Gene-gene interaction between heme oxygenase-1 and liver X receptor-beta and Alzheimer's disease risk

Neurobiol Aging. 2010 Apr;31(4):710-4. doi: 10.1016/j.neurobiolaging.2008.05.025. Epub 2008 Jul 1.


Increasing cellular cholesterol levels results in high amyloid beta (Abeta) synthesis, which is central to the pathogenesis of Alzheimer's disease (AD). Heme oxygenase-1 (HO-1) stimulates oxidation of glial cholesterol to oxysterols, and increased oxysterol concentrations may protect neural tissues by activation of liver X receptor-beta (LXR-beta), which induces transcription of genes associated with reduction of cellular cholesterol concentrations and decrease of Abeta formation. Underexpression of HO-1 in concert with underexpression of LXR-beta would result in increased cholesterol accumulation, induction of Abeta production, and increased AD risk. We examined a functional polymorphism in the HO-1 promoter region (-413, rs2071746), and three LXR-beta polymorphisms in introns 2 (rs2695121), 5 (rs1052533), and 7 (rs1405655), in a group of 414 Spanish AD cases and 442 controls. Subjects carrying both the HO-1 (-413) TT genotype and the LXR-beta (intron 2) TT genotype (OR=2.63), LXR-beta (intron 5) AA genotype (OR=1.90), or LXR-beta (intron 7) TT genotype (OR=1.75) had a higher risk of developing AD than subjects without these risk genotypes. Considering synergistic effects between polymorphisms in cellular cholesterol efflux-related genes may help in determining the risk profile for AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / physiopathology
  • Cholesterol / metabolism*
  • DNA Mutational Analysis
  • Epistasis, Genetic / genetics*
  • Female
  • Gene Expression Regulation / physiology
  • Genetic Markers / genetics
  • Genetic Predisposition to Disease / genetics*
  • Genetic Testing
  • Genotype
  • Heme Oxygenase-1 / genetics*
  • Heme Oxygenase-1 / metabolism
  • Humans
  • Introns / genetics
  • Liver X Receptors
  • Male
  • Middle Aged
  • Orphan Nuclear Receptors / genetics*
  • Polymorphism, Genetic / genetics
  • Promoter Regions, Genetic / genetics


  • Genetic Markers
  • Liver X Receptors
  • Orphan Nuclear Receptors
  • Cholesterol
  • Heme Oxygenase-1