title: Genetic variation in APOE cluster region and Alzheimer's disease risk.
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.
authors.affiliation: Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: Sebastián
authors.initials: S
authors.lastname: Cervantes
authors.forename: Lluís
authors.initials: L
authors.lastname: Samaranch
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Vidal-Taboada
authors.forename: Isabel
authors.initials: I
authors.lastname: Lamet
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Bullido
authors.forename: Ana
authors.initials: A
authors.lastname: Frank-García
authors.forename: Francisco
authors.initials: F
authors.lastname: Coria
authors.forename: Albert
authors.initials: A
authors.lastname: Lleó
authors.forename: Jordi
authors.initials: J
authors.lastname: Clarimón
authors.forename: Elena
authors.initials: E
authors.lastname: Lorenzo
authors.forename: Elena
authors.initials: E
authors.lastname: Alonso
authors.forename: Pascual
authors.initials: P
authors.lastname: Sánchez-Juan
authors.forename: Eloy
authors.initials: E
authors.lastname: Rodríguez-Rodríguez
authors.forename: Onofre
authors.initials: O
authors.lastname: Combarros
authors.forename: Marcel
authors.initials: M
authors.lastname: Rosich
authors.forename: Elisabet
authors.initials: E
authors.lastname: Vilella
authors.forename: Pau
authors.initials: P
authors.lastname: Pastor
mesh_terms: D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics*; D060825:Cognitive Dysfunction / Q000235:genetics; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D001057:Apolipoproteins E