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L. Bretillon, A.M. Bron, N. Acar, C. Joffre, S. Arnavielle, C. Creuzot–Garcher; Genetic Variation of the Cholesterol 24–hydroxylase (CYP46) Gene in Patients With Age–related Macular Degeneration or Primary Open–angle Glaucoma . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3808.
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Purpose: Cholesterol homeostasis in neuronal structures is driven by at least three independent mechanisms: apolipoprotein E (apoE), ATP Binding Cassette Transporter A1 (abca1) and cholesterol 24–hydroxylase (CYP46). CYP46 gene polymorphism and circulating levels of its metabolic product, 24–hydroxycholesterol, may be linked to neurodegenerative diseases. Preliminary data from our research group have shown that CYP46 is specifically expressed in the neural retina. In the present work, we aimed to examine the association of a single nucleotide polymorphism in intron 2 of the CYP46 gene with age–related macular degeneration (AMD) or primary open–angle glaucoma (POAG), two pathologies concerned by neurodegenerative mechanisms. Methods: The frequency of CYP46*C and CYP46*T alleles was analyzed in 55 AMD patients (79±8yr), 64 glaucoma patients (67±14yr) and 75 control subjects (68±15yr). The presence or absence of disease in patients and controls was based on clinical examination. A blood sample was collected for DNA extraction. The common allelic variants of apoE and CYP46*C/CYP46*T alleles were screened through the use of polymerase chain reaction using appropriate primers and restriction enzyme digestion (HhaI for apoE, MspI for CYP46). Genotype frequencies were compared in patients and controls by 2x2 contingency tables and two–tailed P values calculated using Fisher's exact test. Results: The frequency of CYP46*T allele was higher in AMD and POAG patients compared to controls (0.77 and 0.81 compared to 0.73, respectively). Only the difference between POAG patients and control subjects was significant (p<0.05). The odd ratio for the risk of developing glaucoma was estimated to 1.83 (95% confidence interval: 0.93–3.62) and 1.23 in AMD (95% confidence interval: 0.61–2.48). The frequency of the E2 and E4 alleles was slightly higher in glaucoma and AMD patients respectively. Nevertheless, the difference failed to reach statistical significance. Conclusions: Our results support the role of cholesterol homeostasis via CYP46 in the retina. They suggest that CYP46 polymorphism may be involved in the development of neurodegenerative diseases in the eye as it has already been shown in the brain. Finally, cholesterol metabolism may be impaired in POAG and AMD.
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