Primary Open Angle Glaucoma: Association with Cholesterol 24S-Hydroxylase (CYP46A1) Gene Polymorphism and Plasma 24-Hydroxycholesterol Levels
Cynthia Fourgeux 1,
Lucy Martine 1,
Ingemar Björkhem 2,
Ulf Diczfalusy 2,
Corinne Joffre 1,
Niyazi Acar 1,
Catherine Creuzot-Garcher 3,
Alain Bron 3,
and
Lionel Bretillon 4*
1 Eye and Nutrition Research Group, INRA, Dijon, France
2 Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
3 Department of Ophthalmology, University Hospital, Dijon, France; Eye and Nutrition Research Group, University of Burgundy, Dijon, France
4 Eye and Nutrition Research Group, INRA, 17 rue Sully, Dijon, 21065, France
* To whom correspondence should be addressed. E-mail: lionel.bretillon{at}dijon.inra.fr.
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Abstract |
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Purpose. Genetics has made significant contributions to the study of glaucoma over the last few decades. Cholesterol-24S-hydroxylase (CYP46A1) is a cholesterol-metabolizing enzyme that is especially expressed in retinal ganglion cells. CYP46A1 and its metabolic product, 24S-hydroxycholesterol, have been linked to neurodegeneration. A single nucleotide polymorphism (SNP) in CYP46A1 gene, designated as rs754203 and associated with Alzheimer disease, was evaluated as a genetic risk factor for primary open-angle glaucoma (POAG), as well as plasma 24S-hydroxycholesterol levels.
Methods. The frequency of CYP46*C and CYP46*T alleles was analyzed in 150 POAG patients and 118 controls. Plasma 24S-hydroxycholesterol levels were quantified. Sex, age, alleles, and genotype frequencies between POAG patients and controls were compared using the X2 and Student t tests. Odd-ratios (OR) and 95% confidence intervals (CI) were calculated by logistic regression to assess the relative association between disease and age, sex, and genotypes.
Results. The frequency of the TT-genotype was significantly higher in POAG patients compared to controls (61.3% versus 48.3%, respectively, OR=1.26; 95% CI=1.006-1.574, p<0.05). Plasma 24S-hydroxycholesterol levels did not differ between control subjects and POAG patients. The ratio of estimated brain weight to liver volume as an estimate of the capacity of the human body to synthesize and metabolize 24S-hydroxycholesterol was found to correlate to plasma 24S-hydroxycholesterol in controls and POAG patients.
Conclusions. The rs754203 SNP in CYP46A1 was associated with a risk for POAG. This polymorphism was not associated with changes in plasma 24S-hydroxycholesterol, highlighting that despite its retinal origin, 24S-hydroxycholesterol cannot be used as a biomarker for POAG.
Key Words:
candidate genes, case-control study, glaucoma
