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Genetic variation in APOE cluster region and Alzheimer's disease risk |
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| Authors: | Cervantes Sebastián Samaranch Lluís Vidal-Taboada José Manuel Lamet Isabel Bullido María Jesús Frank-García Ana Coria Francisco Lleó Albert Clarimón Jordi Lorenzo Elena Alonso Elena Sánchez-Juan Pascual Rodríguez-Rodríguez Eloy Combarros Onofre Rosich Marcel Vilella Elisabet Pastor Pau |
| Institution: | a Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Pamplona, Spain b Department of Neurology, Clínica Universidad de Navarra, University of Navarra, School of Medicine, Pamplona, Spain c Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain d Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Spain e Servicio de Neurología, Hospital Universitario La Paz (UAM), Madrid, Spain f Clinic for Nervous System Disorders and Service of Neurology, Hospital Universitario Son Dureta, Palma de Mallorca, Spain g Neurology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain h Service of Neurology, Hospital Universitario Marqués de Valdecilla, University of Cantabria, Santander, Spain i Hospital Universitari Psiquiàtric, Institut Pere Mata, IISPV, Universitat Rovira i Virgili, Reus, Spain |
| Abstract: | 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 ε4. Rs5158 (APOC4 intron 1) and rs10413089 (3′ to APOC2) showed a trend toward an increase in AD risk independently from APOE ε4 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. |
| Keywords: | Mild cognitive impairment APOE APOC1 APOC4 APOC2 TOMM40 Alzheimer's disease Genetics Mapping |
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