Variation in NPC1, the gene encoding Niemann-Pick C1, a protein involved in intracellular cholesterol transport, is associated with Alzheimer disease and/or aging in the Polish population

NEUROSCIENCE LETTERS

卷:447

Article

Erickson, Robert P.^1,2  Larson-Thome, Katherine¹  Weberg, Lyndon¹  Szybinska, Aleksandra³  Mossakowska, Malgorzata³  Styczynska, Maria⁴  Barcikowska, Maria⁴  Kuznicki, Jacek^3,5 

[1] Univ Arizona, Dept Pediat, Tucson, AZ 85724 USA

[2] Univ Arizona, Dept Mol & Cellular Biol, Tucson, AZ 85721 USA

[3] Polish Acad Sci, Med Res Ctr, Dept Neurodegenerat Disorders, PL-02106 Warsaw, Poland

[4] Int Inst Mol & Cellular Biol, PL-02109 Warsaw, Poland

[5] M Nencki Inst Expt Biol, PL-02093 Warsaw, Poland

关键词: Alzheimer disease;    Centenarians;    Niemann-Pick C1;    Gene association studies;    Aging;   

DOI  :  10.1016/j.neulet.2008.09.046

来源: Elsevier

【 摘 要 】

There is abundant evidence that cholesterol metabolism, especially as mediated by the intercellular transporter APOE, is involved in the pathogenesis of sporadic, late-onset Alzheimer disease (SLAD). Identification of other genes involved in SLAD pathogenesis has been hampered since gene association studies, whether individual or genome-wide, experience difficulty in finding appropriate controls in as much as 25% or more of normal adults will develop SLAD. Using 152 centenarians as additional controls and 120 regular, 65-75-year-old controls, we show an association of genetic variation in NPC1 with SLAD and/or aging. In this preliminary study, we find gradients of two non-synonymous SNP's allele frequencies in NPC1 from centenarians through normal controls to SLAD in this non-stratified Polish population. An intervening intronic SNP is not in Hardy-Weinberg equilibria and differs between centenarians and controls/SLAD. Haplotypes frequencies determined by fast PHASE were somewhat different, and the predicted genotype frequencies were very different between the three groups. These findings can also be interpreted as indicating a role for NPC1 in aging, a role also suggested by NPC1's role in Dauer formation (hibernation, a longevity state) in Caenorhabditis elegans. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

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