giovanni Dio Fatebenefratelli, MAC Memory Clin, Brescia, Italy
Nacmias, B:
Univ Florence, Dept Neurosci Psychol Drug Res & Child Hlth, Florence, Italy
IRCCS Fdn Don Carlo Gnocchi, Florence, Italy
Sorbi, S:
Univ Florence, Dept Neurosci Psychol Drug Res & Child Hlth, Florence, Italy
IRCCS Fdn Don Carlo Gnocchi, Florence, Italy
Piaceri, I:
Univ Florence, Dept Neurosci Psychol Drug Res & Child Hlth, Florence, Italy
Bagnoli, S:
Univ Florence, Dept Neurosci Psychol Drug Res & Child Hlth, Florence, Italy
Antonell, A:
Inst Invest Biomed August Pi I Sunyer IDIBAPS, Hosp Clin, Alzheimers Dis & Other Cognit Disorders Unit, Fundacio Clin Recerca Biomed, Barcelona, Spain
Sanchez-Valle, R:
Inst Invest Biomed August Pi I Sunyer IDIBAPS, Hosp Clin, Alzheimers Dis & Other Cognit Disorders Unit, Fundacio Clin Recerca Biomed, Barcelona, Spain
De la Casa-Fages, B:
Hosp Gen Univ Gregorio Maranon, Neurol Dept, Movement Disorders Unit, Madrid, Spain
Grandas, F:
Hosp Gen Univ Gregorio Maranon, Neurol Dept, Movement Disorders Unit, Madrid, Spain
Diez-Fairen, M:
Univ Hosp Mutua Terrassa, Dept Neurol PP, Movement Disorders Unit, Barcelona, Spain
Fundacio Recerca Biomed & Social Mutua Terrassa, Barcelona, Spain
Pastor, P:
Univ Hosp Mutua Terrassa, Dept Neurol PP, Movement Disorders Unit, Barcelona, Spain
Fundacio Recerca Biomed & Social Mutua Terrassa, Barcelona, Spain
Ferrari, R:
UCL, Inst Neurol, Dept Neurodegenerat Dis, London, England
Queimalinos-Perez, D:
Hosp Univ Cent Asturias, Lab Genet, Ave Roma S-N, Oviedo 33011, Spain
Perez-Oliveira, S:
Hosp Univ Cent Asturias, Lab Genet, Ave Roma S-N, Oviedo 33011, Spain
Alvarez, V:
Hosp Univ Cent Asturias, Lab Genet, Ave Roma S-N, Oviedo 33011, Spain
Inst Invest Sanitaria Principado Asturias ISPA, Oviedo, Spain
Menendez-Gonzalez, M:
Inst Invest Sanitaria Principado Asturias ISPA, Oviedo, Spain
Hosp Univ Cent Asturias, Serv Neurol, Oviedo, Spain
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