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 a...

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Bibliographic Details
Published in:	European journal of neurology Vol. 30; no. 1; pp. 116 - 124
Main Authors:	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
Format:	Journal Article
Language:	English
Published:	England John Wiley & Sons, Inc 01-01-2023 John Wiley and Sons Inc
Subjects:	Alleles Alternative splicing Aneurysm Blood Brain injury Breakdown Functional analysis Genetic diversity Genotype Head injuries Hemorrhage Humans Inflammation NF-E2-Related Factor 2 - genetics NF‐E2‐related factor 2 Nucleotides Original polymorphism, single nucleotide Polymorphism, Single Nucleotide - genetics Single-nucleotide polymorphism Stroke subarachnoid haemorrhage Subarachnoid hemorrhage Subarachnoid Hemorrhage - genetics Therapeutic targets NF-E2-related factor 2 subarachnoid haemorrhage polymorphism, single nucleotide
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Summary:	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.
Bibliography:	See commentary by A. Pezzini on page 1. Ian Galea, Will Tapper, David Werring and Diederik Bulters are joint senior authors. ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	1351-5101 1468-1331
DOI:	10.1111/ene.15571