Genetic variation in NFE2L2 is associated with outcome following aneurysmal subarachnoid haemorrhage
Gaastra, Ben; Duncan, Poppy; Bakker, Mark K.; Hostettler, Isabel C.; Alg, Varinder S.; Houlden, Henry; Ruigrok, Ynte M.; Galea, Ian; Tapper, Will; Werring, David; Bulters, Diederik
(2023) European Journal of Neurology, volume 30, issue 1, pp. 116 - 124
(Article)
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
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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.
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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, Clinical Neurology, Neurology, Journal Article, Meta-Analysis
ISSN: 1351-5101
Publisher: Wiley-Blackwell
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: © 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.
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