July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
Multimodal genomic analysis of hydroxychloroquine toxicity in a large cohort
Author Affiliations & Notes
  • Ehsan Ullah
    Ophthalmic Genetics and Visual Function Branch, National Eye Institute, Bethesda, Maryland, United States
  • David McGaughey
    Ophthalmic Genetics and Visual Function Branch, National Eye Institute, Bethesda, Maryland, United States
  • Amy Turriff
    Ophthalmic Genetics and Visual Function Branch, National Eye Institute, Bethesda, Maryland, United States
  • Paul A Sieving
    National Eye Institute, Bethesda, Maryland, United States
  • Robert B Hufnagel
    Ophthalmic Genetics and Visual Function Branch, National Eye Institute, Bethesda, Maryland, United States
  • Catherine A Cukras
    The Division of Epidemiology and Clinical Applications, National Eye Institute, Bethesda, Maryland, United States
  • Footnotes
    Commercial Relationships   Ehsan Ullah, None; David McGaughey, None; Amy Turriff, None; Paul Sieving, None; Robert Hufnagel, None; Catherine Cukras, None
  • Footnotes
    Support  NEI Intramural grant
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 6054. doi:
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      Ehsan Ullah, David McGaughey, Amy Turriff, Paul A Sieving, Robert B Hufnagel, Catherine A Cukras; Multimodal genomic analysis of hydroxychloroquine toxicity in a large cohort. Invest. Ophthalmol. Vis. Sci. 2019;60(9):6054.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Hydroxychloroquine is widely used for the treatment of autoimmune diseases and is associated with a risk of vision-threatening retinopathy that increases with prolonged treatment. In two conflicting separate studies, the presence of ABCA4 DNA variants have been implicated in increasing or decreasing the risk for developing toxicity. This study was carried out to better understand the role of ABCA4 and to identify other potential genetic risk factors in hydroxychloroquine toxicity.

Methods : We enrolled 99 individuals with greater than 5 years of hydroxychloroquine use. Cases (49) and controls (50) were determined after full evaluation of functional and structural studies. All samples were genotyped by using Illumina SNP Chip (Infinium OmniExpressExome) which featured 960,919 SNPs. Genotypes were called with Illumina GenomeStudio v2.0 and genetic association analysis was done by using PLINK 1.9.
Extracted DNA from 44 cases and 53 controls was sequenced using a panel including 13 macular dystrophy associated genes (ABCA4, BEST1, CDH3, DRAM2, EFEMP1, ELOVL4, IMPG1, IMPG2, PROM1, RDS, RP1L1, TIMP3, TTLL5). A database of variants was created by using Variant Effect Predictor v92 and GEMINI v0.19. The data was then subjected to association analysis and gene burden test by using R and GEMINI c-alpha test.
Whole exome sequencing (WES) was performed on a subset of 16 cases and 17 controls. Association and gene burden tests were performed across all genes, and for known retinal dystrophy, macular dystrophy, chloroquine metabolism pathway, and autophagy related genes.

Results : Neither risk nor protective association with ABCA4 was noted with individual variants or gene burden. Similarly, no association was seen with other known monogenic maculopathy genes. Genome-wide analysis, including SNP array and WES, did not reveal a significant association between cases and controls.

Conclusions : This is the largest cohort to date for genetic interrogation of hydroxychloroquine toxicity. Contrary to prior studies, we noted no association with ABCA4 variation. Similarly, no individual maculopathy gene, autophagy gene, or hydroxychloroquine metabolism gene association was associated in a genome-wide analysis. A larger, adequately powered study would be necessary to assess genome-wide association to identify potential genetic risk factors for hydroxychloroquine toxicity.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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