Testing for pharmacogenomic predictors of ppRNFL thinning in individuals exposed to vigabatrin.
adverse drug reaction
epilepsy
genome wide association study
polygenic risk score
retina
Journal
Frontiers in neuroscience
ISSN: 1662-4548
Titre abrégé: Front Neurosci
Pays: Switzerland
ID NLM: 101478481
Informations de publication
Date de publication:
2023
2023
Historique:
received:
25
04
2023
accepted:
25
08
2023
medline:
4
10
2023
pubmed:
4
10
2023
entrez:
4
10
2023
Statut:
epublish
Résumé
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. Optical coherence topography (OCT) and GWAS data were processed from VGB-exposed individuals ( 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. 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.
Sections du résumé
Background
UNASSIGNED
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
UNASSIGNED
Optical coherence topography (OCT) and GWAS data were processed from VGB-exposed individuals (
Results
UNASSIGNED
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
UNASSIGNED
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.
Identifiants
pubmed: 37790589
doi: 10.3389/fnins.2023.1156362
pmc: PMC10542409
doi:
Types de publication
Journal Article
Langues
eng
Pagination
1156362Investigateurs
Joseph Willis
(J)
Mojgansadat Borghei
(M)
Simona Donatello
(S)
Martin J Brodie
(MJ)
Pauls Auce
(P)
Andrea Jorgensen
(A)
Sarah R Langley
(SR)
Yvonne Weber
(Y)
Christian Hengsbach
(C)
Martin Krenn
(M)
Fritz Zimprich
(F)
Ekaterina Pataraia
(E)
Karl Martin Klein
(KM)
Hiltrud Muhle
(H)
Rikke S Møller
(RS)
Marina Nikanorova
(M)
Stefan Wolking
(S)
Ellen Campbell
(E)
Antonella Riva
(A)
Marcello Scala
(M)
Informations de copyright
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.
Déclaration de conflit d'intérêts
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.
Références
Acta Ophthalmol. 2014 Mar;92(2):149-57
pubmed: 23387307
Neurology. 2018 Jan 23;90(4):e332-e341
pubmed: 29288229
Nat Genet. 1999 Jun;22(2):159-63
pubmed: 10369257
Neurology. 2001 Nov 27;57(10):1916-7
pubmed: 11723291
Sci Rep. 2022 Dec 13;12(1):21494
pubmed: 36513702
Acta Ophthalmol. 2011 Aug;89(5):452-8
pubmed: 21251242
Ann Neurol. 2004 May;55(5):695-705
pubmed: 15122710
Ther Adv Neurol Disord. 2021 Jul 17;14:17562864211031100
pubmed: 34349839
Cochrane Database Syst Rev. 2020 Jul 30;7:CD007302
pubmed: 32730657
Acta Neurochir (Wien). 2018 Jul;160(7):1325-1336
pubmed: 29623432
Epilepsia. 2001 Apr;42(4):525-30
pubmed: 11440348
BMJ. 1997 Jan 18;314(7075):180-1
pubmed: 9022432
J Hum Genet. 2023 May;68(5):305-312
pubmed: 36599957
Epilepsy Res. 2006 Aug;70(2-3):144-52
pubmed: 16675198
Epilepsia. 1997 Dec;38(12):1270-4
pubmed: 9578521
Invest Ophthalmol Vis Sci. 2018 Feb 1;59(2):693-701
pubmed: 29392315
Pediatr Neurol. 2017 Jan;66:44-52.e1
pubmed: 27816307
Sci Rep. 2020 Mar 26;10(1):5497
pubmed: 32218477
J Med Chem. 1990 Feb;33(2):733-6
pubmed: 2299639
Gigascience. 2019 Jul 1;8(7):
pubmed: 31307061
Twin Res Hum Genet. 2015 Feb;18(1):86-91
pubmed: 25518859
Acta Ophthalmol. 2011 Mar;89(2):143-50
pubmed: 20384607
Genes (Basel). 2017 Jul 12;8(7):
pubmed: 28704921
Acta Neurol Scand. 2012 Oct;126(4):219-28
pubmed: 22632110
Epilepsy Res. 1997 Jan;26(2):389-95
pubmed: 9095401
Biochim Biophys Acta Mol Basis Dis. 2020 Jan 1;1866(1):165560
pubmed: 31648019
Ophthalmology. 2009 Mar;116(3):565-71
pubmed: 19168223
Am J Hum Genet. 2010 Jul 9;87(1):139-45
pubmed: 20598278
Invest Ophthalmol Vis Sci. 2020 Feb 7;61(2):17
pubmed: 32053727
Acta Neurol Scand Suppl. 2011;(192):5-15
pubmed: 22061176
J Biol Chem. 2009 Nov 27;284(48):33561-70
pubmed: 19808661
Ann Neurol. 2011 May;69(5):845-54
pubmed: 21246602
J Lipid Res. 2014 Jun;55(6):1010-8
pubmed: 24548887
Seizure. 2001 Oct;10(7):505-7
pubmed: 11749107
Eye (Lond). 2000 Jun;14 ( Pt 3A):334-9
pubmed: 11026995
Neurology. 1968 Sep;18(9):825-35
pubmed: 5693676
PLoS Genet. 2021 May 12;17(5):e1009497
pubmed: 33979322
Expert Rev Neurother. 2020 Dec;20(12):1315-1324
pubmed: 33078964
Hum Mutat. 2018 Feb;39(2):177-186
pubmed: 29159838
Am J Hum Genet. 2007 Sep;81(3):559-75
pubmed: 17701901
Seizure. 1995 Dec;4(4):267-71
pubmed: 8719918
J Child Neurol. 1999 Feb;14(2):71-4
pubmed: 10073425
Epilepsy Res. 2020 Oct;166:106395
pubmed: 32679486
Epilepsia. 1999 Dec;40(12):1784-94
pubmed: 10612345
Semin Neurol. 2020 Apr;40(2):236-245
pubmed: 32143232
Eur J Neurosci. 2008 Apr;27(8):2177-87
pubmed: 18412635
Mol Cell Neurosci. 2010 Apr;43(4):414-21
pubmed: 20132888
Epilepsy Res. 1998 Feb;29(3):195-200
pubmed: 9551781
Epilepsia. 2010 Dec;51(12):2423-31
pubmed: 21070215
Mol Vis. 2009 Oct 27;15:2202-8
pubmed: 19898635
PLoS One. 2016 Nov 15;11(11):e0166397
pubmed: 27846257
J Neurol Neurosurg Psychiatry. 1999 Dec;67(6):716-22
pubmed: 10567485
Epilepsy Res. 2013 Aug;105(3):262-71
pubmed: 23541931
Expert Opin Pharmacother. 2016 Jun;17(8):1091-101
pubmed: 26933940
Nat Genet. 2007 Jul;39(7):906-13
pubmed: 17572673
Ophthalmology. 2012 Oct;119(10):2152-60
pubmed: 22853973