title: Epistasis between intracellular cholesterol trafficking-related genes (NPC1 and ABCA1) and Alzheimer's disease risk.
abstract: Aberrant cholesterol metabolism has been implicated in Alzheimer's disease (AD). Recent findings have suggested an interaction of Niemann-Pick C1 (NPC1) and ATP-binding cassette transporter A1 (ABCA1) proteins in intracellular cholesterol transport and in maintaining cell cholesterol balance. Underexpression of NPC1 in concert with under-expression of ABCA1 would result in increased cholesterol accumulation and increased AD risk. We examined a functional polymorphism in the ABCA1 promoter region (-477, rs2422493), and four NPC1 polymorphisms in exon 6 (rs18050810), intron 20 (rs4800488), intron 22 (rs2236707), and intron 24 (rs2510344) capturing 85% of genetic variability in the Hap Map Caucasian (CEU) population, in a group of 631 Spanish AD patients and 731 controls. Subjects carrying both the ABCA1 (-477) TT genotype and the NPC1 (exon 6) GG genotype (OR=1.89; 95% CI 1.04-3.41), NPC1 (intron 20) AA genotype (OR=2.05; 95% CI 1.26-3.33), NPC1 (intron 22) AA genotype (OR=2.05; 95% or NPC1 (intron 24) GG genotype (OR=1.89; 95% higher risk of developing AD than subjects without these risk genotypes. Testing for epistatic interaction between genes in the pathway of cholesterol metabolism might be useful for predicting AD risk.
authors.affiliation: Neurology Service and CIBERNED, Marqués de Valdecilla University Hospital (University of Cantabria), Santander, Spain.
authors.forename: Eloy
authors.initials: E
authors.lastname: Rodríguez-Rodríguez
authors.forename: José Luis
authors.initials: JL
authors.lastname: Vázquez-Higuera
authors.forename: Pascual
authors.initials: P
authors.lastname: Sánchez-Juan
authors.forename: Ignacio
authors.initials: I
authors.lastname: Mateo
authors.forename: Ana
authors.initials: A
authors.lastname: Pozueta
authors.forename: Ana
authors.initials: A
authors.lastname: Martínez-García
authors.forename: Ana
authors.initials: A
authors.lastname: Frank
authors.forename: Fernando
authors.initials: F
authors.lastname: Valdivieso
authors.forename: José
authors.initials: J
authors.lastname: Berciano
authors.forename: María J
authors.initials: MJ
authors.lastname: Bullido
authors.forename: Onofre
authors.initials: O
authors.lastname: Combarros
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D004843:Epistasis, Genetic / Q000502:physiology*; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007438:Introns / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D000077296:Niemann-Pick C1 Protein; D011110:Polymorphism, Genetic; D012307:Risk Factors
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D002784:Cholesterol