Affiliations: [a] Neurology Service and CIBERNED, “Marqués de Valdecilla” University Hospital (University of Cantabria), Santander, Spain | [b] Molecular Biology Department and CIBERNED, Centro de Biologıa Molecular Severo Ochoa (C.S.I.C.-U.A.M.), Madrid, Spain | [c] Neurology Service and CIBERNED, Hospital Universitario La Paz (U.A.M.), Madrid, Spain
Correspondence:
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Correspondence to: Onofre Combarros, Neurology Service, Marqués de Valdecilla University Hospital, Avda. Valdecilla s/n, 39008 Santander, Spain. Tel.: +34 942 202507; Fax: +34 942 202655; E-mail: [email protected].
Note: [] Handling Associate Editor: Ewa Golanska
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.
