Abstract 13682: Single Nucleotide Polymorphisms in the Ddah1 Gene Are Associated With Delayed Cerebral Ischemia in Patients With Subarachnoid Hemorrhage

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Juliane Hannemann ◽  
Daniel Appel ◽  
Miriam Seeberger-Steinmeister ◽  
Tabea Brüning ◽  
Julia Zummack ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Single Nucleotide Polymorphisms ◽  
Neurological Outcome ◽  
Delayed Cerebral Ischemia ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Gene Variation ◽  
Icu Admission ◽  
Plasma Adma

Introduction: Delayed cerebral ischemia (DCI) is a major cause of lethality and poor long-term neurological outcome in patients with subarachnoid hemorrhage (SAH). Asymmetric (ADMA) and symmetric dimethylarginine (SDMA) are regulators of vascular NO synthesis from L-arginine. We previously reported that elevated concentrations of both, ADMA and SDMA at ICU admission are associated with the incidence of DCI during follow-up. Dimethylarginines (DMAs) are synthesized by PRMT enzymes; ADMA is metabolized by DDAH1 and DDAH2, whilst SDMA is metabolized by AGXT2. Hypothesis: We hypothesized that common genetic variants in genes encoding the core enzymes of DMA metabolism may predispose individuals for the development of DCI after SAH. Methods: We measured L-arginine, ADMA and SDMA in plasma and cerebrospinal fluid (CSF) of 51 SAH patients at ICU admission and followed them for clinical status and neurological outcome until 30 days post-discharge. Single nucleotide polymorphisms (SNPs) in the NOS3, DDAH1, DDAH2, PRMT1, and AGXT2 genes were analyzed by PCR, and genotypes were related to biomarker levels and outcome. The primary outcome was the incidence of DCI, which was defined as the appearance of new infarctions on cranial computed tomography or magnetic resonance imaging. Results: 18 out of 51 SAH patients developed DCI. DCI patients did not significantly differ from those without DCI in clinical scores. However, patients who developed DCI had higher plasma ADMA and SDMA levels and higher SDMA levels in CSF at admission. DDAH1 gene variation was associated with plasma ADMA (p=0.02), whilst AGXT2 gene variation was associated with plasma SDMA (p=0.02). There was a strong association of all three DDAH1 SNPs that we analyzed with DCI, with carriers of the minor allele of DDAH1 rs233112 having a significantly increased relative risk of developing DCI (RR=2.61 (1.25-5.43), p=0.002). Conclusions: Sequence variation in the DDAH1 gene is associated with the incidence of DCI in SAH patients, suggesting that SNPs in the DDAH1 gene, which regulates plasma ADMA concentration, significantly influences the risk of cerebral ischemia after subarachnoid hemorrhage.

scholarly journals Associations between endothelin polymorphisms and aneurysmal subarachnoid hemorrhage, clinical vasospasm, delayed cerebral ischemia, and functional outcome

2018 ◽  
Vol 128 (5) ◽  
pp. 1311-1317 ◽  
Author(s):  
Christoph J. Griessenauer ◽  
Robert M. Starke ◽  
Paul M. Foreman ◽  
Philipp Hendrix ◽  
Mark R. Harrigan ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Functional Outcome ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Delayed Cerebral Ischemia ◽  
Multivariate Logistic Regression Analysis ◽  
Renin Angiotensin System ◽  
Nucleotide Polymorphisms ◽  
Endothelin 1 ◽  
Potent Vasoconstrictor

OBJECTIVEEndothelin-1, a potent vasoconstrictor, and its receptors may be involved in the pathogenesis of aneurysmal subarachnoid hemorrhage (aSAH), clinical vasospasm, delayed cerebral ischemia (DCI), and functional outcome following aSAH. In the present study, common endothelin single nucleotide polymorphisms (SNPs) and their relation to aSAH were evaluated.METHODSBlood samples from all patients enrolled in the Cerebral Aneurysm Renin Angiotensin System (CARAS) study were used for genetic evaluation. The CARAS study prospectively enrolled patients with aSAH at 2 academic institutions in the US from 2012 to 2015. Common endothelin SNPs were detected using 5′ exonnuclease (TaqMan) genotyping assays. Analysis of associations between endothelin SNPs and aSAH and its clinical sequelae was performed.RESULTSSamples from 149 patients with aSAH and 50 controls were available for analysis. In multivariate logistic regression analysis, the TG (odds ratio [OR] 2.102, 95% confidence interval [CI] 1.048–4.218, p = 0.036) and TT genotypes (OR 7.884, 95% CI 1.003–61.995, p = 0.05) of the endothelin-1 T/G SNP (rs1800541) were significantly associated with aSAH. There was a dominant effect of the G allele (CG/GG genotypes; OR 4.617, 95% CI 1.311–16.262, p = 0.017) of the endothelin receptor A G/C SNP (rs5335) on clinical vasospasm. Endothelin SNPs were not associated with DCI or functional outcome.CONCLUSIONSCommon endothelin SNPs were found to be associated with presentation with aSAH and clinical vasospasm. Further studies are required to elucidate the relevant pathophysiology and its potential implications in the treatment of patients with aSAH.

scholarly journals Endothelial Nitric Oxide Synthase Tagging Single Nucleotide Polymorphisms and Recovery From Aneurysmal Subarachnoid Hemorrhage

2009 ◽  
Vol 11 (1) ◽  
pp. 42-52 ◽  
Author(s):  
Sheila Alexander ◽  
Samuel Poloyac ◽  
Leslie Hoffman ◽  
Matthew Gallek ◽  
Dianxu Ren ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Subarachnoid Hemorrhage ◽  
Single Nucleotide Polymorphisms ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Enos Gene ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Poor Recovery ◽  
Recovery Profile ◽  
Endothelial Nitric Oxide

Aneurysmal subarachnoid hemorrhage (SAH) is a hemorrhagic stroke subtype with a poor recovery profile. Cerebral vasospasm (CV), a narrowing of the cerebral vasculature, significantly contributes to the poor recovery profile. Variation in the endothelial nitric oxide (NO) synthase (eNOS) gene has been implicated in CV and outcome after SAH. The purpose of this project was to explore the potential association between three eNOS tagging single nucleotide polymorphisms (SNPs) and recovery from SAH. We included 195 participants with a diagnosis of SAH and DNA and 6-month outcome data available but without preexisting neurologic disease/deficit. Genotyping was performed using an ABI Prism 7000 Sequence Detection System and TaqMan assays. CV was verified by cerebral angiogram independently read by a neurosurgeon on 118 participants. Modified Rankin Scores (MRS) and Glasgow Outcome Scale (GOS) scores were collected 6 months posthemorrhage. Data were analyzed using descriptive statistics, analysis of variance (ANOVA) and chi-square analysis as appropriate. The sample was primarily female (n = 147; 75.4%) and White (n = 178; 91.3%) with a mean age of 54.6 years. Of the participants with CV data, 56 (47.5%) developed CV within 14 days of SAH. None of the SNPs individually were associated with CV presence; however, a combination of the three variant SNPs was significantly associated with CV (p = .017). Only one SNP (rs1799983, variant allele) was associated with worse 6-month GOS scores (p < .001) and MRS (p < .001). These data indicate that the eNOS gene plays a role in the response to SAH, which may be explained by an influence on CV.

Asymmetric and Symmetric Dimethylarginines are Markers of Delayed Cerebral Ischemia and Neurological Outcome in Patients with Subarachnoid Hemorrhage

2018 ◽  
Vol 29 (1) ◽  
pp. 84-93 ◽  
Author(s):  
Daniel Appel ◽  
Miriam Seeberger ◽  
Edzard Schwedhelm ◽  
Patrick Czorlich ◽  
Alwin E. Goetz ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Neurological Outcome ◽  
Delayed Cerebral Ischemia

scholarly journals Sequence Variation in the DDAH1 Gene Predisposes for Delayed Cerebral Ischemia in Subarachnoidal Hemorrhage

2020 ◽  
Vol 9 (12) ◽  
pp. 3900
Author(s):  
Juliane Hannemann ◽  
Daniel Appel ◽  
Miriam Seeberger-Steinmeister ◽  
Tabea Brüning ◽  
Julia Zummack ◽  
...  
Keyword(s):  
Relative Risk ◽  
Cerebral Ischemia ◽  
Delayed Cerebral Ischemia ◽  
Cranial Computed Tomography ◽  
Nucleotide Polymorphisms ◽  
Post Discharge ◽  
Subarachnoidal Hemorrhage ◽  
Plasma Adma ◽  
Oxide Synthase

Delayed cerebral ischemia (DCI) often causes poor long-term neurological outcome after subarachnoidal hemorrhage (SAH). Asymmetric dimethylarginine (ADMA) inhibits nitric oxide synthase (NOS) and is associated with DCI after SAH. We studied single nucleotide polymorphisms (SNPs) in the NOS3, DDAH1, DDAH2, PRMT1, and AGXT2 genes that are part of the L-arginine–ADMA–NO pathway, and their association with DCI. We measured L-arginine, ADMA and symmetric dimethylarginine (SDMA) in plasma and cerebrospinal fluid (CSF) of 51 SAH patients at admission; follow-up was until 30 days post-discharge. The primary outcome was the incidence of DCI, defined as new infarctions on cranial computed tomography, which occurred in 18 of 51 patients. Clinical scores did not significantly differ in patients with or without DCI. However, DCI patients had higher plasma ADMA and SDMA levels and higher CSF SDMA levels at admission. DDAH1 SNPs were associated with plasma ADMA, whilst AGXT2 SNPs were associated with plasma SDMA. Carriers of the minor allele of DDAH1 rs233112 had a significantly increased relative risk of DCI (Relative Risk = 2.61 (1.25–5.43), p = 0.002). We conclude that the DDAH1 gene is associated with ADMA concentration and the incidence of DCI in SAH patients, suggesting a pathophysiological link between gene, biomarker, and clinical outcome in patients with SAH.

scholarly journals Matrix metalloproteinase-9 gene polymorphisms and their interaction with environment on subarachnoid hemorrhage risk

2018 ◽  
Vol 243 (9) ◽  
pp. 749-753 ◽  
Author(s):  
Tao Wang ◽  
Wanxing Fu ◽  
Shuang Song ◽  
Yanlong Han ◽  
Lihong Yao ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Single Nucleotide Polymorphisms ◽  
Matrix Metalloproteinase ◽  
Dimensionality Reduction ◽  
Multifactor Dimensionality Reduction ◽  
Matrix Metalloproteinase 9 ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Hemorrhage Risk ◽  
Metalloproteinase 9

The current study aimed to investigate the relations of three single nucleotide polymorphisms of matrix metalloproteinase-9 gene, and single nucleotide polymorphisms-smoking interaction to subarachnoid hemorrhage risk. The optimal pattern of the interaction among single nucleotide polymorphisms and smoking was selected by generalized multifactor dimensionality reduction. The association between the three single nucleotide polymorphisms within the matrix metalloproteinase-9 gene was analyzed by logistic regression test. As well as genetic risk of subarachnoid hemorrhage interactions with smoking, the risk of subarachnoid hemorrhage in carriers with the rs3918242 (T) was significantly higher than in carriers carrying CC (genotype: CT + TT vs. CC), adjusted OR (95% CI) = 1.58 (1.25–2.03), and in carriers carrying rs17576- (genotype: AG + GG vs. AA), adjust OR (95% CI) = 1.62 (1.19–2.13). However, after adjusting for covariates, we did not find any direct association between rs17577 and subarachnoid hemorrhage risk. The generalized multifactor dimensionality reduction model shows a potential relation between rs3918242 and smoking risk for subarachnoid hemorrhage ( P = 0.0010). After covariates adjustment, current smokers with rs3918242-CT or TT genotype, compared to never-smokers with rs3918242-CC genotype, OR (95% CI) = 2.57 (1.74–3.46), have a higher subarachnoid hemorrhage risk. Our study showed that the rs3918242 (T) and rs17576 (G), the cross reaction between rs3918242 and smoking increased the risk of subarachnoid hemorrhage. Impact statement Matrix metalloproteinase-9 ( MMP-9) is a possible candidate gene for some diseases, including metabolic syndrome, stroke, coronary artery disease (CAD). But to date, limited data focused on the relationship between MMP-9 gene SNPs and SAH susceptibility. The purpose of this study was to evaluate SNPs of MMP-9 gene and their interaction with environmental factors with SAH risk based on a Chinese population.

The Association Between Spontaneous Hyperventilation, Delayed Cerebral Ischemia, and Poor Neurological Outcome in Patients with Subarachnoid Hemorrhage

2015 ◽  
Vol 23 (3) ◽  
pp. 330-338 ◽  
Author(s):  
Craig A. Williamson ◽  
Kyle M. Sheehan ◽  
Renuka Tipirneni ◽  
Christopher D. Roark ◽  
Aditya S. Pandey ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Neurological Outcome ◽  
Delayed Cerebral Ischemia ◽  
Poor Neurological Outcome

Association between factor XIII single nucleotide polymorphisms and aneurysmal subarachnoid hemorrhage

2009 ◽  
Vol 110 (3) ◽  
pp. 475-481 ◽  
Author(s):  
Claes Ladenvall ◽  
Ludvig Csajbok ◽  
Karin Nylén ◽  
Katarina Jood ◽  
Bengt Nellgård ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Single Nucleotide Polymorphisms ◽  
Plasminogen Activator ◽  
Factor Xiii ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Tissue Type ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Increased Risk ◽  
Pai 1

Object Family studies have suggested a role of genetic factors in susceptibility to aneurysmal subarachnoid hemorrhage (aSAH), but the underlying genetic risk factors remain poorly defined. There is an activation of the fibrinolytic system in aSAH, and fibrinolytic markers may be useful in predicting outcome. The authors investigate associations between putative functional variants in genes of importance for fibrinolysis and aSAH and/or outcome following aSAH. Methods One hundred eighty-three patients presenting with aSAH at a neurointensive care unit were consecutively recruited. Two healthy controls per case, matched for age, sex, and geographic region, were randomly recruited. Outcome was assessed after 1 year according to the extended Glasgow Outcome Scale. Single nucleotide polymorphisms (SNPs) in the tissue-type plasminogen activator (tPA), plasminogen activator inhibitor type 1 (PAI-1), thrombin activatable fibrinolysis inhibitor (TAFI), and factor XIII (FXIII) genes were investigated. Results Participants carrying the FXIII 34Leu allele showed an increased risk of aSAH. When adjusting for smoking and hypertension, 2 haplotypes, differing on either the FXIII Val34Leu or the Pro564Leu position, showed an association to aSAH. No significant association was observed for the tPA -7351 C > T, PAI-1 -675 4G > 5G, or TAFI Ala147Thr SNPs. No specific SNP or haplotype was associated with outcome after aSAH, whereas a weak association was observed for a tPA/PAI-1 genotype combination. Conclusions Polymorphisms in the FXIII gene showed association to aSAH. The finding of an increased risk of bleeding in FXIII 34Leu carriers is biologically plausible.

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