Testing for pharmacogenomic predictors of ppRNFL thinning in individuals exposed to vigabatrin.
| Title: | Testing for pharmacogenomic predictors of ppRNFL thinning in individuals exposed to vigabatrin. |
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| Authors: | Boothman I; School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland.; The SFI Futureneuro Research Centre, Royal College of Surgeons in Ireland, Dublin, Ireland.; The SFI Centre for Research Training in Genomics Data Science, Galway, Ireland.; Clayton LM; Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, United Kingdom.; Chalfont Centre for Epilepsy, Bucks, United Kingdom.; McCormack M; School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland.; Driscoll AM; School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland.; Stevelink R; Department of Genetics, University Medical Center Utrecht, Utrecht, Netherlands.; Moloney P; School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland.; Krause R; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.; Kunz WS; Division of Neurochemistry, Department of Epileptology, University Bonn Medical Center, Bonn, Germany.; Diehl S; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.; O'Brien TJ; Departments of Neuroscience and Neurology, Central Clinical School, The Alfred Hospital, Monash University, Melbourne, VIC, Australia.; Sills GJ; School of Life Sciences, University of Glasgow, Glasgow, United Kingdom.; de Haan GJ; Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, Netherlands.; Zara F; 'IRCCS'G. Gaslini' Institute, Genova, Italy.; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genova, Italy.; Koeleman BP; Department of Genetics, University Medical Center Utrecht, Utrecht, Netherlands.; Depondt C; Department of Neurology, Hôpital Erasme, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium.; Marson AG; Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom.; Stefansson H; deCODE Genetics, Reykjavik, Iceland.; Stefansson K; deCODE Genetics, Reykjavik, Iceland.; Craig J; Department of Neurology, Royal Victoria Hospital, Belfast Health and Social Care Trust, Belfast, United Kingdom.; Johnson MR; Division of Brain Sciences, Imperial College Faculty of Medicine, London, United Kingdom.; Striano P; 'IRCCS'G. Gaslini' Institute, Genova, Italy.; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genova, Italy.; Lerche H; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.; Furney SJ; Genomic Oncology Research Group, Deptartment of Physiology and Medical Physics, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland.; Delanty N; School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland.; Sisodiya SM; Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, United Kingdom.; Chalfont Centre for Epilepsy, Bucks, United Kingdom.; Cavalleri GL; School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland.; The SFI Futureneuro Research Centre, Royal College of Surgeons in Ireland, Dublin, Ireland.; The SFI Centre for Research Training in Genomics Data Science, Galway, Ireland. |
| Corporate Authors: | Consortium EpiPGX |
| Source: | Frontiers in neuroscience [Front Neurosci] 2023 Sep 08; Vol. 17, pp. 1156362. Date of Electronic Publication: 2023 Sep 08 (Print Publication: 2023). |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Frontiers Research Foundation Country of Publication: Switzerland NLM ID: 101478481 Publication Model: eCollection Cited Medium: Print ISSN: 1662-4548 (Print) Linking ISSN: 1662453X NLM ISO Abbreviation: Front Neurosci Subsets: PubMed not MEDLINE |
| Imprint Name(s): | Original Publication: Lausanne : Frontiers Research Foundation |
| Abstract: | Background: The anti-seizure medication vigabatrin (VGB) is effective for controlling seizures, especially infantile spasms. However, use is limited by VGB-associated visual field loss (VAVFL). The mechanisms by which VGB causes VAVFL remains unknown. Average peripapillary retinal nerve fibre layer (ppRNFL) thickness correlates with the degree of visual field loss (measured by mean radial degrees). Duration of VGB exposure, maximum daily VGB dose, and male sex are associated with ppRNFL thinning. Here we test the hypothesis that common genetic variation is a predictor of ppRNFL thinning in VGB exposed individuals. Identifying pharmacogenomic predictors of ppRNFL thinning in VGB exposed individuals could potentially enable safe prescribing of VGB and broader use of a highly effective drug.; Methods: Optical coherence topography (OCT) and GWAS data were processed from VGB-exposed individuals (n = 71) recruited through the EpiPGX Consortium. We conducted quantitative GWAS analyses for the following OCT measurements: (1) average ppRNFL, (2) inferior quadrant, (3) nasal quadrant, (4) superior quadrant, (5) temporal quadrant, (6) inferior nasal sector, (7) nasal inferior sector, (8) superior nasal sector, and (9) nasal superior sector. Using the summary statistics from the GWAS analyses we conducted gene-based testing using VEGAS2. We conducted nine different PRS analyses using the OCT measurements. To determine if VGB-exposed individuals were predisposed to having a thinner RNFL, we calculated their polygenic burden for retinal thickness. PRS alleles for retinal thickness were calculated using published summary statistics from a large-scale GWAS of inner retinal morphology using the OCT images of UK Biobank participants.; Results: The GWAS analyses did not identify a significant association after correction for multiple testing. Similarly, the gene-based and PRS analyses did not reveal a significant association that survived multiple testing.; Conclusion: We set out to identify common genetic predictors for VGB induced ppRNFL thinning. Results suggest that large-effect common genetic predictors are unlikely to exist for ppRNFL thinning (as a marker of VAVFL). Sample size was a limitation of this study. However, further recruitment is a challenge as VGB is rarely used today because of this adverse reaction. Rare variants may be predictors of this adverse drug reaction and were not studied here.; (Copyright © 2023 Boothman, Clayton, McCormack, Driscoll, Stevelink, Moloney, Krause, Kunz, Diehl, O’Brien, Sills, de Haan, Zara, Koeleman, Depondt, Marson, Stefansson, Stefansson, Craig, Johnson, Striano, Lerche, Furney, Delanty, Consortium, Sisodiya and Cavalleri.) |
| Competing Interests: | The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. |
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| Contributed Indexing: | Investigator: J Willis; M Borghei; S Donatello; MJ Brodie; P Auce; A Jorgensen; SR Langley; Y Weber; C Hengsbach; M Krenn; F Zimprich; E Pataraia; KM Klein; H Muhle; RS Møller; M Nikanorova; S Wolking; E Campbell; A Riva; M Scala; Keywords: adverse drug reaction; epilepsy; genome wide association study; polygenic risk score; retina |
| Entry Date(s): | Date Created: 20231004 Latest Revision: 20231005 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC10542409 |
| DOI: | 10.3389/fnins.2023.1156362 |
| PMID: | 37790589 |
| Database: | MEDLINE |
Journal Article