Haptoglobin genotype and outcome after aneurysmal subarachnoid haemorrhage
Haptoglobin genotype and outcome after aneurysmal subarachnoid haemorrhage
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.
1-9
Morton, Matthew J.
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Hostettler, Isabel C
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Kazmi, Nabila
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Alg, Varinder
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Bonner, Stephen
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Brown, Martin M
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Durnford, A.
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Gaastra, Benjamin
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Garland, Patrick
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Grieve, Joan
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Kitchen, Neil
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Walsh, Daniel
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Zolnourian, Ardalan
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Houlden, Henry
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Gaunt, Tom R.
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Bulters, Diederik
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Werring, David J.
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Galea, Ian
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March 2020
Morton, Matthew J.
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Hostettler, Isabel C
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Kazmi, Nabila
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Alg, Varinder
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Bonner, Stephen
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Brown, Martin M
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Durnford, A.
e915b595-7dee-40c6-901d-c9845a7e4f54
Gaastra, Benjamin
c7b7f371-706b-4d59-9150-94e8f254e205
Garland, Patrick
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Grieve, Joan
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Kitchen, Neil
f0586d86-9678-4566-a057-7164e75d56d3
Walsh, Daniel
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Zolnourian, Ardalan
5e8d4881-cdfd-4cb1-8eae-b98b13104648
Houlden, Henry
b4cd8392-164c-4d35-8933-690a804ebb18
Gaunt, Tom R.
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Bulters, Diederik
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Werring, David J.
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Galea, Ian
66209a2f-f7e6-4d63-afe4-e9299f156f0b
Morton, Matthew J., Hostettler, Isabel C, Kazmi, Nabila, Alg, Varinder, Bonner, Stephen, Brown, Martin M, Durnford, A., Gaastra, Benjamin, Garland, Patrick, Grieve, Joan, Kitchen, Neil, Walsh, Daniel, Zolnourian, Ardalan, Houlden, Henry, Gaunt, Tom R., Bulters, Diederik, Werring, David J. and Galea, Ian
(2020)
Haptoglobin genotype and outcome after aneurysmal subarachnoid haemorrhage.
Journal of Neurology Neurosurgery and Psychiatry, , [321697].
(doi:10.1136/jnnp-2019-321697).
Abstract
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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Morton et al_postprint
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Accepted/In Press date: 11 December 2019
e-pub ahead of print date: 14 January 2020
Published date: March 2020
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© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.
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Local EPrints ID: 436675
URI: http://eprints.soton.ac.uk/id/eprint/436675
ISSN: 0022-3050
PURE UUID: 6983147a-4b06-4db7-9dde-830ff859f5ed
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Date deposited: 20 Dec 2019 17:54
Last modified: 17 Mar 2024 04:07
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Contributors
Author:
Matthew J. Morton
Author:
Isabel C Hostettler
Author:
Nabila Kazmi
Author:
Varinder Alg
Author:
Stephen Bonner
Author:
Martin M Brown
Author:
A. Durnford
Author:
Joan Grieve
Author:
Neil Kitchen
Author:
Daniel Walsh
Author:
Ardalan Zolnourian
Author:
Henry Houlden
Author:
Tom R. Gaunt
Author:
Diederik Bulters
Author:
David J. Werring
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