Objective After aneurysmal subarachnoid haemorrhage (aSAH), extracellular haemoglobin (Hb) in the subarachnoid space is bound by haptoglobin, neutralising Hb toxicity and helping its clearance. Two exons in the HP gene (encoding haptoglobin) exhibit copy number variation (CNV), giving rise to HP1 and HP2 alleles, which influence haptoglobin expression level and possibly haptoglobin function. We hypothesised that the HP CNV associates with long-term outcome beyond the first year after aSAH.
Methods The HP CNV was typed using quantitative PCR in 1299 aSAH survivors in the Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study, a retrospective multicentre cohort study with a median follow-up of 18 months. To investigate mediation of the HP CNV effect by haptoglobin expression level, as opposed to functional differences, we used rs2000999, a single nucleotide polymorphism associated with haptoglobin expression independent of the HP CNV. Outcome was assessed using modified Rankin and Glasgow Outcome Scores. SAH volume was dichotomised on the Fisher grade. Haemoglobin-haptoglobin complexes were measured in cerebrospinal fluid (CSF) of 44 patients with aSAH and related to the HP CNV.
Results The HP2 allele associated with a favourable long-term outcome after high-volume but not low-volume aSAH (multivariable logistic regression). However rs2000999 did not predict outcome. The HP2 allele associated with lower CSF haemoglobin-haptoglobin complex levels. The CSF Hb concentration after high-volume and low-volume aSAH was, respectively, higher and lower than the Hb-binding capacity of CSF haptoglobin.
Conclusion The HP2 allele carries a favourable long-term prognosis after high-volume aSAH. Haptoglobin and the Hb clearance pathway are therapeutic targets after aSAH.
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MJM, ICH and NK are joint first authors.
DJW and IG are joint senior authors.
GOSH Collaborators Mr Gareth Roberts, Royal Preston Hospital, Fulwood, UK; Mr Timothy Jones, St George’s Hospital, London, UK; Mr Giles Critchley, Hurstwood Park Neurological Centre, Haywards Heath, UK; Prof Pankaj Sharma, Imperial Healthcare, Charing Cross Hospital, London, UK; Mr Richard Nelson, Frenchay Hospital, Bristol, UK; Prof Peter Whitfield, Derriford Hospital, Plymouth, England; Mr Stuart Ross, Leeds General Infirmary, Leeds, UK; Mr Hiren Patel, Salford Royal Hospital, Salford, UK; Prof Paul Eldridge, The Walton Centre, Liverpool, UK; Dr Kari Saastamoinen, The Royal London Hospital, London, UK; Mr Umang Patel, Sheffield Teaching Hospitals NHS Trust, Sheffield, UK; Dr Enas Lawrance, Mayday Hospital, Croydon, UK; Dr Subha Vandabona, Mount Gould Hospital, Plymouth, UK; Prof David Mendelow, Newcastle University Hospital NHS Trust, Gosforth, UK; Ms Rachael Teal and Dr Orlando Warner, Oxford Radcliffe Infirmary, Oxford, UK; Mr Angelos Kolias and Prof Peter J Kirkpatrick, Addenbrooke's Hospital, Cambridge, UK.
Contributors Concept: DJW, IG. Design: MJM, NK, TRG, ICH, DOB, DJW, IG. Data contributors: DJW, DOB, all GOSH investigators and ALSPAC. Analysis: MJM, NK, ICH, IG. Manuscript: all authors.
Funding The GOSH study was funded by The Stroke Association and supported by the National Institute of Health Research (NIHR) Stroke Research Network (DJW). This research was also funded by UK MRC grant MR/L01453X/1 (MJM, IG) and by Cancer Research UK program grant C18281/A19169 (NK). TRG receives funding from the UK MRC (MRC Integrative Epidemiology Unit, MC_UU_00011/4). The UK Medical Research Council (MRC) and Wellcome Trust (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. GWAS data were generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. A comprehensive list of grant funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). This publication is the work of the authors who will serve as guarantors for the contents of this paper.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Anonymised aggregate data will be shared after formal request to the corresponding author in accordance with the University of Southampton’s data-sharing policies and contracts with the coauthors and their institutions.
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