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

Increasing cellular cholesterol levels results in high amyloid beta (Aβ) 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-β (LXR-β), which induces transcription of genes associated with reduction of cellular cholesterol concentrations and decrease of Aβ formation. Underexpression of HO-1 in concert with underexpression of LXR-β would result in increased cholesterol accumulation, induction of Aβ production, and increased AD risk. We examined a functional polymorphism in the HO-1 promoter region (−413, rs2071746), and three LXR-β 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-β (intron 2) TT genotype (OR = 2.63), LXR-β (intron 5) AA genotype (OR = 1.90), or LXR-β (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.