Common synonymous variants in ABCA4 are protective for chloroquine induced maculopathy (toxic maculopathy) Neuro-ophthalmology

Felix Grassmann, Richard Bergholz, Julia Mändl, Herbert Jägle, Klaus Ruether, Bernhard Hf Weber*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

37 Citations (Scopus)
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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.

Original languageEnglish
Article number18
Number of pages7
JournalBMC Ophthalmology
Early online date6 Mar 2015
Publication statusPublished - 2015

Bibliographical note

Acknowledgments: We are grateful to the patients and control subjects for their participation in this study. We also want to thank Kerstin Meier and Yvonne Bilek for her excellent technical support. This work was supported in part by institutional funds (Institute of Human Genetics, Regensburg, and Charité Eye Clinic, Berlin). Design, collection, analysis or interpretation of data was not influenced by the respective funding bodies.


  • ABCA4
  • Age-related macular degeneration
  • Chloroquine induced maculopathy
  • Genetic association
  • Stargardt's disease


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