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Genetic variation in NFE2L2 is associated with outcome following aneurysmal subarachnoid haemorrhage
Author(s) -
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
Publication year - 2023
Publication title -
european journal of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 124
eISSN - 1468-1331
pISSN - 1351-5101
DOI - 10.1111/ene.15571
Subject(s) - single nucleotide polymorphism , medicine , subarachnoid hemorrhage , snp , glasgow outcome scale , modified rankin scale , bioinformatics , minor allele frequency , genetics , genotype , anesthesia , gene , biology , ischemia , glasgow coma scale , ischemic stroke
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.