Epistasis Between Intracellular Cholesterol Trafficking-Related Genes (NPC1 and ABCA1) and Alzheimer's Disease Risk

• Published in: Journal of Alzheimer's disease 2010-01, Vol.21 (2), p.619-625
• Main Authors: Rodrıguez-Rodrıguez, Eloy, Vázquez-Higuera, José Luis, Sánchez-Juan, Pascual, Mateo, Ignacio, Pozueta, Ana, Martínez-García, Ana, Frank, Ana, Valdivieso, Fernando, Berciano, José, Bullido, María J., Combarros, Onofre
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - epidemiology; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cholesterol - metabolism; Epistasis, Genetic - physiology; Exons - genetics; Female; Gene Frequency; Genetic Predisposition to Disease - epidemiology; Humans; Introns - genetics; Male; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Middle Aged; Polymorphism, Genetic; Risk Factors
• ISSN: 1387-2877; 1875-8908
• DOI: 10.3233/JAD-2010-100432

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.