NDLI: Common synonymous variants in ABCA4 are protective for chloroquine induced maculopathy (toxic maculopathy)

Content Provider	Springer Nature : BioMed Central
Author	Grassmann, Felix Bergholz, Richard Mändl, Julia Jägle, Herbert Ruether, Klaus Weber, Bernhard HF
Abstract	Background Chloroquine (CQ) and hydroxychloroquine (HCQ) are used to treat auto-immune related diseases such as rheumatoid arthritis (RA) or systemic lupus erythematosus. Both drugs however can cause retinal toxicity eventually leading to irreversible maculopathy and retinopathy. Established risk factors are duration and dosage of treatment while the involvement of genetic factors contributing to toxic maculopathy is largely unclear. To address the latter issue, this study aimed to expand on earlier efforts by (1) evaluating risk-altering variants known to be associated with age-related macular degeneration (AMD), a frequent maculopathy in individuals over 55 years of age, and (2) determining the contribution of genetic variants in the coding sequence of the ABCA4 gene. Methods The ABCA4 gene was analyzed by deep sequencing technology using a personal genome machine (Ion Torrent) with 200 bp read length. Assessment of AMD variants was done by restriction enzyme digestion of PCR products and TaqMan SNP genotyping. Effect sizes, p-values and confidence intervals of common variants were evaluated by logistic regression (Firth’s bias corrected). To account for multiple testing, p-values were adjusted according to the false discovery rate. Results We found no effects of known AMD-associated variants on the risk of toxic maculopathy. In contrast, we report a statistically significant association of common variants in the ABCA4 gene with retinal disease, assessed by a score-based variance-component test (PSKAT = 0.0055). This association remained significant after adjustment for environmental factors like age and duration of medication and was driven by three common variants in ABCA4 (c.5682G > C, c.5814A > G, c.5844A > G), all conferring a reduced risk for toxic maculopathy. Conclusions Our findings demonstrate that minor alleles of common genetic variants in ABCA4 significantly reduce susceptibility to develop toxic maculopathy under CQ treatment. A refined risk profile based on genetic and environmental factors may have implications for revised recommendations in CQ as well as HCQ treatment.
Related Links	https://bmcophthalmol.biomedcentral.com/counter/pdf/10.1186/s12886-015-0008-0.pdf
Ending Page	7
Page Count	7
Starting Page	1
File Format	HTM / HTML
ISSN	14712415
DOI	10.1186/s12886-015-0008-0
Journal	BMC Ophthalmology
Issue Number	1
Volume Number	15
Language	English
Publisher	BioMed Central
Publisher Date	2015-03-06
Access Restriction	Open
Subject Keyword	Ophthalmology Chloroquine induced maculopathy ABCA4 Age-related macular degeneration Stargardt’s disease Genetic association
Content Type	Text
Resource Type	Article
Subject	Ophthalmology
Journal Impact Factor	1.7/2023
5-Year Journal Impact Factor	2/2023

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
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