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Original research
Haptoglobin genotype and outcome after spontaneous intracerebral haemorrhage
  1. Isabel Charlotte Hostettler1,
  2. Matthew J Morton2,
  3. Gareth Ambler3,
  4. Nabila Kazmi4,
  5. Tom Gaunt4,
  6. Duncan Wilson1,
  7. Clare Shakeshaft1,
  8. H R Jäger5,
  9. Hannah Cohen6,
  10. Tarek A Yousry5,
  11. Rustam Al-Shahi Salman7,
  12. Gregory Lip8,
  13. Martin M Brown1,
  14. Keith Muir9,
  15. Henry Houlden10,
  16. Diederik O Bulters11,
  17. Ian Galea12,
  18. David J Werring1
  19. On behalf of the CROMIS-2 collaborators
    1. 1Stroke Research Centre, University College London, Queen Square Institute of Neurology, London, UK
    2. 2Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
    3. 3Department of Statistical Science, University College London, London, UK
    4. 4MRC Integrative Epidemiology Unit (IEU), Faculty of Health Sciences, University of Bristol, Bristol, UK
    5. 5Neuroradiological Academic Unit, Department of Brain Repair and Rehabilitation, University College London, Queen Square Institute of Neurology, London, UK
    6. 6Department of Haematology, University College London, London, UK
    7. 7Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
    8. 8Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart and Chest Hospital, Liverepool, UK
    9. 9Institute of Neuroscience and Psychology, Queen Elizabeth University Hospital, University of Glasgow, Glasgow, UK
    10. 10MRC Centre for Neuromuscular Diseases, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK
    11. 11Department of Neurosurgery, University Hospital Southampton NHS Foundation Trust, Southampton, UK
    12. 12Faculty of Medicine, University of Southampton, Southampton, UK
    1. Correspondence to Dr David J Werring, Stroke Research Centre, University College London, Institute of Neurology, London WC1N 3BG, UK; d.werring{at}ucl.ac.uk

    Abstract

    Objective Haptoglobin is a haemoglobin-scavenging protein that binds and neutralises free haemoglobin and modulates inflammation and endothelial progenitor cell function. A HP gene copy number variation (CNV) generates HP1 and HP2 alleles, while the single-nucleotide polymorphism rs2000999 influences their levels. The HP1 allele is hypothesised to improve outcome after spontaneous (non-traumatic) intracerebral haemorrhage (ICH). We investigated the associations of the HP CNV genotype and rs2000999 with haematoma volume, perihaematomal oedema (PHO) volume, functional outcome and mortality after ICH.

    Methods We included patients with neuroimaging-proven ICH, available DNA and 6-month follow-up in an observational cohort study (CROMIS-2). We classified patients into three groups according to the HP CNV: 1–1, 2–1 or 2–2 and also dichotomised HP into HP1-containing genotypes (HP1-1 and HP2-1) and HP2-2 to evaluate the HP1 allele. We measured ICH and PHO volume on CT; PHO was measured by oedema extension distance. Functional outcome was assessed by modified Rankin score (unfavourable outcome defined as mRS 3–6).

    Results We included 731 patients (mean age 73.4, 43.5% female). Distribution of HP CNV genotype was: HP1-1 n=132 (18.1%); HP2-1 n=342 (46.8%); and HP2-2 n=257 (35.2%). In the multivariable model mortality comparisons between HP groups, HP2-2 as reference, were as follows: OR HP1-1 0.73, 95% CI 0.34 to 1.56 (p value=0.41) and OR HP2-1 0.5, 95% CI 0.28 to 0.89 (p value=0.02) (overall p value=0.06). We found no evidence of association of HP CNV or rs200999 with functional outcome, ICH volume or PHO volume.

    Conclusion The HP2-1 genotype might be associated with lower 6-month mortality after ICH; this finding merits further study.

    • stroke
    • MRI
    • congnition
    • cerebrovascular disease
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    Footnotes

    • IG and DJW are joint senior authors.

    • Twitter @Isabel Hostettler, @BleedingStroke

    • Contributors ICH: design and conceptualised study; acquisition of data; performed laboratory work; analysed the data; drafted the manuscript; revised the manuscript. MJM: performed laboratory work; analysed the data; drafted the manuscript; revised the manuscript. GA: design and conceptualised study; analysed the data; drafted the manuscript; revised the manuscript. NK and TG: analysed the data; drafted the manuscript; revised the manuscript. DW: acquisition of data; analysed the data; drafted the manuscript; revised the manuscript. CS and HRJ: design and conceptualised study; acquisition of data; revised the manuscript. HC, RA-SS, GL, MMB, KM and HH: design and conceptualised study; revised the manuscript. TY: revised the manuscript. DOB: design and conceptualised study; acquisition of data; analysed the data; drafted the manuscript; revised the manuscript. IG: design and conceptualised study; interpreted the data; revised the manuscript for intellectual content. DJW: design and conceptualised study; interpreted the data; drafted the manuscript; revised the manuscript; obtained funding for the study.

    • Funding DJW and DW received funding from the Stroke Foundation/British Heart Foundation. This work was undertaken at UCLH/UCL which receives a proportion of funding from the Department of Health’s National Institute for Health Research (NIHR) Biomedical Research Centers funding scheme. MJM and IG received funding from the Medical Research Council (MR/L01453X/1). NK received funding from Cancer Research UK program grant C18281/A19169. 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. This publication is the work of the authors and ICH will serve as guarantor of the contents of this paper. A comprehensive list of grant funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf).

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Ethics approval Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

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