Genetic variation in NFE2L2 is associated with outcome following aneurysmal subarachnoid haemorrhage
Genetic variation in NFE2L2 is associated with outcome following aneurysmal subarachnoid haemorrhage
Background and purpose
Nuclear factor erythroid 2-related factor 2 (NRF2; encoded by the NFE2L2 gene) has been implicated in outcome following aneurysmal subarachnoid haemorrhage (aSAH) through its activity as a regulator of inflammation, oxidative injury and blood breakdown product clearance. The aim of this study was to identify whether genetic variation in NFE2L2 is associated with clinical outcome following aSAH.
Methods
Ten tagging single nucleotide polymorphisms (SNPs) in NFE2L2 were genotyped and tested for association with dichotomized clinical outcome, assessed by the modified Rankin scale, in both a discovery and a validation cohort. In silico functional analysis was performed using a range of bioinformatic tools.
Results
One SNP, rs10183914, was significantly associated with outcome following aSAH in both the discovery (n = 1007) and validation cohorts (n = 466). The risk of poor outcome was estimated to be 1.33-fold (95% confidence interval 1.12–1.58) higher in individuals with the T allele of rs10183914 (pmeta-analysis = 0.001). In silico functional analysis identified rs10183914 as a potentially regulatory variant with effects on transcription factor binding in addition to alternative splicing with the T allele, associated with a significant reduction in the NFE2L2 intron excision ratio (psQTL = 1.3 × 10−7).
Conclusions
The NFE2L2 SNP, rs10183914, is significantly associated with outcome following aSAH. This is consistent with a clinically relevant pathophysiological role for oxidative and inflammatory brain injury due to blood and its breakdown products in aSAH. Furthermore, our findings support NRF2 as a potential therapeutic target following aSAH and other forms of intracranial haemorrhage.
NF-E2-related factor 2, polymorphism, single nucleotide, subarachnoid haemorrhage
116-124
Gaastra, Ben
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Duncan, Poppy
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Bakker, Mark K.
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Hostettler, Isabel C.
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Alg, Varinder S.
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Houlden, Henry
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Ruigrok, Ynte M.
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Galea, Ian
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Tapper, Will
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Werring, David
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Bulters, Diederik
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January 2023
Gaastra, Ben
c7b7f371-706b-4d59-9150-94e8f254e205
Duncan, Poppy
ef7bde2a-ed01-43a1-b047-e3670ac8184e
Bakker, Mark K.
9d4329de-a731-4b13-8087-5772fc81ab36
Hostettler, Isabel C.
82239c37-f728-4295-bfe1-48b06a56fae3
Alg, Varinder S.
2e789ed1-328a-491d-bb70-8db65bb71a62
Houlden, Henry
b4cd8392-164c-4d35-8933-690a804ebb18
Ruigrok, Ynte M.
36542439-1c84-4e9a-97c3-bf9591cf8120
Galea, Ian
66209a2f-f7e6-4d63-afe4-e9299f156f0b
Tapper, Will
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Werring, David
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Bulters, Diederik
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Gaastra, Ben, Duncan, Poppy, Bakker, Mark K., Hostettler, Isabel C., Alg, Varinder S., Houlden, Henry, Ruigrok, Ynte M., Galea, Ian, Tapper, Will, Werring, David and Bulters, Diederik
(2023)
Genetic variation in NFE2L2 is associated with outcome following aneurysmal subarachnoid haemorrhage.
European Journal of Neurology, 30 (1), .
(doi:10.1111/ene.15571).
Abstract
Background and purpose
Nuclear factor erythroid 2-related factor 2 (NRF2; encoded by the NFE2L2 gene) has been implicated in outcome following aneurysmal subarachnoid haemorrhage (aSAH) through its activity as a regulator of inflammation, oxidative injury and blood breakdown product clearance. The aim of this study was to identify whether genetic variation in NFE2L2 is associated with clinical outcome following aSAH.
Methods
Ten tagging single nucleotide polymorphisms (SNPs) in NFE2L2 were genotyped and tested for association with dichotomized clinical outcome, assessed by the modified Rankin scale, in both a discovery and a validation cohort. In silico functional analysis was performed using a range of bioinformatic tools.
Results
One SNP, rs10183914, was significantly associated with outcome following aSAH in both the discovery (n = 1007) and validation cohorts (n = 466). The risk of poor outcome was estimated to be 1.33-fold (95% confidence interval 1.12–1.58) higher in individuals with the T allele of rs10183914 (pmeta-analysis = 0.001). In silico functional analysis identified rs10183914 as a potentially regulatory variant with effects on transcription factor binding in addition to alternative splicing with the T allele, associated with a significant reduction in the NFE2L2 intron excision ratio (psQTL = 1.3 × 10−7).
Conclusions
The NFE2L2 SNP, rs10183914, is significantly associated with outcome following aSAH. This is consistent with a clinically relevant pathophysiological role for oxidative and inflammatory brain injury due to blood and its breakdown products in aSAH. Furthermore, our findings support NRF2 as a potential therapeutic target following aSAH and other forms of intracranial haemorrhage.
Text
Euro J of Neurology - 2022 - Gaastra - Genetic variation in NFE2L2 is associated with outcome following aneurysmal
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More information
Accepted/In Press date: 6 September 2022
e-pub ahead of print date: 23 September 2022
Published date: January 2023
Additional Information:
Funding Information:
The GOSH study is funded by the Stroke Association. The study received funds from the Medical Research Council (MR/L01453X/1). Ben Gaastra is funded by the Royal College of Surgeons, Society of British Neurological Surgeons, Barrow Foundation UK and the Guarantors of Brain. We acknowledge the support from the Netherlands Cardiovascular Research Initiative: An initiative with support of the Dutch Heart Foundation, CVON2015‐08 ERASE. The Utrecht cohort has received funding from the European Research Council under the European Union's Horizon 2020 research and innovation programme (grant agreement No. 852173).
Funding Information:
The authors acknowledge Mathew Morton for liaising with LGC and the IRIDIS High Performance Computing Facility. The Genotype‐Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by the National Cancer Institute (NCI), National Human Genome Research Institute (NHGRI), National Heart, Lung and Blood Institute (NHLBI), National Institute on Drug Abuse (NIDA), National Institute of Mental Health (NIMH) and National Institute of Neurological Disease and Stroke (NINDS). The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 1 February 2022.
Publisher Copyright:
© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.
Keywords:
NF-E2-related factor 2, polymorphism, single nucleotide, subarachnoid haemorrhage
Identifiers
Local EPrints ID: 470439
URI: http://eprints.soton.ac.uk/id/eprint/470439
ISSN: 1351-5101
PURE UUID: 29d14915-9d9e-40a7-9d1b-7c65ec4d7a58
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Date deposited: 11 Oct 2022 16:32
Last modified: 17 Mar 2024 04:07
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Contributors
Author:
Poppy Duncan
Author:
Mark K. Bakker
Author:
Isabel C. Hostettler
Author:
Varinder S. Alg
Author:
Henry Houlden
Author:
Ynte M. Ruigrok
Author:
Will Tapper
Author:
David Werring
Author:
Diederik Bulters
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