title: CYP46A1 variants influence Alzheimer's disease risk and brain cholesterol metabolism.
abstract: BACKGROUND
  Cholesterol 24S-hydroxylase (CYP46) catalyzes the conversion of cholesterol to 24S-hydroxycholesterol, the primary cerebral cholesterol elimination product. Only few gene variations in CYP46 gene (CYP46A1) have been investigated for their relevance as genetic risk factors of Alzheimer's disease (AD) and results are contradictory.
  
  
  METHODS
  We performed a gene variability screening in CYP46A1 and investigated the effect of gene variants on the risk of AD and on CSF levels of cholesterol and 24S-hydroxycholesterol.
  
  
  RESULTS
  Two of the identified 16 SNPs in CYP46A1 influenced AD risk in our study (rs7157609: p=0.016; rs4900442: p=0.019). The interaction term of both SNPs was also associated with an increased risk of AD (p=0.006). Haplotypes including both SNPs were calculated and haplotype G-C was identified to influence the risk of AD (p=0.005). AD patients and non-demented controls, who were carriers of the G-C haplotype, presented with reduced CSF levels of 24S-hydroxycholesterol (p=0.001) and cholesterol (p<0.001).
  
  
  CONCLUSIONS
  Our results suggest that CYP46A1 gene variations might act as risk factor for AD via an influence on brain cholesterol metabolism.
authors.affiliation: Department of Psychiatry, University of Bonn, Germany. heike.koelsch@ukb.uni-bonn.de
authors.forename: Heike
authors.initials: H
authors.lastname: Kölsch
authors.forename: Dieter
authors.initials: D
authors.lastname: Lütjohann
authors.forename: Frank
authors.initials: F
authors.lastname: Jessen
authors.forename: Julius
authors.initials: J
authors.lastname: Popp
authors.forename: Frank
authors.initials: F
authors.lastname: Hentschel
authors.forename: Peter
authors.initials: P
authors.lastname: Kelemen
authors.forename: Sandra
authors.initials: S
authors.lastname: Schmitz
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Maier
authors.forename: Reinhard
authors.initials: R
authors.lastname: Heun
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002784:Cholesterol / Q000134:cerebrospinal fluid / Q000235:genetics / Q000378:metabolism*; D000072556:Cholesterol 24-Hydroxylase; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D006888:Hydroxycholesterols / Q000134:cerebrospinal fluid / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D013250:Steroid Hydroxylases / Q000235:genetics* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D006888:Hydroxycholesterols; C044563:24-hydroxycholesterol; D002784:Cholesterol; D013250:Steroid Hydroxylases; D000072556:Cholesterol 24-Hydroxylase