Gene-gene interaction between heme oxygenase-1 and liver X receptor-beta and Alzheimer's disease risk.
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.
Infante
Jon
J
Neurology Service and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Marqués de Valdecilla University Hospital (University of Cantabria), Santander, Spain.
Rodríguez-Rodríguez
Eloy
E
Mateo
Ignacio
I
Llorca
Javier
J
Vázquez-Higuera
José Luis
JL
Berciano
José
J
Combarros
Onofre
O
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002784:Cholesterol / Q000378:metabolism*; D004252:DNA Mutational Analysis; D004843:Epistasis, Genetic / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007438:Introns / Q000235:genetics; D000071518:Liver X Receptors; D008297:Male; D008875:Middle Aged; D057093:Orphan Nuclear Receptors / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics
D005819:Genetic Markers; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D002784:Cholesterol; D051547:Heme Oxygenase-1