Single Nucleotide Polymorphism in the Cholesterol-24S-Hydroxylase (CYP46A1) Gene and Its Association withCFHandLOC387715Gene Polymorphisms in Age-Related Macular Degeneration

Abstract

PURPOSE. We investigated the association of single nucleotide polymorphism (SNP) in the cholesterol-24S-hydroxylase (CY-P46A1) gene, according to CFH and LOC387715 SNPs, with age-related macular degeneration (AMD). METHODS.We enrolled 1388 AMD patients with neovascular AMD or geographic atrophy and 487 unrelated control subjects. SNPs were genotyped in the CYP46A1 (rs754203), LOC387715 (rs10490924), and CFH (rs1061170) genes. Plasma 24S-hydroxycholesterol, the metabolic product of CYP46A1, was quantified by gas chromatography-mass spectrometry using an authentic deuterated internal standard in subgroups of patients and controls. The v 2 test was used to compare categoric allelic and genotype distributions between cases and controls. The odds ratio (OR) with a 95% confidence interval (95% CI) was calculated for AMD risk, and adjusted for age and gender. Significance levels were set at P < 0.05. RESULTS.The rs754203 SNP in the CYP46A1 gene was not associated with AMD (crude OR ¼ 1.2, 95% CI ¼ 0.9-1.4, P ¼ 0.2). The crude OR for risk of AMD was 2.9 (95% CI ¼ 2.4-3.4, P < 0.0001) according to the number of rs10490924 T alleles in the LOC387715 gene, and 2.0 (95% CI ¼ 1.7-2.3, P < 0.0001) according to the number of rs1061170 C alleles in the CFH gene. After adjustment for age and gender, an OR of 2.2 (95% CI ¼ 1.1-4.1, P ¼ 0.04) was obtained for AMD cases with the C allele in the CYP46A1 gene, and carrying no risk alleles in the CFH and LOC387715 genes.CONCLUSIONS. The rs754203 C allele in the CYP46A1 gene may confer a higher risk for exudative AMD in patients who carry no risk alleles in the CFH and LOC387715 genes. Additional studies with larger sample sizes are needed in AMD subjects at no risk in CFH and LOC387715. (Invest Ophthalmol Vis Sci.

Cholesterol in the retina: The best is yet to come

“…One of these SNPs (rs754203) was evaluated for association with primary open-angle glaucoma and AMD. The rs754203 was found to be a risk factor for the former but not the latter (Fourgeux et al, 2012; Fourgeux et al, 2009). The association with primary angle glaucoma was not, however, confirmed in a different study (Mossbock et al, 2011).…”

Systemic and ocular fluid compounds as potential biomarkers in age-related macular degeneration

“…36,267 In contrast, higher cholesterol was associated with AMD in 10 studies, although these were all case-control studies, and only half studied nAMD. 8,57,67,88,97,109,134,152,246,342 The vast majority of studies (Supplementary Table 4), however, did not demonstrate a difference in cholesterol levels between AMD patients and controls, including a meta-analysis of 3 large populationbased studies, 190 and several large population-based studies. 33,37,42,50,61,73,141,143,157,160,161,176,177,184,199,261,304,306,321,331,345,354,367,371 Triglycerides are molecules that have a glycerol backbone connected to 3 fatty acids of variable length.…”

24(S)-Hydroxycholesterol protects the ex vivo rat retina from injury by elevated hydrostatic pressure

“…Thus, the relationship between cyp46a1 and glaucoma remains uncertain. Despite this, it is possible that 24(S)-HC synthesis is involved in glaucomatous retinal degeneration, and experimental IOP elevation in rats facilitates retinal cyp46a1 expression followed by sustained increases in 24(S)-HC 28 . In the present study using an ex vivo glaucoma model ( Fig.…”