Genetic variation in APOE cluster region and Alzheimer's disease risk
Por:
Cervantes, S, Samaranch, L, Vidal-Taboada, JM, Lamet, I, Bullido, MJ, Frank-Garcia, A, Coria, F, Lleo, A, Clarimon, J, Lorenzo, E, Alonso, E, Sanchez-Juan, P, Rodriguez-Rodriguez, E, Combarros, O, Rosichi, M, Vilella, E, Pastor, P
Publicada:
1 nov 2011
Resumen:
We report the fine mapping/sequencing results of promoter and regulatory regions of APOE cluster genes (APOE, APOC1, APOC4, APOC2, and TOMM40) in Alzheimer's disease (AD) risk as well as in the progression from mild cognitive impairment (MCI) to AD. Long-range sequencing in 29 MCI subjects who progressed to dementia revealed 7 novel variants. Two potentially relevant novel variants and 34 single nucleotide polymorphisms (SNPs) were genotyped in a large sample of AD, MCI, and control subjects (n = 1453). Globally, very little association signal was observed in our sample in the absence of APOE epsilon 4. Rs5158 (APOC4 intron 1) and rs10413089 (3' to APOC2) showed a trend toward an increase in AD risk independently from APOE epsilon 4 associated risk though it did not survive multiple test correction (uncorrected p = 0.0099 and 0.01, respectively). Interestingly, rs10413089 showed a similar effect in an independent series. The analysis of the discovery sample showed an association of TOMM40 single nucleotide polymorphisms with progression from MCI stage to AD (rs59007384 and rs11556510), as well as with a shorter time to progression from MCI status to AD (rs10119), though these results could not be replicated in independent series. Further studies are needed to investigate the role of APOE cluster variants in AD risk. (C) 2011 Elsevier Inc. All rights reserved.
Filiaciones:
Cervantes, S:
Univ Navarra, Sch Med, Ctr Appl Med Res, Neurogenet Lab,Div Neurosci, Pamplona 31008, Spain
Univ Navarra, Sch Med, Dept Neurol, Univ Navarra Clin, E-31080 Pamplona, Spain
Samaranch, L:
Univ Navarra, Sch Med, Ctr Appl Med Res, Neurogenet Lab,Div Neurosci, Pamplona 31008, Spain
Vidal-Taboada, JM:
Univ Navarra, Sch Med, Ctr Appl Med Res, Neurogenet Lab,Div Neurosci, Pamplona 31008, Spain
Lamet, I:
Univ Navarra, Sch Med, Dept Neurol, Univ Navarra Clin, E-31080 Pamplona, Spain
Bullido, MJ:
Ctr Biol Mol Severo Ochoa CSIC UAM, Madrid, Spain
Inst Salud Carlos III, CIBERNED, Madrid, Spain
Frank-Garcia, A:
Inst Salud Carlos III, CIBERNED, Madrid, Spain
Hosp Univ La Paz UAM, Serv Neurol, Madrid, Spain
Coria, F:
Hosp Univ Son Dureta, Clin Nervous Syst Disorders, Palma de Mallorca, Spain
Hosp Univ Son Dureta, Serv Neurol, Palma de Mallorca, Spain
Lleo, A:
Inst Salud Carlos III, CIBERNED, Madrid, Spain
Univ Autonoma Barcelona, Dept Neurol, Hosp Santa Creu & St Pau, E-08193 Barcelona, Spain
Clarimon, J:
Inst Salud Carlos III, CIBERNED, Madrid, Spain
Univ Autonoma Barcelona, Dept Neurol, Hosp Santa Creu & St Pau, E-08193 Barcelona, Spain
Lorenzo, E:
Univ Navarra, Sch Med, Ctr Appl Med Res, Neurogenet Lab,Div Neurosci, Pamplona 31008, Spain
Alonso, E:
Univ Navarra, Sch Med, Ctr Appl Med Res, Neurogenet Lab,Div Neurosci, Pamplona 31008, Spain
Sanchez-Juan, P:
Inst Salud Carlos III, CIBERNED, Madrid, Spain
Univ Cantabria, Serv Neurol, Hosp Univ Marques Valdecilla, E-39005 Santander, Spain
Rodriguez-Rodriguez, E:
Inst Salud Carlos III, CIBERNED, Madrid, Spain
Univ Cantabria, Serv Neurol, Hosp Univ Marques Valdecilla, E-39005 Santander, Spain
Combarros, O:
Inst Salud Carlos III, CIBERNED, Madrid, Spain
Univ Cantabria, Serv Neurol, Hosp Univ Marques Valdecilla, E-39005 Santander, Spain
Rosichi, M:
Univ Rovira & Virgili, Inst Pere Mata, IISPV, Hosp Univ Psiquiatr, E-43201 Reus, Spain
Vilella, E:
Univ Rovira & Virgili, Inst Pere Mata, IISPV, Hosp Univ Psiquiatr, E-43201 Reus, Spain
Pastor, P:
Univ Navarra, Sch Med, Ctr Appl Med Res, Neurogenet Lab,Div Neurosci, Pamplona 31008, Spain
Univ Navarra, Sch Med, Dept Neurol, Univ Navarra Clin, E-31080 Pamplona, Spain
Inst Salud Carlos III, CIBERNED, Madrid, Spain
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