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Haplotype analysis of SERPINE1 gene: Risk for aneurysmal subarachnoid hemorrhage and clinical outcomes.

ABSTRACT: BACKGROUND:Aneurysmal subarachnoid hemorrhage (aSAH) has high fatality and permanent disability rates due to the severe damage to brain cells and inflammation. The SERPINE1 gene that encodes PAI-1 for the regulation of tissue plasminogen activator is considered an important therapeutic target for aSAH. METHODS:Six SNPs in the SERPINE1 gene (in order of rs2227631, rs1799889, rs6092, rs6090, rs2227684, rs7242) were investigated. Blood samples were genotyped with Taqman genotyping assays and pyrosequencing. The experiment-wide statistically significant threshold for single marker analysis was set at p < 0.01 after evaluation of independent markers. Haplotype analysis was performed in Haplo.stats package with permutation tests. Bonferroni correction for multiple comparison in dominant, additive, and recessive model was applied. RESULTS:A total of 146 aSAH patients and 49 control subjects were involved in this study. The rs2227631 G allele is significant (p = 0.01) for aSAH compared to control. In aSAH group, haplotype analysis showed that G5GGGT homozygotes in recessive model were associated with delayed cerebral ischemia (p < 0.01, Odds Ratio = 5.14, 95% CI = 1.45-18.18), clinical vasospasm (p = 0.01, Odds Ratio = 4.58, 95% CI = 1.30-16.13), and longer intensive care unit stay (p = 0.01). By contrast, the G5GGAG carriers were associated with less incidence of cerebral edema (p < 0.01) and higher Glasgow Coma Scale (p < 0.01). The A4GGGT carriers were associated with less incidence of severe hypertension (>140/90) (p < 0.01). CONCLUSION:The results suggested an important regulatory role of the SERPINE1 gene polymorphism in clinical outcomes of aSAH.

SUBMITTER: Lin M

PROVIDER: S-EPMC6687628 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Haplotype analysis of SERPINE1 gene: Risk for aneurysmal subarachnoid hemorrhage and clinical outcomes.

Lin Mingkuan M Griessenauer Christoph J CJ Starke Robert M RM Tubbs R Shane RS Shoja Mohammadali M MM Foreman Paul M PM Vyas Nilesh A NA Walters Beverly C BC Harrigan Mark R MR Hendrix Philipp P Fisher Winfield S WS Pittet Jean-Francois JF Mathru Mali M Lipsky Robert H RH

Molecular genetics & genomic medicine 20190703 8

<h4>Background</h4>Aneurysmal subarachnoid hemorrhage (aSAH) has high fatality and permanent disability rates due to the severe damage to brain cells and inflammation. The SERPINE1 gene that encodes PAI-1 for the regulation of tissue plasminogen activator is considered an important therapeutic target for aSAH.<h4>Methods</h4>Six SNPs in the SERPINE1 gene (in order of rs2227631, rs1799889, rs6092, rs6090, rs2227684, rs7242) were investigated. Blood samples were genotyped with Taqman genotyping as ...[more]

PMID: 31268630

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Project description:Objective: Systemic inflammation after subarachnoid hemorrhage (SAH) is implicated in delayed cerebral ischemia (DCI) and adverse clinical outcomes. We hypothesize that early changes in peripheral leukocytes will be associated with outcomes after SAH. Methods: SAH patients admitted between January 2009 and December 2016 were enrolled into a prospective observational study and were assessed for Hunt Hess Scale (HHS) at admission, DCI, and modified Ranked Scale (mRS) at discharge. Total white blood cell (WBC) counts and each component of the differential cell count were determined on the day of admission (day 0) to 8 days after bleed (day 8). Global cerebral edema (GCE) was assessed on admission CT, and presence of any infection was determined. Statistical tests included student's t-test, Chi-square test, and multivariate logistic regression (MLR) models. Results: A total of 451 subjects were analyzed. Total WBCs and neutrophils decreased initially reaching a minimum at day 4-5 after SAH. Monocyte count increased gradually after SAH and peaked between day 6-8, while basophils and lymphocytes decreased initially from day 0 to 1 and steadily increased thereafter. Neutrophil to lymphocyte ratio (NLR) reached a peak on day 1 and decreased thereafter. WBCs, neutrophils, monocytes, and NLR were higher in patients with DCI and poor functional outcomes. WBCs, neutrophils, and NLR were higher in subjects who developed infections. In MLR models, neutrophils and monocytes were associated with DCI and worse functional outcomes, while NLR was only associated with worse functional outcomes. Occurrence of infection was associated with poor outcome. Neutrophils and NLR were associated with infection, while monocytes were not. Monocytes were higher in males, and ROC curve analysis revealed improved ability of monocytes to predict DCI and poor functional outcomes in male subjects. Conclusions: Monocytosis was associated with DCI and poor functional outcomes after SAH. The association between neutrophils and NLR and infection may impact outcomes. Early elevation in monocytes had an improved ability to predict DCI and poor functional outcomes in males, which was independent of the occurrence of infection.

Project description:OBJECTIVE:The aim of the study was to assess the relation between cerebrovascular function early after aneurysmal subarachnoid hemorrhage onset and functional and rehabilitation outcomes. DESIGN:Observational cohort study of subarachnoid hemorrhage patients (n = 133) admitted to rehabilitation (n = 49), discharged home (n = 52), or died before discharge (n = 10). We obtained hemodynamic markers of cerebral autoregulatory function from blood flow velocities in the middle cerebral artery and arterial pressure waveforms, recorded daily on days 2-4 after symptom onset, and functional independence measure (FIM) scores and FIM efficiency for those admitted to acute rehabilitation. RESULTS:Compared to those discharged home, the range of pressures within which autoregulation is effective was lower in patients admitted to rehabilitation (4.6 [0.2] vs. 3.9 [0.2] mm Hg) and those who died (2.7 [0.4], P = 0.04). For those admitted to rehabilitation, autoregulatory range and the ability of cerebrovasculature to increase flow were related to discharge FIM score (R = 0.33 and 0.43, P < 0.01) and efficiency (R = 0.33 and 0.47 P < 0.01). The latter marker, along with subarachnoid hemorrhage severity and admission FIM, explained 84% and 69% of the variability in discharge FIM score and efficiency, respectively, even after accounting for age. CONCLUSIONS:Early cerebrovascular function is a major contributor to functional outcomes after subarachnoid hemorrhage and may represent a modifiable target to develop therapeutic approaches. TO CLAIM CME CREDITS:Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME OBJECTIVES: Upon completion of this article, the reader should be able to: (1) Define cerebral autoregulation; (2) Explain the importance of the integrity of cerebral autoregulation for longer-term functional and rehabilitation outcomes after aneurysmal subarachnoid hemorrhage; and (3) Theorize why treatment strategies that may be effective in reducing large-vessel vasospasms after an aneurysmal subarachnoid hemorrhage might not always translate into improved functional outcomes. LEVEL:Advanced ACCREDITATION: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 0.5 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

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Haplotype analysis of SERPINE1 gene: Risk for aneurysmal subarachnoid hemorrhage and clinical outcomes.

Publications

Haplotype analysis of SERPINE1 gene: Risk for aneurysmal subarachnoid hemorrhage and clinical outcomes.

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