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.
Highlights
Aberrant cholesterol metabolism has been implicated in Alzheimers disease (AD), with increased cellular cholesterol levels inducing high amyloid beta (Aβ) production and the development of neurofibrillary tangles [1, 2], which are central to the pathogenesis of AD
Since the four Niemann-Pick C1 (NPC1) polymorphisms in our study are in almost complete linkage disequilibrium forming one block, we have tested only three independent comparisons examining the interaction between the ATP-binding cassette transporter A1 (ABCA1) and NPC1 genes; when applying the conservative Bonferroni adjustment, statistical significance should be set up at p < 0.017, which is reached by the interaction between ABCA1 (−477) and NPC1 (p = 0.004), NPC1 intron 22 (p = 0.01), or NPC1 (p = 0.01)
We have shown, for the first time, that the NPC1 and ABCA1 genes may interact in determining the risk for AD, with subjects carrying both the ABCA1 (−477) TT genotype and the NPC1 GG genotype, NPC1 AA genotype, NPC1 AA genotype, or NPC1 GG genotype having a higher risk of developing AD
Summary
Aberrant cholesterol metabolism has been implicated in Alzheimers disease (AD), with increased cellular cholesterol levels inducing high amyloid beta (Aβ) production and the development of neurofibrillary tangles [1, 2], which are central to the pathogenesis of AD. Niemann-Pick C1 (NPC1) protein and ATP-binding cassette transporter A1 (ABCA1) protein affect redistributing late endosomal/lysosomal intracellular cholesterol transport to other cellular sites including the plasma membrane and the endoplasmic reticulum [3, 4]. Considering the postulated common pathway of NPC1 and ABCA1 in intracellular cholesterol trafficking, we examined the combined contribution of these genes to the susceptibility for AD in a case-control study. We focused on a functional polymorphism in the ABCA1 (−477, rs2422493) gene [14] previously associated with AD risk [11, 15], and we examined one NPC1 polymorphism in exon 6 (rs18050810) previously analyzed in AD [7] and three other NPC1 polymorphisms in intron 20 (rs4800488), intron 22 (rs2236707), and intron 24 (rs2510344)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
