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.
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 fastPHASE 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.
Erickson
Robert P
RP
Department of Pediatrics, University of Arizona, 1501N. Campbell Avenue, P.O. Box 245073, Tucson, AZ 85724-5073, USA. erickson@peds.arizona.edu
Larson-Thomé
Katherine
K
Weberg
Lyndon
L
Szybinska
Aleksandra
A
Mossakowska
Malgorzata
M
Styczynska
Maria
M
Barcikowska
Maria
M
Kuznicki
Jacek
J
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D000544:Alzheimer Disease / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D016009:Chi-Square Distribution; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D000077296:Niemann-Pick C1 Protein; D011044:Poland; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein