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Eric chi-Hsien Peng, Yao Li, Chyuan-Sheng Lin, Stephen Tsang; Personalized Medicine: Choloroquine Toxicity in human RPE is Dependent on ARMS2 and HTRA1 Genotypes. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2837.
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© ARVO (1962-2015); The Authors (2016-present)
Genome-wide association studies (GWAS) and linkage studies identified the CFH (402H allele), ARMS2, and HTRA1 genes as risk factors for RPE pathology. Among Caucasians, 0.5% are double homozygous for the CFH- (402H) and T-in/del-A-risk alleles which is similar to incidence of hydroxy-chloroquine retinotoxicity. To test the hypothesis that ARMS2 and HTRA1 genetic risk alleles contribute to hydroxychloroquine retinotoxicity, we treated RPE from genetically stratified human donors with chloroquine (CQ).
Two human fetal RPE lines double homozygous for the ARMS2-HTRA1 (T-in/del-A) high-risk alleles, and one heterozygous for low-risk (G-Wt-G; T-in/del-A) were isolated. Only donors who carry low AMD risk 402Y haplotypes in the CFH locus were selected. Genotypically characterized RPE cells were exposed to 10 to 1000 mm CQ, and cell death was quantified using EtBr/AO staining. Lysosomes and lipid bodies were stained and observed by confocal microscopy.
CQ-treated RPE with ARMS2-HTRA1 (T-in/del-A) risk alleles showed marked increase in cytosolic vacuoles, an indicator of lysosomal dysfunction. Lipid bodies identified by LipidTOX , and colocalized with LAMP-2, and CQ-dilated lysosomes. The heterozygote low-risk RPE line (G-Wt-G; T-in/del-A) seemed to be more resistant to CQ-toxicity.
Our findings suggest a possible role of ARMS2 and HTRA1 as risk factors in the susceptibility to hydroxy-chloroquine toxicity.
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