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Haptoglobin genotype and outcome after aneurysmal subarachnoid haemorrhage

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, neutralizing 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 hypothesized 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 of 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 dichotomized on the Fisher grade. Haemoglobin-haptoglobin complexes were measured in cerebrospinal fluid (CSF) of 44 aSAH patients, 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.
0022-3050
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, Ben
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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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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, Ben
c6a69fe5-84a6-4a41-990c-8999afb00822
Garland, Patrick
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Grieve, Joan
acaf2870-6cf4-43c3-b5de-225c4c9ee539
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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Morton, Matthew J., Hostettler, Isabel C, Kazmi, Nabila, Alg, Varinder, Bonner, Stephen, Brown, Martin M, Durnford, A., Gaastra, Ben, 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, 1-9, [321697]. (doi:10.1136/jnnp-2019-321697).

Record type: Article

Abstract

Objective: After aneurysmal subarachnoid haemorrhage (aSAH), extracellular haemoglobin (Hb) in the subarachnoid space is bound by haptoglobin, neutralizing 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 hypothesized 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 of 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 dichotomized on the Fisher grade. Haemoglobin-haptoglobin complexes were measured in cerebrospinal fluid (CSF) of 44 aSAH patients, 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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Accepted/In Press date: 11 December 2019
e-pub ahead of print date: 14 January 2020

Identifiers

Local EPrints ID: 436675
URI: http://eprints.soton.ac.uk/id/eprint/436675
ISSN: 0022-3050
PURE UUID: 6983147a-4b06-4db7-9dde-830ff859f5ed
ORCID for Matthew J. Morton: ORCID iD orcid.org/0000-0003-1986-0863
ORCID for Ian Galea: ORCID iD orcid.org/0000-0002-1268-5102

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Date deposited: 20 Dec 2019 17:54
Last modified: 26 Nov 2021 02:47

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Contributors

Author: Matthew J. Morton ORCID iD
Author: Isabel C Hostettler
Author: Nabila Kazmi
Author: Varinder Alg
Author: Stephen Bonner
Author: Martin M Brown
Author: A. Durnford
Author: Ben Gaastra
Author: Patrick Garland
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
Author: Ian Galea ORCID iD

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