Exome sequencing and genome-wide association analyses unveils the genetic predisposition in hydroxychloroquine retinopathy

Hsun-I Chiu; Hui-Chen Cheng; Chih-Chiau Wu; Shih-Jen Chen; De-Kuang Hwang; Yi-Ming Huang; Yu-Bai Chou; Po-Kang Lin; Tai-Chi Lin; Ko-Hua Chen; Pei-Yu Lin; Yu-Fan Chang; An-Guor Wang

doi:10.1038/s41433-024-03044-x

Exome sequencing and genome-wide association analyses unveils the genetic predisposition in hydroxychloroquine retinopathy

Eye (Lond). 2024 Mar 28. doi: 10.1038/s41433-024-03044-x. Online ahead of print.

Authors

Hsun-I Chiu^{1

2}, Hui-Chen Cheng^{1

2

3

4

5}, Chih-Chiau Wu¹, Shih-Jen Chen^{1

2}, De-Kuang Hwang^{1

2}, Yi-Ming Huang^{1

2}, Yu-Bai Chou^{1

2}, Po-Kang Lin^{1

2}, Tai-Chi Lin^{1

2}, Ko-Hua Chen^{1

2}, Pei-Yu Lin^{1

2}, Yu-Fan Chang^{1

2}, An-Guor Wang^{6

7}

Affiliations

¹ Department of Ophthalmology, Taipei Veterans General Hospital, Taipei, Taiwan.
² Department of Ophthalmology, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
³ Program in Molecular Medicine, College of Life Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan.
⁴ Department of Life Sciences and Institute of Genome Sciences, College of Life Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan.
⁵ Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.
⁶ Department of Ophthalmology, Taipei Veterans General Hospital, Taipei, Taiwan. agwang@vghtpe.gov.tw.
⁷ Department of Ophthalmology, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan. agwang@vghtpe.gov.tw.

PMID: 38548946
DOI: 10.1038/s41433-024-03044-x

Abstract

Objectives: To unveil the candidate susceptibility genes in chloroquine/hydroxychloroquine (CQ/HCQ) retinopathy using whole exome sequencing (WES) and genome-wide association study (GWAS).

Methods: Patients with a diagnosis of CQ/HCQ retinopathy based on the comprehensive demographic and ocular examination were included. The peripheral blood was extracted for WES and GWAS analyses. The Chinese Han Southern database from 1000 genomes was used as control group to compare the affected percentage. Multivariate logistic regression analysis adjusted for age, HCQ dose, duration and renal disease were used to analyze the correlation between genetic variants and visual outcome. A poor vision outcome was defined as visual acuity <6/12. An abnormal anatomical outcome was defined as disruption of ellipsoid zone in the fovea.

Results: Twenty-nine patients with an average age of 60.9 ± 13.4 years, treatment duration of 12.1 ± 6.2 years, daily dose of 8.5 ± 4.1 mg/kg, and the cumulative dose of 1637.5 ± 772.5 g, were genotyped. Several candidate genes associated with CQ/HCQ retinopathy were found, including RP1L1, RPGR and RPE65, with a difference of affected percentage over 50% in mutation between the case and control groups. New foci in CCDC66: rs56616026 (OR = 63.43, p = 1.63 × 10^-8) and rs56616023 (OR = 104.7, p = 5.02 × 10^-10) were identified significantly associated with HCQ retinopathy. Multivariate analysis revealed increased genetic variants were significantly associated with poor functional (OR = 1.600, p = 0.004) and structural outcome (OR = 1.318, p = 0.043).

Conclusions: Several candidate susceptibility genes including RP1L1, RPGR, RPE65 and CCDC66 were identified to be associated with CQ/HCQ retinopathy. In addition to disease susceptibility, patients with increased genetic variants are more vulnerable to poor visual outcomes.

Abstract

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