title: Common synonymous variants in ABCA4 are protective for chloroquine induced maculopathy (toxic maculopathy).
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.
authors.affiliation: Institute of Human Genetics, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany. Felix.Grassmann@klinik.uni-regensburg.de.
authors.forename: Felix
authors.initials: F
authors.lastname: Grassmann
authors.affiliation: Charité Augenklinik Campus Virchow-Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany. richard.bergholz@charite.de.
authors.forename: Richard
authors.initials: R
authors.lastname: Bergholz
authors.affiliation: Institute of Human Genetics, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany. Julia.Maendl@klinik.uni-regensburg.de.
authors.forename: Julia
authors.initials: J
authors.lastname: Mändl
authors.affiliation: Department of Ophthalmology, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany. Herbert.Jaegle@klinik.uni-regensburg.de.
authors.forename: Herbert
authors.initials: H
authors.lastname: Jägle
authors.affiliation: Augenklinik, Sankt Gertrauden-Krankenhaus, Paretzer Strasse 12, 10713, Berlin, Germany. ruether@freenet.de.
authors.forename: Klaus
authors.initials: K
authors.lastname: Ruether
authors.affiliation: Institute of Human Genetics, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany. bweb@klinik.uni-regensburg.de.
authors.forename: Bernhard H F
authors.initials: BH
authors.lastname: Weber
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000368:Aged; D000483:Alleles; D018501:Antirheumatic Agents / Q000633:toxicity*; D002738:Chloroquine / Q000633:toxicity*; D005260:Female; D005838:Genotype; D060005:Genotyping Techniques; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012160:Retina / Q000187:drug effects; D012164:Retinal Diseases / Q000139:chemically induced / Q000235:genetics* / Q000517:prevention & control*; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA
chemical_list: C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters; D018501:Antirheumatic Agents; D002738:Chloroquine