Genetic variation in NFE2L2 is associated with outcome following aneurysmal subarachnoid haemorrhage

Ben Gaastra; Poppy Duncan; Mark K. Bakker; Isabel C. Hostettler; Varinder S. Alg; Henry Houlden; Ynte M. Ruigrok; Ian Galea; Will Tapper; David Werring; Diederik Bulters

doi:10.1111/ene.15571

Genetic variation in NFE2L2 is associated with outcome following aneurysmal subarachnoid haemorrhage

Ben Gaastra^*, Poppy Duncan, Mark K. Bakker, Isabel C. Hostettler, Varinder S. Alg, Henry Houlden, Ynte M. Ruigrok, Ian Galea, Will Tapper, David Werring, Diederik Bulters

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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 (p_{meta-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 (p_sQTL = 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.

Original language	English
Pages (from-to)	116-124
Number of pages	9
Journal	European Journal of Neurology
Volume	30
Issue number	1
DOIs	https://doi.org/10.1111/ene.15571
Publication status	Published - Jan 2023

Keywords

NF-E2-related factor 2
polymorphism, single nucleotide
subarachnoid haemorrhage
single nucleotide
polymorphism
Polymorphism, Single Nucleotide/genetics
Subarachnoid Hemorrhage/genetics
Humans
Alleles
Genotype
NF-E2-Related Factor 2/genetics

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Euro J of Neurology - 2022 - Gaastra - Genetic variation in NFE2L2 is associated with outcome following aneurysmalFinal published version, 919 KBLicence: CC BY

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@article{076ba8ae69454a8ea16f26674456a1b2,

title = "Genetic variation in NFE2L2 is associated with outcome following aneurysmal subarachnoid haemorrhage",

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.",

keywords = "NF-E2-related factor 2, polymorphism, single nucleotide, subarachnoid haemorrhage, single nucleotide, polymorphism, Polymorphism, Single Nucleotide/genetics, Subarachnoid Hemorrhage/genetics, Humans, Alleles, Genotype, NF-E2-Related Factor 2/genetics",

author = "Ben Gaastra and Poppy Duncan and Bakker, {Mark K.} and Hostettler, {Isabel C.} and Alg, {Varinder S.} and Henry Houlden and Ruigrok, {Ynte M.} and Ian Galea and Will Tapper and David Werring and Diederik Bulters",

note = "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: {\textcopyright} 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.",

year = "2023",

month = jan,

doi = "10.1111/ene.15571",

language = "English",

volume = "30",

pages = "116--124",

journal = "European Journal of Neurology",

issn = "1351-5101",

publisher = "Wiley-Blackwell",

number = "1",

}

TY - JOUR

T1 - Genetic variation in NFE2L2 is associated with outcome following aneurysmal subarachnoid haemorrhage

AU - Gaastra, Ben

AU - Duncan, Poppy

AU - Bakker, Mark K.

AU - Hostettler, Isabel C.

AU - Alg, Varinder S.

AU - Houlden, Henry

AU - Ruigrok, Ynte M.

AU - Galea, Ian

AU - Tapper, Will

AU - Werring, David

AU - Bulters, Diederik

N1 - 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.

PY - 2023/1

Y1 - 2023/1

N2 - 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.

AB - 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.

KW - NF-E2-related factor 2

KW - polymorphism, single nucleotide

KW - subarachnoid haemorrhage

KW - single nucleotide

KW - polymorphism

KW - Polymorphism, Single Nucleotide/genetics

KW - Subarachnoid Hemorrhage/genetics

KW - Humans

KW - Alleles

KW - Genotype

KW - NF-E2-Related Factor 2/genetics

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U2 - 10.1111/ene.15571

DO - 10.1111/ene.15571

M3 - Article

C2 - 36148820

AN - SCOPUS:85139026451

SN - 1351-5101

VL - 30

SP - 116

EP - 124

JO - European Journal of Neurology

JF - European Journal of Neurology

IS - 1

ER -

Genetic variation in NFE2L2 is associated with outcome following aneurysmal subarachnoid haemorrhage

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