title: Interaction between HMGCR and ABCA1 cholesterol-related genes modulates Alzheimer's disease risk.
abstract: A number of studies suggest that increased cellular cholesterol levels induce high amyloid beta (Abeta) production, which is central to the pathogenesis of Alzheimer's disease (AD). In the brain, glial cells have hydroxy-methylglutaryl-coenzyme A reductase (HMGCR) as the major rate-limiting enzyme in the novo synthesis of cholesterol, which once synthesized, is secreted via the cholesterol transporter ABCA1. Overexpression of HMGCR in concert with underexpression of ABCA1 would result in increased cholesterol accumulation, induction of Abeta production, and increased AD risk. We examined two HMGCR polymorphisms located in 5'-UTR (rs3931914) and promoter (-911, rs3761740) regions of the gene, and two ABCA1 polymorphisms (-14, rs1800977; and -477, rs2422493) located in promoter region of the gene, in a group of 325 Spanish AD patients and 383 controls. Subjects carrying both the HMGCR (5'-UTR) GG genotype and the ABCA1 (-14) TT genotype (adjusted by age, sex and APOE status OR=2.77; 95% CI=1.16-6.61; p=0.02), or the ABCA1 (-477) TT genotype (adjusted by age, sex and APOE status OR=2.07; 95% CI=1.14-3.78; p=0.02) had a higher risk of developing AD than subjects without these risk genotypes, and this genetic interaction was observed in either the presence or the absence of the APOE epsilon4 allele. Considering synergistic effects between polymorphisms in synthesis and secretion cholesterol-related genes may help in determining the risk profile for AD.
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Marqués de Valdecilla University Hospital, University of Cantabria, Santander, Spain.
authors.forename: Eloy
authors.initials: E
authors.lastname: Rodríguez-Rodríguez
authors.forename: Ignacio
authors.initials: I
authors.lastname: Mateo
authors.forename: Jon
authors.initials: J
authors.lastname: Infante
authors.forename: Javier
authors.initials: J
authors.lastname: Llorca
authors.forename: Inés
authors.initials: I
authors.lastname: García-Gorostiaga
authors.forename: José Luis
authors.initials: JL
authors.lastname: Vázquez-Higuera
authors.forename: Pascual
authors.initials: P
authors.lastname: Sánchez-Juan
authors.forename: José
authors.initials: J
authors.lastname: Berciano
authors.forename: Onofre
authors.initials: O
authors.lastname: Combarros
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D053327:Apolipoprotein E4; D006903:Hydroxymethylglutaryl CoA Reductases