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Genetic Variability in the Iron Homeostasis Pathway and Patient Outcomes After Aneurysmal Subarachnoid Hemorrhage

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Abstract

Background/Objective

Iron can be detrimental to most tissues both in excess and in deficiency. The brain in particular is highly susceptible to the consequences of excessive iron, especially during blood brain barrier disruption after injury. Preliminary evidence suggests that iron homeostasis is important during recovery after neurologic injury; therefore, the exploration of genetic variability in genes involved in iron homeostasis is an important area of patient outcomes research. The purpose of this study was to examine the relationship between tagging single nucleotide polymorphisms (SNPs) in candidate genes related to iron homeostasis and acute and long-term patient outcomes after aneurysmal subarachnoid hemorrhage (aSAH).

Methods

This study was a longitudinal, observational, candidate gene association study of participants with aSAH that used a two-tier design including tier 1 (discovery, n = 197) and tier 2 (replication, n = 277). Participants were followed during the acute outcome phase for development of cerebral vasospasm and delayed cerebral ischemia (DCI) and during the long-term outcome phase for death and gross functional outcome using the Glasgow Outcome Scale (GOS; poor = 1–3). Genetic association analyses were performed using a logistic regression model adjusted for age, sex, and Fisher grade. Approximate Bayes factors (ABF) and Bayesian false discovery probabilities (BFDP) were used to prioritize and interpret results.

Results

In tier 1, 235 tagging SNPs in 28 candidate genes were available for analysis and 26 associations (20 unique SNPs in 12 genes) were nominated for replication in tier 2. In tier 2, we observed an increase in evidence of association for three associations in the ceruloplasmin (CP) and cubilin (CUBN) genes. We observed an association of rs17838831 (CP) with GOS at 3 months (tier 2 results, odds ratio [OR] = 2.10, 95% confidence interval [CI] = 1.14–3.86, p = 0.018, ABF = 0.52, and BFDP = 70.8%) and GOS at 12 months (tier 2 results, OR = 1.86, 95% CI 0.98–3.52, p = 0.058, ABF = 0.72, and BFDP = 77.3%) as well as rs10904850 (CUBN) with DCI (tier 2 results, OR = 0.70, 95% CI 0.48–1.02, p = 0.064, ABF = 0.59, and BFDP = 71.8%).

Conclusions

Among the genes examined, our findings support a role for CP and CUBN in patient outcomes after aSAH. In an effort to translate these findings into clinical utility and improve outcomes after aSAH, additional research is needed to examine the functional roles of these genes after aSAH.

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Acknowledgements

We would like to acknowledge Sandra Deslouches for her expertise and work in the laboratory, Tiffany Wang for her help formatting the Supplemental Tables associated with this publication, and the anonymous reviewers who took the time to critically evaluate this paper as their feedback improved the clarity and quality of this work.

Funding

Research reported in this publication was supported by the National Institute of Nursing Research of the National Institutes of Health under Award Nos. F31NR017311, R01NR004339, R01NR013610, and T32NR009759 with additional support from the Nightingale Awards of Pennsylvania, Center for Jonas Nursing and Veterans Healthcare, Jayne F. Wiggins Memorial Award, and Sigma Theta Tau—Eta Chapter. The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health or supporting foundations.

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Authors and Affiliations

  1. Department of Health Promotion and Development, School of Nursing, University of Pittsburgh, 440 Victoria Building, 3500 Victoria Street, Pittsburgh, PA, 15261, USA

    Lacey W. Heinsberg & Yvette P. Conley

  2. Department of Acute and Tertiary Care, School of Nursing, University of Pittsburgh, Pittsburgh, PA, USA

    Sheila A. Alexander & Elizabeth A. Crago

  3. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

    Ryan L. Minster, Daniel E. Weeks & Yvette P. Conley

  4. Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA

    Samuel M. Poloyac

  5. Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

    Daniel E. Weeks

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  1. Lacey W. Heinsberg
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Contributions

All authors meet authorship criteria, have read and approved the submitted manuscript, and certify that they have participated sufficiently in the work to take responsibility for the content including the concept, design, analysis, writing, or revision. Lacey W. Heinsberg contributed to the study conception and design, acquisition, analysis, and interpretation of data, and drafted, critically revised, and gave final approval for the manuscript. Sheila A. Alexander contributed to the study design, interpretation of data, and critically revised and gave final approval for the manuscript. Elizabeth A. Crago contributed to the acquisition and interpretation of data and critically revised and gave final approval for the manuscript. Ryan L. Minster contributed to the analysis and interpretation of data and critically revised and gave final approval for the manuscript. Samuel M. Poloyac contributed to acquisition and interpretation of data and critically revised and gave final approval for the manuscript. Daniel E. Weeks contributed to the study design, analysis and interpretation of data, and critically revised and gave final approval for the manuscript. Yvette P. Conley contributed to the study conception and design, acquisition and interpretation of data, and critically revised and gave final approval for the manuscript. All authors agree to be accountable for all aspects of the work in ensuring that questions relating to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Lacey W. Heinsberg.

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Conflict of interest

LW Heinsberg reports Grants from the National Institutes of Health, University of Pittsburgh Jayne F. Wiggins Memorial Scholarship, Eta Chapter, Sigma Theta Tau, Inc., Jonas Foundation, and the Nightingale Awards of Pennsylvania during the conduct of this study. YP Conley, DE Weeks, and EA Crago reports Grants from the National Institutes of Health. SA Alexander, RL Minster, and SM Poloyac report nothing to disclose.

Ethical Conduct of Research

Informed consent was obtained from all study participants. Institutional Review Board approval at the University of Pittsburgh is in place (IRB approval number STUDY19100368) and we have adhered to ethical considerations in the protection of all human subjects involved.

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Heinsberg, L.W., Alexander, S.A., Crago, E.A. et al. Genetic Variability in the Iron Homeostasis Pathway and Patient Outcomes After Aneurysmal Subarachnoid Hemorrhage. Neurocrit Care 33, 749–758 (2020). https://doi.org/10.1007/s12028-020-00961-z

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