Epistasis between intracellular cholesterol trafficking-related genes (NPC1 and ABCA1) and Alzheimer's disease risk

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. Undere...

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Detalles Bibliográficos
Autores: Rodríguez Rodríguez, Eloy Manuel, Vázquez Higuera, José Luis, Sánchez-Juan, Pascual|||0000-0002-6081-8037, Mateo Fernández, José Ignacio, Pozueta, Ana, Martínez García, Ana, Frank García, Ana, Valdivieso Amate, Fernando, Berciano, José Ángel|||0000-0001-9261-9748, Bullido, María Jesús, Combarros Pascual, Onofre
Tipo de recurso: artículo
Fecha de publicación:2010
País:España
Institución:Universidad de Cantabria (UC)
Repositorio:UCrea Repositorio Abierto de la Universidad de Cantabria
Idioma:inglés
OAI Identifier:oai:repositorio.unican.es:10902/6232
Acceso en línea:http://hdl.handle.net/10902/6232
Access Level:acceso abierto
Palabra clave:Alzheimer's disease
NPC1
ABCA1
Cholesterol
Polymorphism
Epistasis
Descripción
Sumario: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 underexpression 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 Hap Map 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% CI 1.18-3.58), or NPC1 (intron 24) GG genotype (OR = 1.89; 95% CI 1.16-3.07) had a 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.

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