Publications by authors named "Caspar Grond-Ginsbach"

78 Publications

Genetic Variation in Associates with Stanford Type B Aortic Dissection Risk and Clinical Outcome.

Authors:
Philipp Erhart Daniel Körfer Caspar Grond-Ginsbach Jia-Lu Qiao Moritz S Bischoff Maja Hempel Christian P Schaaf Armin Grau Dittmar Böckler

J Cardiovasc Dev Dis 2022 Jan 5;9(1). Epub 2022 Jan 5.

Department of Vascular and Endovascular Surgery, Heidelberg University Hospital, 69120 Heidelberg, Germany.

Genetic variation in (low-density lipoprotein receptor-related protein 1) was reported to be associated with thoracic aortic dissections and aneurysms. The aims of this study were to confirm this association in a prospective single-center patient cohort of patients with acute Stanford type B aortic dissections (STBAD) and to assess the impact of variation on clinical outcome. The single nucleotide variation (SNV) rs11172113 within the gene was genotyped in 113 STBAD patients and 768 healthy control subjects from the same population. The T-allele of rs11172113 was more common in STBAD patients as compared to the reference group (72.6% vs. 59.6%) and confirmed to be an independent risk factor for STBAD ( = 0.002) after sex and age adjustment in a logistic regression model analyzing diabetes, smoking and hypertension as additional risk factors. Analysis of clinical follow-up (median follow-up 2.0 years) revealed that patients with the T-allele were more likely to suffer aorta-related complications (T-allele 75.6% vs. 63.8%; = 0.022). In this study sample of STBAD patients, variation in was an independent risk factor for STBAD and affected clinical outcome.
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http://dx.doi.org/10.3390/jcdd9010014DOI Listing
January 2022

Cervical Artery Dissection and Sports.

Authors:
Stefan T Engelter Christopher Traenka Caspar Grond-Ginsbach Tobias Brandt Maani Hakimi Bradford B Worrall Stephanie Debette Alessandro Pezzini Didier Leys Turgut Tatlisumak Christian H Nolte Philippe Lyrer

Front Neurol 2021 31;12:663830. Epub 2021 May 31.

Department of Neurology and Stroke Center, University Hospital Basel and University of Basel, Basel, Switzerland.

Cervical artery dissection (CeAD) occurring in the context of sports is a matter of concern for CeAD patients. They seek advice on the role of sports in CeAD and on the safety of resuming sports after CeAD. The scarcity of studies and guidelines addressing these issues poses a challenge. We aimed at summarizing the current knowledge about CeAD and sports in order to provide an informed, comprehensive opinion for counseling CeAD patients. We took into account pathophysiological considerations, observations of cases reports, series, and registries, and conclusions by analogy from aortic dissection or inherited connective tissue syndromes. In summary, practicing active sports as the cause of CeAD seems uncommon. It seems recommendable to refrain from any kind of sports activities for at least 1 month, which can be extended in case of an unfavorable clinical or neurovascular course. We recommend starting with sport activities at low intensity-preferably with types of endurance sports-and to gradually increase the pace in an individually tailored manner, taking into circumstances of the occurrences of the CeAD in the individual patient (particularly in relation to sports), the meaning of sports activities for the individual well-being, the presence or absence of comorbidities and of neurological sequela, neurovascular findings, and whether there are signs of an underlying connective tissue alteration. Major limitations and several forms of bias are acknowledged. Still, in the absence of any better data, the summarized observations and considerations might help clinicians in advising and counseling patients with CeAD in clinical practice.
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http://dx.doi.org/10.3389/fneur.2021.663830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200565PMC
May 2021

The copy number variation and stroke (CaNVAS) risk and outcome study.

Authors:
John W Cole Taiwo Adigun Rufus Akinyemi Onoja Matthew Akpa Steven Bell Bowang Chen Jordi Jimenez Conde Uxue Lazcano Dobao Israel Fernandez Myriam Fornage Cristina Gallego-Fabrega Christina Jern Michael Krawczak Arne Lindgren Hugh S Markus Olle Melander Mayowa Owolabi Kristina Schlicht Martin Söderholm Vinodh Srinivasasainagendra Carolina Soriano Tárraga Martin Stenman Hemant Tiwari Margaret Corasaniti Natalie Fecteau Beth Guizzardi Haley Lopez Kevin Nguyen Brady Gaynor Timothy O'Connor

PLoS One 2021 19;16(4):e0248791. Epub 2021 Apr 19.

University of Maryland School of Medicine, Baltimore, MD, United States of America.

Background And Purpose: The role of copy number variation (CNV) variation in stroke susceptibility and outcome has yet to be explored. The Copy Number Variation and Stroke (CaNVAS) Risk and Outcome study addresses this knowledge gap.

Methods: Over 24,500 well-phenotyped IS cases, including IS subtypes, and over 43,500 controls have been identified, all with readily available genotyping on GWAS and exome arrays, with case measures of stroke outcome. To evaluate CNV-associated stroke risk and stroke outcome it is planned to: 1) perform Risk Discovery using several analytic approaches to identify CNVs that are associated with the risk of IS and its subtypes, across the age-, sex- and ethnicity-spectrums; 2) perform Risk Replication and Extension to determine whether the identified stroke-associated CNVs replicate in other ethnically diverse datasets and use biomarker data (e.g. methylation, proteomic, RNA, miRNA, etc.) to evaluate how the identified CNVs exert their effects on stroke risk, and lastly; 3) perform outcome-based Replication and Extension analyses of recent findings demonstrating an inverse relationship between CNV burden and stroke outcome at 3 months (mRS), and then determine the key CNV drivers responsible for these associations using existing biomarker data.

Results: The results of an initial CNV evaluation of 50 samples from each participating dataset are presented demonstrating that the existing GWAS and exome chip data are excellent for the planned CNV analyses. Further, some samples will require additional considerations for analysis, however such samples can readily be identified, as demonstrated by a sample demonstrating clonal mosaicism.

Conclusion: The CaNVAS study will cost-effectively leverage the numerous advantages of using existing case-control data sets, exploring the relationships between CNV and IS and its subtypes, and outcome at 3 months, in both men and women, in those of African and European-Caucasian descent, this, across the entire adult-age spectrum.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248791PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055008PMC
September 2021

Acute Stanford type B aortic dissection-who benefits from genetic testing?

Authors:
Philipp Erhart Laura Gieldon Marius Ante Daniel Körfer Tim Strom Caspar Grond-Ginsbach Dittmar Böckler

J Thorac Dis 2020 Nov;12(11):6806-6812

Department of Vascular and Endovascular Surgery, Ruprechts-Karls University Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany.

Background: Stanford type B aortic dissection is a rare, life-threatening complex phenotype associated with several modifiable and genetic risk factors. In the current study of a hospital-based, consecutive series of aortic dissection patients we propose a selection based on age and family history of aortic disease for genetic testing and detection of causative gene variants.

Methods: In this single center cohort study from 2013 to 2018 patients with acute Stanford type B aortic dissections were consecutively treated and analyzed by next generation sequencing based on selection criteria (age of disease onset ≤45 years and/or positive familial history for aortic disease) to detect genome-wide pathogenic variants in protein-coding sequences and to identify large copy number variants (CNV). Variants in a predefined panel of 30 genes associated with the familial thoracic aortic aneurysm and dissection (TAAD) syndrome were evaluated.

Results: From 105 patients nine matched selection criteria for genetic testing. Next-generation sequencing analysis revealed causal variants in (fibrillin-1) in three patients: a pathogenic missense variant [c.6661T>C, p.(Cys2221Arg)] and two truncating variants [c.4786C>T, p.(Arg1596Ter)] and [c.6366C>CA, p.(Asp2123GlufsTer5)]. A fourth patient carried a large (>1,000,000 bp) CNV in the long arm of chromosome 10, deleting eleven genes, including the whole (actin alpha 2) gene. The latter two genetic findings have not been reported before.

Conclusions: Selection of patients on the basis of young age and familial inheritance of aortic disease favors the identification of disease-causing genetic variants in a clinical cohort of patients with Stanford type B aortic dissection.
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http://dx.doi.org/10.21037/jtd-20-2421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711383PMC
November 2020

Outcomes of thoracic endovascular aortic repair in thoracic aortic aneurysm and penetrating aortic ulcer using the Conformable Gore TAG within and outside the instructions for use.

Authors:
Katrin Meisenbacher Matthias Hagedorn Caspar Grond-Ginsbach Dorothea Weber Dittmar Böckler Moritz S Bischoff

Vascular 2021 Aug 2;29(4):486-498. Epub 2020 Nov 2.

Department of Vascular and Endovascular Surgery, Heidelberg University Hospital, Germany.

Objective: To describe the outcome of thoracic endovascular aortic repair (TEVAR) in thoracic aortic aneurysm and penetrating aortic ulcer with respect to instructions for use status.

Methods: Between October 2009 and September 2017, a total of 532 patients underwent TEVAR; of which 195 have been treated using the Conformable GORE® TAG® thoracic endoprosthesis (CTAG). Fifty-six patients of this cohort underwent TEVAR for thoracic aortic aneurysm/penetrating aortic ulcer using the CTAG. Depending on the preoperative computed tomography angiography findings, patients were classified as inside or outside the device's instructions for use. All inside instruction for use patients underwent postoperative reclassification regarding the instructions for use status. Study endpoints included TEVAR-related reintervention, exclusion of the pathology (endoleak type I/III), TEVAR-related mortality, and graft-related serious adverse events. The median duration of follow-up was 29.7 months (range: 0-109.4 months).

Results: Of the 56 patients, 17 were primarily classified as outside instruction for use, and in additional 13 patients, TEVAR was performed outside instruction for use, leading to 30 outside instruction for use patients (53.6%). Twenty-six patients (46.4%) were treated inside instruction for use. Reintervention-free survival was lower in outside instruction for use patients ( = 0.016) with a hazard ratio of 9.74 (confidence interval 1.2-80.2;  = 0.034) for TEVAR-related reintervention. With respect to endoleak type I/III, relevant difference was detected between inside/outside instruction for use status ( = 0.012). The serious adverse event rate was 30.4%, mainly in outside instruction for use patients ( = 0.004). Logistic regression analysis indicated an association between graft-related serious adverse event/instructions for use status (odds ratio 6.11; confidence interval 1.6-30.06;  = 0.012). In-hospital death was seen more frequently in outside instruction for use patients ( = 0.12) as was procedure-related death (log-rank test:  = 0.21).

Conclusion: TEVAR for thoracic aortic aneurysm/penetrating aortic ulcer is frequently performed outside instruction for use despite preoperative inside instruction for use eligibility, leading to important consequences for technical/clinical outcome. Instructions for use adherence in TEVAR should be of interest for further large-scale studies.
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http://dx.doi.org/10.1177/1708538120970033DOI Listing
August 2021

Rare genetic variants in patients with cervical artery dissection.

Authors:
Christopher Traenka Manja Kloss Tim Strom Philippe Lyrer Tobias Brandt Leo H Bonati Caspar Grond-Ginsbach Stefan Engelter

Eur Stroke J 2019 Dec 12;4(4):355-362. Epub 2019 Jul 12.

Department of Neurology and Stroke Center, University Hospital and University of Basel, Basel, Switzerland.

Introduction: The potential role of genetic alterations in cervical artery dissection (CeAD) pathogenesis is poorly understood. We aimed to identify pathogenic genetic variants associated with cervical artery dissection by using whole exome sequencing.

Patients And Methods: CeAD-patients with either a family history of cervical artery dissection (f-CeAD) or recurrent cervical artery dissection (r-CeAD) from the CeAD-databases of two experienced stroke centres were analysed by whole exome sequencing.Variants with allele frequency <0.05 and classified as pathogenic by predicting algorithms (SIFT or Polyphen-2) or the ClinVar database were explored. First, we analysed a panel of 30 candidate genes associated with arterial dissection (any site) or aneurysm according to the OMIM (online Mendelian Inheritance of Men) database. Second, we performed a genome-wide search for pathogenic variants causing other vascular phenotypes possibly related to cervical artery dissection.Findings were classified as CeAD-causing (pathogenic variants in genes from the arterial dissection or aneurysm panel) or suggestive (pathogenic variants in genes associated with other vascular phenotypes and variants of unknown significance in genes from the arterial dissection or aneurysm panel). All other variants were classified as benign/uncertain.

Results: Among 43 CeAD-patients, 28 patients (17 pedigrees) had f-CeAD and 15 had r-CeAD. No CeAD-causing variants were identified in r-CeAD patients. Among f-CeAD-patients, 5/17 pedigrees carried CeAD-causing variants in COL3A1, COL4A1, COL4A3, COL4A4, COL5A1, COL5A2 and FBN1. Suggestive variants in ABCC6, COL3A1, COL5A2, MEF2A, and RNF213 were detected in three pedigrees with f-CeAD and six patients with r-CeAD. CeAD-causing variants were rare and exclusively found in f-CeAD-patients, suggesting differences between the genetic architectures of f-CeAD and r-CeAD. The identified variants indicate a high genetic heterogeneity of the study sample.
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http://dx.doi.org/10.1177/2396987319861869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921947PMC
December 2019

Artery occlusion independently predicts unfavorable outcome in cervical artery dissection.

Authors:
Christopher Traenka Caspar Grond-Ginsbach Barbara Goeggel Simonetti Tiina M Metso Stéphanie Debette Alessandro Pezzini Manja Kloss Jennifer J Majersik Andrew M Southerland Didier Leys Ralf Baumgartner Valeria Caso Yannick Béjot Gian Marco De Marchis Urs Fischer Alexandros Polymeris Hakan Sarikaya Vincent Thijs Bradford B Worrall Anna Bersano Tobias Brandt Henrik Gensicke Leo H Bonati Emmanuel Touzeé Juan J Martin Hugues Chabriat Turgut Tatlisumak Marcel Arnold Stefan T Engelter Philippe Lyrer

Neurology 2020 01 22;94(2):e170-e180. Epub 2019 Nov 22.

From the Department of Neurology and Stroke Center (C.T., G.M.D.M., A. Polymeris, H.G., L.H.B., S.T.E., P.L.), University Hospital Basel and University of Basel; Neurorehabilitation Unit (C.T., H.G., S.T.E.), University of Basel and University Center for Medicine of Aging and Rehabilitation, Felix Platter Hospital, Basel, Switzerland; Departments of Neurology (C.G.-G., M.K.) and Vascular and Endovascular Surgery (C.G.-G.), Heidelberg University Hospital, Germany; Department of Neurology (B.G.S., U.F., H.S., M.A.), University Hospital Bern; Ospedale San Giovanni (B.G.S.), Bellinzona, Switzerland; Department of Neurology (T.M.M., T.T.), Helsinki University Central Hospital, Finland; Department of Neurology (S.D.), Bordeaux University Hospital; Inserm U1219 (S.D.), Bordeaux; University of Bordeaux (S.D.), France; Department of Neurology (S.D.), Boston University School of Medicine, MA; Department of Clinical and Experimental Sciences (A.Pezzini.), Neurology Clinic, University of Brescia, Italy; Department of Neurology (J.J.M.), University of Utah, Salt Lake City; Departments of Neurology and Public Health Sciences (A.M.S., B.B.W.), University of Virginia Health System, Charlottesville; Univ-Lille (D.L.), Inserm U1171, CHU Lille, France; Neuro Center (R.B.), Clinic Hirslanden, Zurich, Switzerland; Stroke Unit and Division of Internal and Cardiovascular Medicine (V.C.), University of Perugia, Italy; Centre Hospitalier Universitaire Dijon Bourgogne (Y.B.), EA7460, Pathophysiology and Epidemiology of Cardio-Cerebro-Vascular Diseases, University of Burgundy, Dijon, France; Department of Neurology (H.S.), University Hospital of Zurich, Switzerland; Stroke Theme (V.T.), Florey Institute of Neuroscience and Mental Health, University of Melbourne, Heidelberg; Department of Neurology (V.T.), Austin Health, Heidelberg, Victoria, Australia; Cerebrovascular Unit Fondazione IRCCS Istituto Neurologico Carlo Besta (A.B.), Milan, Italy; Swiss National Accident Insurance Institution (T.B.), Lucerne, Switzerland; Normandie Université (E.T.), Université Caen Normandie, Inserm U1037, Department of Neurology, CHU Caen Normandie; Department of Neurology (E.T.), CH Sainte-Anne, University Paris Descartes, France; Department of Neurology (J.J.M.), Sanatorio Allende, Cordoba, Argentina; Department of Neurology (H.C.), Lariboisière Hospital, Paris, France; Department of Neurology (T.T.), Sahlgrenska University Hospital; and Department of Clinical Neuroscience Institute for Neuroscience and Physiology (T.T.), Sahlgrenska Academy at University of Gothenburg, Sweden.

Objective: To assess the impact of dissected artery occlusion (DAO) on functional outcome and complications in patients with cervical artery dissection (CeAD).

Methods: We analyzed combined individual patient data from 3 multicenter cohorts of consecutive patients with CeAD (the Cervical Artery Dissection and Ischemic Stroke Patients [CADISP]-Plus consortium dataset). Patients with data on DAO and functional outcome were included. We compared patients with DAO to those without DAO. Primary outcome was favorable functional outcome (i.e., modified Rankin Scale [mRS] score 0-1) measured 3-6 months from baseline. Secondary outcomes included delayed cerebral ischemia, major hemorrhage, recurrent CeAD, and death. We performed univariate and multivariable binary logistic regression analyses and calculated odds ratios (OR) with 95% confidence intervals (CI), with adjustment for potential confounders.

Results: Of 2,148 patients (median age 45 years [interquartile range (IQR) 38-52], 43.6% women), 728 (33.9%) had DAO. Patients with DAO more frequently presented with cerebral ischemia (84.6% vs 58.5%, < 0.001). Patients with DAO were less likely to have favorable outcome when compared to patients without DAO (mRS 0-1: 59.6% vs 80.1%, < 0.001). After adjustment for age, sex, and initial stroke severity, DAO was independently associated with less favorable outcome (mRS 0-1: OR 0.65, CI 0.50-0.84, = 0.001). Delayed cerebral ischemia occurred more frequently in patients with DAO than in patients without DAO (4.5% vs 2.9%, = 0.059).

Conclusion: DAO independently predicts less favorable functional outcome in patients with CeAD. Further research on vessel patency, collateral status and effects of revascularization therapies particularly in patients with DAO is warranted.
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http://dx.doi.org/10.1212/WNL.0000000000008654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988986PMC
January 2020

Unexpected excessive apixaban exposure: case report of a patient with polymorphisms of multiple apixaban elimination pathways.

Authors:
Andrea Huppertz Caspar Grond-Ginsbach Chris Dumschat Kathrin I Foerster Jürgen Burhenne Johanna Weiss David Czock Jan C Purrucker Timolaos Rizos Walter E Haefeli

BMC Pharmacol Toxicol 2019 08 29;20(1):53. Epub 2019 Aug 29.

Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.

Background: Apixaban effectively lowers the risk of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation. Systemic exposure to a given apixaban dose depends on multiple clearance pathways. Though routine quantification of direct oral anticoagulants (DOACs) in neurological emergency situations has not been widely established, suspected associations of DOAC peak concentrations with bleeding events and DOAC trough concentrations with efficacy and safety suggest that such information might support clinical decision making.

Case Presentation: We describe the case of a 75 year-old woman with atrial fibrillation maintained on apixaban who was admitted due to suspected acute stroke. Clinical work-up did not confirm ischemic or hemorrhagic stroke but routine quantification of apixaban revealed an excessively high apixaban plasma concentration (~ 3 h after the last drug intake: 1100 ng/ml (expected range: 91-321 ng/ml); ~ 12 h after drug intake: 900 ng/ml (expected range: 41-230 ng/ml)) and a substantially prolonged elimination half-life (~ 31 h). The corresponding apixaban concentration-to-dose ratio was 9900 (ng/ml)/(mg/kg/d) and 8100 (ng/ml)/(mg/kg/d), respectively (expected range: 249-463 (ng/ml)/(mg/kg/d)). Renal function was only moderately impaired (creatinine 1.36 mg/dl (0.5-1.1 mg/dl), creatinine clearance 40 ml/min). Genotype analyses revealed that the patient was a CYP3A5*3/*3 non-expressor, a heterozygous carrier of the ABCG2 c.421C/A alleles, and a homozygous carrier of ABCB1 c.2677 T/T and ABCB1 c.3435 T/T. In the absence of known drug interactions explaining apixaban clearance impairment, excessive apixaban concentrations were most probably caused by moderate renal impairment combined with multiple functional polymorphisms of apixaban clearance pathways.

Conclusions: This case suggests that concurrent genetic polymorphisms can impair multiple apixaban elimination pathways and thus substantially increase its exposure.
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http://dx.doi.org/10.1186/s40360-019-0331-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716843PMC
August 2019

Inflammasome activity in leucocytes decreases with abdominal aortic aneurysm progression.

Authors:
Philipp Erhart Sinan Cakmak Caspar Grond-Ginsbach Maani Hakimi Dittmar Böckler Susanne Dihlmann

Int J Mol Med 2019 Oct 7;44(4):1299-1308. Epub 2019 Aug 7.

Department of Vascular and Endovascular Surgery, University Hospital Heidelberg, D-69120 Heidelberg, Germany.

Abdominal aortic aneurysms (AAAs) are characterized by chronic inflammatory cell infiltration. The present extended immunohistochemistry study aimed to characterize inflammation in AAA and aortic control samples. In specific, the composition of the infiltrating immune cells and the expression of five inflammasome components in these immune cells were evaluated, in order to characterize their role in AAA development. A total of 104 biopsies from 48 AAA patients and 40 healthy specimens from organ donors were evaluated for their grade of inflammation. Infiltrating leukocytes were characterized by specific markers (CD3, CD20 and CD68), intramural localization and inflammasome protein expression [NLR family pyrin domain containing 3 (NLRP3), absent in melanoma 2 (AIM2), apoptosis‑associated speck‑like protein containing a caspase recruitment domain (ASC), Caspase‑1 and Caspase‑5]. Macrophages, B and T lymphocytes were detected to a similar extent in grade 1, 2 and 3 AAA specimens, whereas in control samples, B and T lymphocytes were rarely observed in grade 1 lesions. Expression frequencies of NLRP3, AIM2 and Caspase‑5 were significantly higher in grade 1 lesions of AAA samples compared with grade 1 lesions in control samples. Finally, AIM2, ASC, and Caspase‑5 displayed significantly lower expression frequencies in grade 3 compared with grade 2 AAA specimens, and all inflammasome components were less frequently detected in grade 3 than in grade 1 lesions of AAA. This indicates that inflammasome activities decrease with AAA progression in infiltrating leukocytes. No statistically significant association was found for grade 2 and grade 3 lesions and total leukocyte count, C‑reactive protein levels, maximal aortic diameter, plasma cholesterol level or biomechanical parameters (derived from finite element analysis) of the respective patients. Overall, the aortic wall of AAA contained lymphocytes and macrophages with different states of activity. The present data suggested that therapeutic inhibition of specific inflammasome components might counteract AAA development and progression.
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http://dx.doi.org/10.3892/ijmm.2019.4307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713432PMC
October 2019

Pathogenic TSR1 Gene Variants in Patients With Spontaneous Coronary Artery Dissection.

Authors:
Caspar Grond-Ginsbach Dittmar Böckler Christopher Newton-Cheh

J Am Coll Cardiol 2019 07;74(2):177-178

Cardiovascular Research Center & Center for Genomic Medicine, Massachusetts General Hospital, Program in Medical and Population Genetics, Broad Institute; Boston, Massachusetts.

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http://dx.doi.org/10.1016/j.jacc.2019.06.005DOI Listing
July 2019

Genetic Imbalance Is Associated With Functional Outcome After Ischemic Stroke.

Authors:
Dorothea Pfeiffer Bowang Chen Kristina Schlicht Philip Ginsbach Sherine Abboud Anna Bersano Steve Bevan Tobias Brandt Valeria Caso Stéphanie Debette Philipp Erhart Sandra Freitag-Wolf Giacomo Giacalone Armin J Grau Eyad Hayani Christina Jern Jordi Jiménez-Conde Manja Kloss Michael Krawczak Jin-Moo Lee Robin Lemmens Didier Leys Christoph Lichy Jane M Maguire Juan J Martin Antti J Metso Tiina M Metso Braxton D Mitchell Alessandro Pezzini Jonathan Rosand

Stroke 2019 02;50(2):298-304

Center for Genomic Medicine (J.R.), Massachusetts General Hospital, Boston.

Background and Purpose- We sought to explore the effect of genetic imbalance on functional outcome after ischemic stroke (IS). Methods- Copy number variation was identified in high-density single-nucleotide polymorphism microarray data of IS patients from the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) and SiGN (Stroke Genetics Network)/GISCOME (Genetics of Ischaemic Stroke Functional Outcome) networks. Genetic imbalance, defined as total number of protein-coding genes affected by copy number variations in an individual, was compared between patients with favorable (modified Rankin Scale score of 0-2) and unfavorable (modified Rankin Scale score of ≥3) outcome after 3 months. Subgroup analyses were confined to patients with imbalance affecting ohnologs-a class of dose-sensitive genes, or to those with imbalance not affecting ohnologs. The association of imbalance with outcome was analyzed by logistic regression analysis, adjusted for age, sex, stroke subtype, stroke severity, and ancestry. Results- The study sample comprised 816 CADISP patients (age 44.2±10.3 years) and 2498 SiGN/GISCOME patients (age 67.7±14.2 years). Outcome was unfavorable in 122 CADISP and 889 SiGN/GISCOME patients. Multivariate logistic regression analysis revealed that increased genetic imbalance was associated with less favorable outcome in both samples (CADISP: P=0.0007; odds ratio=0.89; 95% CI, 0.82-0.95 and SiGN/GISCOME: P=0.0036; odds ratio=0.94; 95% CI, 0.91-0.98). The association was independent of age, sex, stroke severity on admission, stroke subtype, and ancestry. On subgroup analysis, imbalance affecting ohnologs was associated with outcome (CADISP: odds ratio=0.88; 95% CI, 0.80-0.95 and SiGN/GISCOME: odds ratio=0.93; 95% CI, 0.89-0.98) whereas imbalance without ohnologs lacked such an association. Conclusions- Increased genetic imbalance was associated with poorer functional outcome after IS in both study populations. Subgroup analysis revealed that this association was driven by presence of ohnologs in the respective copy number variations, suggesting a causal role of the deleterious effects of genetic imbalance.
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http://dx.doi.org/10.1161/STROKEAHA.118.021856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441497PMC
February 2019

Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke.

Authors:
John W Cole Huichun Xu Kathleen Ryan Thomas Jaworek Nicole Dueker Patrick McArdle Brady Gaynor Yu-Ching Cheng Jeffrey O'Connell Steve Bevan Rainer Malik Naveed Uddin Ahmed Philippe Amouyel Sheraz Anjum Joshua C Bis David Crosslin John Danesh Stefan T Engelter Myriam Fornage Philippe Frossard Christian Gieger Anne-Katrin Giese Caspar Grond-Ginsbach Weang Kee Ho Elizabeth Holliday Jemma Hopewell M Hussain W Iqbal S Jabeen Jim Jannes

PLoS One 2018 1;13(11):e0206554. Epub 2018 Nov 1.

University of Adelaide, Adelaide, Australia.

Background And Purpose: Polymorphisms in coagulation genes have been associated with early-onset ischemic stroke. Here we pursue an a priori hypothesis that genetic variation in the endothelial-based receptors of the thrombomodulin-protein C system (THBD and PROCR) may similarly be associated with early-onset ischemic stroke. We explored this hypothesis utilizing a multi-stage design of discovery and replication.

Methods: Discovery was performed in the Genetics-of-Early-Onset Stroke (GEOS) Study, a biracial population-based case-control study of ischemic stroke among men and women aged 15-49 including 829 cases of first ischemic stroke (42.2% African-American) and 850 age-comparable stroke-free controls (38.1% African-American). Twenty-four single-nucleotide-polymorphisms (SNPs) in THBD and 22 SNPs in PROCR were evaluated. Following LD pruning (r2≥0.8), we advanced uncorrelated SNPs forward for association analyses. Associated SNPs were evaluated for replication in an early-onset ischemic stroke population (onset-age<60 years) consisting of 3676 cases and 21118 non-stroke controls from 6 case-control studies. Lastly, we determined if the replicated SNPs also associated with older-onset ischemic stroke in the METASTROKE data-base.

Results: Among GEOS Caucasians, PROCR rs9574, which was in strong LD with 8 other SNPs, and one additional independent SNP rs2069951, were significantly associated with ischemic stroke (rs9574, OR = 1.33, p = 0.003; rs2069951, OR = 1.80, p = 0.006) using an additive-model adjusting for age, gender and population-structure. Adjusting for risk factors did not change the associations; however, associations were strengthened among those without risk factors. PROCR rs9574 also associated with early-onset ischemic stroke in the replication sample (OR = 1.08, p = 0.015), but not older-onset stroke. There were no PROCR associations in African-Americans, nor were there any THBD associations in either ethnicity.

Conclusion: PROCR polymorphisms are associated with early-onset ischemic stroke in Caucasians.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0206554PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211695PMC
April 2019

Copy Number Variation and Risk of Stroke.

Authors:
Caspar Grond-Ginsbach Philipp Erhart Bowang Chen Manja Kloss Stefan T Engelter John W Cole

Stroke 2018 10;49(10):2549-2554

Department of Neurology, Veterans Affairs Medical Center and University of Maryland School of Medicine, Baltimore (J.W.C.).

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http://dx.doi.org/10.1161/STROKEAHA.118.020371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209107PMC
October 2018

The role of clinical and neuroimaging features in the diagnosis of CADASIL.

Authors:
Anna Bersano Gloria Bedini Hugh Stephen Markus Paolo Vitali Enrico Colli-Tibaldi Franco Taroni Cinzia Gellera Silvia Baratta Lorena Mosca Paola Carrera Maurizio Ferrari Cristina Cereda Gaetano Grieco Silvia Lanfranconi Franca Mazucchelli Davide Zarcone Maria Luisa De Lodovici Giorgio Bono Giorgio Battista Boncoraglio Eugenio Agostino Parati Maria Vittoria Calloni Patrizia Perrone Bianca Maria Bordo Cristina Motto Elio Agostoni Alessandro Pezzini Alessandro Padovani Giuseppe Micieli Anna Cavallini Graziella Molini

J Neurol 2018 Dec 11;265(12):2934-2943. Epub 2018 Oct 11.

AO Melegnano-Ospedale di Vizzolo Predabissi, Melegnano, Italy.

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common familial cerebral small vessel disease, caused by NOTCH3 gene mutations. The aim of our study was to identify clinical and neuroradiological features which would be useful in identifying which patients presenting with lacunar stroke and TIA are likely to have CADASIL.

Methods: Patients with lacunar stroke or TIA were included in the present study. For each patient, demographic and clinical data were collected. MRI images were centrally analysed for the presence of lacunar infarcts, microbleeds, temporal lobe involvement, global atrophy and white matter hyperintensities.

Results: 128 patients (mean age 56.3 ± 12.4 years) were included. A NOTCH3 mutation was found in 12.5% of them. A family history of stroke, the presence of dementia and external capsule lesions on MRI were the only features significantly associated with the diagnosis of CADASIL. Although thalamic, temporal pole gliosis and severe white matter hyperintensities were less specific for CADASIL diagnosis, the combination of a number of these factors together with familial history for stroke result in a higher positive predictive value and specificity.

Conclusions: A careful familial history collection and neuroradiological assessment can identify patients in whom NOTCH3 genetic testing has a higher yield.
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http://dx.doi.org/10.1007/s00415-018-9072-8DOI Listing
December 2018

Determinants and outcome of multiple and early recurrent cervical artery dissections.

Authors:
Annette Compter Sabrina Schilling Cloé Juliette Vaineau Barbara Goeggel-Simonetti Tiina M Metso Andrew Southerland Alessandro Pezzini Manja Kloss Emmanuel Touzé Bradford B Worrall Vincent Thijs Yannick Bejot Peggy Reiner Caspar Grond-Ginsbach Anna Bersano Tobias Brandt Valeria Caso Philippe A Lyrer Christopher Traenka Christoph Lichy Juan José Martin Didier Leys Hakan Sarikaya Ralph W Baumgartner Simon Jung Urs Fischer Stefan T Engelter Jean Dallongeville Hugues Chabriat Turgut Tatlisumak

Neurology 2018 08 1;91(8):e769-e780. Epub 2018 Aug 1.

From the Department of Neuro-oncology (A.C.), Netherlands Cancer Institute/Antoni van Leeuwenhoek; Department of Neurology (A.C.), MC Slotervaart, Amsterdam, the Netherlands; University of Bordeaux (S.S., S.D.); Bordeaux Population Health (S.S., S.D.), INSERM Center U1219, France; Department of Neurology (C.J.V., B.G.-S., H.S., S.J., U.F., M.A.), University Hospital Inselspital and University of Bern; Division of Neuropediatrics (B.G.-S.), San Giovanni Hospital Bellinzona, Switzerland; Department of Neurology (T.M.M., T.T.), Helsinki University Central Hospital, Finland; Departments of Neurology and Public Health Sciences (A.S., B.B.W.), University of Virginia, Charlottesville; Department of Clinical and Experimental Sciences (A.P.), Neurology Clinic, University of Brescia, Italy; Department of Neurology (M.K., C.G.-G., C.L.), Heidelberg University Hospital, Germany; Normandie Université (E.T.), Unicaen, CHU Caen, Inserm U1237; Université Paris Descartes (E.T.), CH Ste Anne, Inserm U894, Paris, France; Stroke Division (V.T.), Florey Institute for Neuroscience and Mental Health, University of Melbourne; Department of Neurology (V.T.), Austin Health, Heidelberg, Victoria, Australia; Department of Neurology (Y.B.), Dijon University Hospital; Department of Neurology (P.R., H.C., M.-G.B.), Lariboisière Hospital, Paris 7 University, DHU Neurovasc Sorbonne Paris Cité, France; Cerebrovascular Unit (A.B.), IRCCS Foundation C. Besta Neurological Institute, Milan, Italy; Suva/Swiss National Accident Insurance Fund (T.B.), Lucerne, Switzerland; Stroke Unit and Division of Internal and Cardiovascular Medicine (V.C.), University of Perugia, Italy; Department of Neurology and Stroke Center (P.A.L., C.T., S.T.E.), Department of Clinical Research, University Hospital and University of Basel, Switzerland; Neurology Clinic (C.L.), Memmingen Hospital, Germany; Department of Neurology (J.J.M.), Sanatorio Allende, Cordoba, Argentina; Department of Neurology (D.L.), Lille University, INSERM U1171, France; NeuroCentre (R.W.B.), Clinic Hirslanden Zürich, Switzerland; Neurorehabilitation Unit (S.T.E.), University Center for Medicine of Aging and Rehabilitation, Felix Platter Hospital, University of Basel, Switzerland; INSERM 1176 (J.D.), Institut Pasteur de Lille, France; Department of Clinical Neuroscience (T.T.), Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg; Department of Neurology (T.T.), Sahlgrenska University Hospital, Gothenburg, Sweden; and Department of Neurology-Memory Clinic (S.D.), Bordeaux University Hospital, France.

Objective: To assess putative risk factors and outcome of multiple and early recurrent cervical artery dissection (CeAD).

Methods: We combined data from 2 multicenter cohorts and compared patients with multiple CeAD at initial diagnosis, early recurrent CeAD within 3 to 6 months, and single nonrecurrent CeAD. Putative risk factors, clinical characteristics, functional outcome, and risk of recurrent ischemic events were assessed.

Results: Of 1,958 patients with CeAD (mean ± SD age 44.3 ± 10 years, 43.9% women), 1,588 (81.1%) had single nonrecurrent CeAD, 340 (17.4%) had multiple CeAD, and 30 (1.5%) presented with single CeAD at admission and had early recurrent CeAD. Patients with multiple or early recurrent CeAD did not significantly differ with respect to putative risk factors, clinical presentation, and outcome. In multivariable analyses, patients with multiple or early recurrent CeAD more often had recent infection (odds ratio [OR] 1.81, 95% confidence interval [CI] 1.29-2.53), vertebral artery dissection (OR 1.82, 95% CI 1.34-2.46), family history of stroke (OR 1.55, 95% CI 1.06-2.25), cervical pain (OR 1.36, 95% CI 1.01-1.84), and subarachnoid hemorrhage (OR 2.85, 95% CI 1.01-8.04) at initial presentation compared to patients with single nonrecurrent CeAD. Patients with multiple or early recurrent CeAD also had a higher incidence of cerebral ischemia (hazard ratio 2.77, 95% CI 1.49-5.14) at 3 to 6 months but no difference in functional outcome compared to patients with single nonrecurrent CeAD.

Conclusion: Patients with multiple and early recurrent CeAD share similar risk factors, clinical characteristics, and functional outcome. Compared to patients with single nonrecurrent CeAD, they are more likely to have recurrent cerebral ischemia at 3 to 6 months, possibly reflecting an underlying transient vasculopathy.
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http://dx.doi.org/10.1212/WNL.0000000000006037DOI Listing
August 2018

Genetics of Spontaneous Coronary Artery Dissection Gains New Momentum.

Authors:
Caspar Grond-Ginsbach Stefan T Engelter

Circ Genom Precis Med 2018 04;11(4):e002148

Neurology Department, University of Heidelberg, Germany (C.G.-G.). Department of Neurology & Stroke Center, Department of Clinical Research, University Hospital and University of Basel, Switzerland (S.T.E.). Neurorehabilitation Unit, University Center for Medicine of Aging & Rehabilitation, Felix Platter Hospital, University of Basel, Switzerland (S.T.E.).

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http://dx.doi.org/10.1161/CIRCGEN.118.002148DOI Listing
April 2018

Clinical outcome and cerebrospinal fluid profiles in patients with tick-borne encephalitis and prior vaccination history.

Authors:
Thorsten Lenhard Daniela Ott Nurith J Jakob Francisco Martinez-Torres Caspar Grond-Ginsbach Uta Meyding-Lamadé

Ticks Tick Borne Dis 2018 05 1;9(4):882-888. Epub 2018 Mar 1.

Department of Neurology, Krankenhaus Nordwest Frankfurt, Steinbacher Hohl, Germany.

Background: Tick-borne encephalitis (TBE) is endemic in southern and eastern districts of Germany. Approximately 10-14% of the infected individuals suffer from long-term disability and in 1.5-3.6% the course is fatal. Two well-tolerated vaccines are available, which provide high protection and which have been confirmed in several field studies. Here we investigate clinical course, long-term outcome and cerebrospinal fluid (CSF) characteristics of TBE cases with a prior history of any vaccination as well as real vaccination breakthrough (VBT).

Methods: A case series of 11 patients with a prior history of vaccination, part of a recently published lager cohort of 111 TBE cases. Evaluation included clinical data, degree of disability (modified RANKIN scale, mRS) and analysis of CSF and serum samples. Furthermore, metadata for extended analysis on clinical outcome of TBE with VBT were analysed.

Results: One patient had a clear VBT and ten of them had irregular vaccinations schedules (IVS). Infection severity did not differ in patients with IVS as compared to a non-vaccinated control cohort (median mRS: both 3.0) but these patients showed a stronger cellular immune response as measured by CSF pleocytosis (IVS, 205 cells/μL versus non-vaccinated control, 114 cell/μL, P < 0.05) and by differential pattern of CSF (intrathecal) immunoglobulin synthesis. However, shift analysis of VBT metadata using linear-by-linear association revealed a more serious course of TBE in patients with VBT than in a non-vaccinated control cohort (χ = 9.95, P = 0.002). Furthermore, ordinal logistic regression analysis showed that VBT patients had an age-corrected, 2.65 fold (CI: 1.110-6.328; χ = 4.813; p = 0.028) significant higher risk to suffer from moderate or severe infections, respectively.

Conclusion: A history of IVS surprisingly seems to have no impact on the clinical course of TBE but may leave marks in the specific brain immune response. VBT patients, however, carry an age-independent, significant risk to experience a severe infection.
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http://dx.doi.org/10.1016/j.ttbdis.2018.02.021DOI Listing
May 2018

Recurrence of cervical artery dissection: An underestimated risk.

Authors:
Manja Kloss Caspar Grond-Ginsbach Peter Ringleb Ingrid Hausser Werner Hacke Tobias Brandt

Neurology 2018 04 16;90(16):e1372-e1378. Epub 2018 Mar 16.

From the Department of Neurology (M.K., C.G.-G., P.R., W.H.), University of Heidelberg; Institute of Pathology IPH (I.H.), Heidelberg University Hospital, Germany; and Suva/Swiss National Accident Insurance Fund (T.B.), Lucerne, Switzerland.

Objective: To explore the recurrence of cervical artery dissection (CeAD).

Methods: A single-center consecutive series of 282 CeAD patients was prospectively recruited during first admission from 1995 to 2012. Patients with a follow-up of at least 1 year (n = 238) were eligible for the current analysis. All patients with clinical symptoms or signs of recurrent CeAD on ultrasound were examined by MRI. Dermal connective tissue morphology was studied in 108 (45.4%) patients.

Results: Median follow-up was 52 months (range 12-204 months). In all, 221 (92.8%) patients presented with monophasic CeAD, including 188 (79.0%) patients with a single CeAD event, 11 (4.6%) with simultaneous dissections in multiple cervical arteries, and 22 (9.2%) with subsequent events within a single phase of 4 weeks. Seventeen patients (7.1%) had late (>1 month after the initial event) recurrent CeAD events, including 5 (2.1%) with multiple recurrences. Patients with late recurrences were younger (37.5 ± 6.9 years) than those without (43.8 ± 9.9; = 0.011). Ischemic stroke occurred in 164 (68.9%) patients at first diagnosis, but only 4 of 46 (8.7%) subsequent events caused stroke ( < 0.0001), while 19 (41.3%) were asymptomatic. Connective tissue abnormalities were found in 54 (56.3%) patients with monophasic and 8 (66.7%) with late recurrent dissections ( = 0.494).

Conclusion: Twenty-two (9.2%) patients had new CeAD events within 1 month and 17 (7.1%) later recurrences. The risk for new events was significantly higher (about 60-fold) during the acute phase than during later follow-up. Connective tissue abnormalities were not more frequent in patients with late recurrent events than in those with monophasic CeAD.
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http://dx.doi.org/10.1212/WNL.0000000000005324DOI Listing
April 2018

University education and cervical artery dissection.

Authors:
Lars Kellert Armin Grau Alessandro Pezzini Stéphanie Debette Didier Leys Valeria Caso Vincent N Thijs Anna Bersano Emmanuel Touzé Turgut Tatlisumak Christopher Traenka Philippe A Lyrer Stefan T Engelter Tiina M Metso Caspar Grond-Ginsbach Manja Kloss

J Neurol 2018 May 24;265(5):1065-1070. Epub 2018 Feb 24.

Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.

Background And Purpose: We investigated whether university education is more likely in cervical artery dissection (CeAD)-patients than in age- and sex-matched patients with ischemic stroke (IS) due to other causes (non-CeAD-IS-patients).

Methods: Patients from the Cervical Artery Dissection and Ischemic Stroke Patients study with documented self-reported profession before onset of IS due to CeAD (n = 715) or non-CeAD causes (n = 631) were analyzed. In the reported profession, the absence or presence of university education was assessed. Professions could be rated as academic or non-academic in 518 CeAD and 456 non-CeAD patients. Clinical outcome at 3 months was defined as excellent if modified Rankin Scale was 0-1.

Results: University education was more frequent in CeAD-patients (100 of 518, 19.3%) than in non-CeAD-IS-patients (61 of 456, 13.4%, p = 0.008). CeAD-patients with and without university education differed significantly with regard to smoking (39 vs. 57%, p = 0.001) and excellent outcome (80 vs. 66%, p = 0.004). In logistic regression analysis, university education was associated with excellent outcome in CeAD-patients (OR 2.44, 95% CI 1.37-5.38) independent of other outcome predictors such as age (OR 0.97, 95% CI 0.84-0.99), NIHSS (OR 0.80, 95% CI 0.76-0.84) and local signs (OR 2.77, 95% CI 1.37-5.57).

Conclusion: We observed a higher rate of university education in patients with CeAD compared with non-CeAD patients in our study population. University education was associated with favorable outcome in CeAD-patients. The mechanism behind this association remains unclear.
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http://dx.doi.org/10.1007/s00415-018-8798-7DOI Listing
May 2018

Familial aortic disease and a large duplication in chromosome 16p13.1.

Authors:
Philipp Erhart Tobias Brandt Beate K Straub Ingrid Hausser Sabine Hentze Dittmar Böckler Caspar Grond-Ginsbach

Mol Genet Genomic Med 2018 05 14;6(3):441-445. Epub 2018 Feb 14.

Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany.

Background And Purpose: A recurrent duplication of chromosome 16p13.1 was associated with aortic dissection as well as with cervical artery dissection. We explore the segregation of this duplication in a family with familial aortic disease.

Methods: Whole exome sequencing (WES) analysis was performed in a patient with a family history of aortic diseases and ischemic stroke due to an aortic dissection extending into both carotid arteries.

Results: The index patient, his affected father, and an affected sister of his father carried a large duplication of region 16p13.1, which was also verified by quantitative PCR. The duplication was also found in clinically asymptomatic sister of the index patient. WES did not detect pathogenic variants in a predefined panel of 11 genes associated with aortic disease, but identified rare deleterious variants in 14 genes that cosegregated with the aortic phenotype.

Conclusions: The cosegregation of duplication 16p13.1 with the aortic phenotype in this family suggested a causal relationship between the duplication and aortic disease. Variants in known candidate genes were excluded as disease-causing in this family, but cosegregating variants in other genes might modify the contribution of duplication 16p13.1 on aortic disease.
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http://dx.doi.org/10.1002/mgg3.371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014459PMC
May 2018

Departure from Hardy Weinberg Equilibrium and Genotyping Error.

Authors:
Bowang Chen John W Cole Caspar Grond-Ginsbach

Front Genet 2017 31;8:167. Epub 2017 Oct 31.

Department of Neurology, University of Heidelberg, Heidelberg, Germany.

Departure from Hardy Weinberg Equilibrium (HWE) may occur due to a variety of causes, including purifying selection, inbreeding, population substructure, copy number variation or genotyping error. We searched for specific characteristics of HWE-departure due to genotyping error. Genotypes of a random set of genetic variants were obtained from the Exome Aggregation Consortium (ExAC) database. Variants with <80% successful genotypes or with minor allele frequency (MAF) <1% were excluded. HWE-departure (d-HWE) was considered significant at < 10E-05 and classified as d-HWE with loss of heterozygosity (LoH d-HWE) or d-HWE with excess heterozygosity (gain of heterozygosity: GoH d-HWE). Missing genotypes, variant type (single nucleotide polymorphism (SNP) vs. insertion/deletion); MAF, standard deviation (SD) of MAF across populations (MAF-SD) and copy number variation were evaluated for association with HWE-departure. The study sample comprised 3,204 genotype distributions. HWE-departure was observed in 134 variants: LoH d-HWE in 41 (1.3%), GoH d-HWE in 93 (2.9%) variants. LoH d-HWE was more likely in variants located within deletion polymorphisms ( < 0.001) and in variants with higher MAF-SD ( = 0.0077). GoH d-HWE was associated with low genotyping rate, with variants of insertion/deletion type and with high MAF (all at < 0.001). In a sub-sample of 2,196 variants with genotyping rate >98%, LoH d-HWE was found in 29 (1.3%) variants, but no GoH d-HWE was detected. The findings of the non-random distribution of HWE-violating SNPs along the chromosome, the association with common deletion polymorphisms and indel-variant type, and the finding of excess heterozygotes in genomic regions that are prone to cross-hybridization were confirmed in a large sample of short variants from the 1,000 Genomes Project. We differentiated between two types of HWE-departure. GoH d-HWE was suggestive for genotyping error. LoH d-HWE, on the contrary, pointed to natural variabilities such as population substructure or common deletion polymorphisms.
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http://dx.doi.org/10.3389/fgene.2017.00167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5671567PMC
October 2017

Gene Expression Profiling in Abdominal Aortic Aneurysms After Finite Element Rupture Risk Assessment.

Authors:
Philipp Erhart Sandra Schiele Philip Ginsbach Caspar Grond-Ginsbach Maani Hakimi Dittmar Böckler Justo Lorenzo-Bermejo Susanne Dihlmann

J Endovasc Ther 2017 12 31;24(6):861-869. Epub 2017 Aug 31.

1 Department of Vascular and Endovascular Surgery, Universitätsklinikum Heidelberg, Germany.

Purpose: To investigate the association between local biomechanical rupture risk calculations from finite element analysis (FEA) and whole-genome profiling of the abdominal aortic aneurysm (AAA) wall to determine if AAA wall regions with highest and lowest estimated rupture risk show different gene expression patterns.

Methods: Six patients (mean age 74 years; all men) scheduled for open surgery to treat asymptomatic AAAs (mean diameter 55.2±3.5 mm) were recruited for the study. Rupture risk profiles were estimated by FEA from preoperative computed tomography angiography data. During surgery, AAA wall samples of ~10 mm were extracted from the lowest and highest rupture risk locations identified by the FEA. Twelve samples were processed for RNA extraction and subsequent whole genome expression profiling. Expression of single genes and of predefined gene groups were compared between vessel wall areas with highest and lowest predicted rupture risk.

Results: Normalized datasets comprised 15,079 gene transcripts with expression above background. In biopsies with high rupture risk, upregulation of 18 and downregulation of 18 genes was detected when compared to the low-risk counterpart. Global analysis of predefined gene groups revealed expression differences in genes associated with extracellular matrix (ECM) degradation (p<0.001), matrix metalloproteinase activity (p<0.001), and chemokine signaling (p<0.001).

Conclusion: Increased expression of genes involved in degrading ECM components was present in AAA wall regions with highest biomechanical stress, supporting the thesis of mechanotransduction. More experimental studies with cooperation of multicenter vascular biobanks are necessary to understand AAA etiologies and identify further parameters of FEA model complementation.
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http://dx.doi.org/10.1177/1526602817729165DOI Listing
December 2017

Cerebral Small Vessel Disease Is Associated with Dysregulation in the Ubiquitin Proteasome System and Other Major Cellular Pathways in Specific Brain Regions.

Authors:
Marie-Françoise Ritz Caspar Grond-Ginsbach Felix Fluri Manja Kloss Markus Tolnay Nils Peters Stefan Engelter Philippe Lyrer

Neurodegener Dis 2017 16;17(6):261-275. Epub 2017 Aug 16.

Department of Biomedicine, University of Basel, Brain Tumor Biology Laboratory, Basel, Switzerland.

Background/aims: Cerebral small vessel disease (SVD) is characterized by periventricular white matter (WM) changes and can lead to vascular dementia, the second most common form of age-dependent dementia. The pathogenesis of the disease remains poorly understood, and studies of its molecular basis are limited. By profiling gene expression of dissected postmortem brain tissue in SVD patients and comparisons with tissue of nonneurological controls, we aimed to identify genes and processes that are involved in the pathogenesis of SVD to gain new pathogenetic insights.

Methods: We performed genome-wide expression analyses in postmortem brain tissue samples dissected from frontal, temporal, and occipital lobes as well as basal nuclei comprising thalamus, basal ganglia, and hippocampus from 5 SVD cases and 5 nonaffected control cases. Cellular pathways associated with differently expressed genes were identified in each brain region individually.

Results: This analysis disclosed regional differences, with frontal lobe and thalamus showing the highest numbers of genes with significantly altered expression. Biological functions and pathways associated with changed gene expression depicted brain area-specific defective pathways. Vessel-associated functions, such as increased extracellular matrix-receptor interactions and cell adhesion molecules, were enhanced in all regions. Inflammation and apoptosis were induced particularly in basal nuclei and temporal and occipital regions. Interestingly, genes associated with the ubiquitin-dependent proteolysis (ubiquitin proteasome system) pathway were downregulated in the frontal lobe and in the thalamus, leading to the formation of protein aggregates.

Conclusion: This analysis deciphers brain region-specific molecular processes to increase the present knowledge of SVD pathology and determine new potential therapeutic targets.
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http://dx.doi.org/10.1159/000478529DOI Listing
July 2018

Next generation sequencing analysis of patients with familial cervical artery dissection.

Authors:
Caspar Grond-Ginsbach Tobias Brandt Manja Kloss Suna Su Aksay Philipp Lyrer Christopher Traenka Philipp Erhart Juan Jose Martin Ayse Altintas Aksel Siva Gabriel R de Freitas Andreas Thie Jochen Machetanz Ralf W Baumgartner Martin Dichgans Stefan T Engelter

Eur Stroke J 2017 Jun 9;2(2):137-143. Epub 2017 Feb 9.

Department of Neurology and Stroke Center, Basel University Hospital, Basel, Switzerland.

Background: The cause of cervical artery dissection is not well understood. We test the hypothesis that mutations in genes associated with known arterial connective tissue disorders are enriched in patients with familial cervical artery dissection.

Patients And Methods: Patient duos from nine pedigrees with familial cervical artery dissection were analyzed by whole exome sequencing. Single nucleotide variants in a panel of 11 candidate genes (ACTA2, MYH11, FBN1, TGFBR1, TGFBR2, TGFB2, COL3A1, COL4A1, SMAD3, MYLK and SLC2A10) were prioritized according to functionality (stop-loss, nonsense, and missense variants with polyphen-2 score ≥0.95). Variants classified as "benign" or "likely benign" in the ClinVar database were excluded from further analysis. For comparison, non-benign stop-loss, nonsense and missense variants with polyphen-2 score ≥0.95 in the same panel of candidate genes were identified in the European non-Finnish population of the ExAC database ( = 33,370).

Results: Non-benign Single nucleotide variants in both affected patients were identified in four of the nine cervical artery dissection families (COL3A1; Gly324Ser, FBN1: Arg2554Trp, COL4A1: Pro116Leu, and TGFBR2: Ala292Thr) yielding an allele frequency of 22.2% (4/18). In the comparison group, 1782 variants were present in 33,370 subjects from the ExAC database (allele frequency: 1782/66,740 = 2.7%;  = 0.0008; odds ratio = 14.2; 95% confidence interval = 3.8-52.9).

Conclusion: Cervical artery dissection families showed enrichment for non-benign variants in genes associated with arterial connective tissue disorders. The observation that findings differed across families indicates genetic heterogeneity of familial cervical artery dissection.
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http://dx.doi.org/10.1177/2396987317693402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453217PMC
June 2017

Cerebrovascular disease: CeAD and migraine - an association built on shifting sands.

Authors:
Caspar Grond-Ginsbach Manja Kloss

Nat Rev Neurol 2017 May 18;13(5):261-262. Epub 2017 Apr 18.

Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, D-69120 Heidelberg, Germany.

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http://dx.doi.org/10.1038/nrneurol.2017.55DOI Listing
May 2017

Genetic Imbalance in Patients with Cervical Artery Dissection.

Authors:
Caspar Grond-Ginsbach Bowang Chen Michael Krawczak Rastislav Pjontek Philip Ginsbach Yanxiang Jiang Shérine Abboud Marie-Luise Arnold Anna Bersano Tobias Brandt Valeria Caso Stéphanie Debette Martin Dichgans Andreas Geschwendtner Giacomo Giacalone Juan-José Martin Antti J Metso Tiina M Metso Armin J Grau Manja Kloss Christoph Lichy Alessandro Pezzini Christopher Traenka Stefan Schreiber Vincent Thijs Emmanuel Touzé Elisabetta Del Zotto Turgut Tatlisumak Didier Leys Philippe A Lyrer

Curr Genomics 2017 Apr;18(2):206-213

Department of Neurology and Stroke Center, Basel University Hospital, Basel, Switzerland.

Background: Genetic and environmental risk factors are assumed to contribute to the susceptibility to cervical artery dissection (CeAD). To explore the role of genetic imbalance in the etiology of CeAD, copy number variants (CNVs) were identified in high-density microarrays samples from the multicenter CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) study and from control subjects from the CADISP study and the German PopGen biobank. Microarray data from 833 CeAD patients and 2040 control subjects (565 subjects with ischemic stroke due to causes different from CeAD and 1475 disease-free individuals) were analyzed. Rare genic CNVs were equally frequent in CeAD-patients (16.4%; n=137) and in control subjects (17.0%; n=346) but differed with respect to their genetic content. Compared to control subjects, CNVs from CeAD patients were enriched for genes associated with muscle organ development and cell differentiation, which suggests a possible association with arterial development. CNVs affecting cardiovascular system development were more common in CeAD patients than in control subjects (p=0.003; odds ratio (OR) =2.5; 95% confidence interval (95% CI) =1.4-4.5) and more common in patients with a familial history of CeAD than in those with sporadic CeAD (p=0.036; OR=11.2; 95% CI=1.2-107).

Conclusion: The findings suggest that rare genetic imbalance affecting cardiovascular system development may contribute to the risk of CeAD. Validation of these findings in independent study populations is warranted.
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http://dx.doi.org/10.2174/1389202917666160805152627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5345335PMC
April 2017

Cervical artery dissection in patients ≥60 years: Often painless, few mechanical triggers.

Authors:
Christopher Traenka Daphne Dougoud Barbara Goeggel Simonetti Tiina M Metso Stéphanie Debette Alessandro Pezzini Manja Kloss Caspar Grond-Ginsbach Jennifer J Majersik Bradford B Worrall Didier Leys Ralf Baumgartner Valeria Caso Yannick Béjot Annette Compter Peggy Reiner Vincent Thijs Andrew M Southerland Anna Bersano Tobias Brandt Henrik Gensicke Emmanuel Touzé Juan J Martin Hugues Chabriat Turgut Tatlisumak Philippe Lyrer Marcel Arnold Stefan T Engelter

Neurology 2017 Apr 3;88(14):1313-1320. Epub 2017 Mar 3.

From the Department of Neurology and Stroke Center (C.T., H.G., P.L., S.T.E.), University Hospital Basel and University of Basel; Department of Neurology (D.D., B.G.S., M.A.), University Hospital Berne; Ospedale San Giovanni (B.G.S.), Bellinzona, Switzerland; Department of Neurology (T.M.M., T.T.), Helsinki University Central Hospital, Finland; Department of Neurology (S.D.), Bordeaux University Hospital; Inserm U1219 (S.D.), Bordeaux; Bordeaux University (S.D.), France; Department of Neurology (S.D.), Boston University School of Medicine, MA; Department of Clinical and Experimental Sciences (A.P.), Neurology Clinic, University of Brescia, Italy; Department of Neurology (M.K., C.G.-G.), Heidelberg University Hospital, Germany; Department of Neurology (J.J.M.), University of Utah, Salt Lake City; Departments of Neurology and Public Health Sciences (B.B.W., A.M.S.), University of Virginia Health System, Charlottesville; Univ Lille 2 (D.L.), INSERM U 1171, CHU Lille, France; Neuro Center (R.B.), Clinic Hirslanden, Zurich, Switzerland; Stroke Unit and Division of Internal and Cardiovascular Medicine (V.C.), University of Perugia, Italy; Centre Hospitalier Universitaire Le Bocage (Y.B.), Dijon, France; Department of Neurology and Neurosurgery (A.C.), Brain Centre Rudolf Magnus, University Medical Centre Utrecht, the Netherlands; Department of Neurology (P.R., H.C.), Lariboisière Hospital, Paris 7 University, DHU Neurovasc Sorbonne Paris Cité, France; Florey Institute of Neuroscience and Mental Health (V.T.); Department of Neurology (V.T.), Austin Health, Heidelberg, Australia; Cerebrovascular Unit (A.B.), IRCCS Foundation C. Besta Neurological Institute, Milan, Italy; Clinics for Neurologic Rehabilitation (T.B.), Kliniken Schmieder, Heidelberg, Germany; Normandie Univ (E.T.), UNICAEN, Inserm U919, Department of Neurology, CHU Caen; Department of Neurology (E.T.), CH Sainte-Anne, University Paris Descartes, France; Department of Neurology (J.J.M.), Sanatorio Allende, Cordoba, Argentina; Department of Neurology (T.T.), Sahlgrenska University Hospital and Institute for Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Sweden; and Neurorehabilitation Unit (S.T.E.), University of Basel and University Center for Medicine of Aging and Rehabilitation, Felix Platter Hospital, Basel, Switzerland.

Objective: In a cohort of patients diagnosed with cervical artery dissection (CeAD), to determine the proportion of patients aged ≥60 years and compare the frequency of characteristics (presenting symptoms, risk factors, and outcome) in patients aged <60 vs ≥60 years.

Methods: We combined data from 3 large cohorts of consecutive patients diagnosed with CeAD (i.e., Cervical Artery Dissection and Ischemic Stroke Patients-Plus consortium). We dichotomized cases into 2 groups, age ≥60 and <60 years, and compared clinical characteristics, risk factors, vascular features, and 3-month outcome between the groups. First, we performed a combined analysis of pooled individual patient data. Secondary analyses were done within each cohort and across cohorts. Crude and adjusted odds ratios (OR [95% confidence interval]) were calculated.

Results: Among 2,391 patients diagnosed with CeAD, we identified 177 patients (7.4%) aged ≥60 years. In this age group, cervical pain (OR 0.47 [0.33-0.66]), headache (OR 0.58 [0.42-0.79]), mechanical trigger events (OR 0.53 [0.36-0.77]), and migraine (OR 0.58 [0.39-0.85]) were less frequent than in younger patients. In turn, hypercholesterolemia (OR 1.52 [1.1-2.10]) and hypertension (OR 3.08 [2.25-4.22]) were more frequent in older patients. Key differences between age groups were confirmed in secondary analyses. In multivariable, adjusted analyses, favorable outcome (i.e., modified Rankin Scale score 0-2) was less frequent in the older age group (OR 0.45 [0.25, 0.83]).

Conclusion: In our study population of patients diagnosed with CeAD, 1 in 14 was aged ≥60 years. In these patients, pain and mechanical triggers might be missing, rendering the diagnosis more challenging and increasing the risk of missed CeAD diagnosis in older patients.
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http://dx.doi.org/10.1212/WNL.0000000000003788DOI Listing
April 2017

Association between infectious burden, socioeconomic status, and ischemic stroke.

Authors:
Frederick Palm Pirkko J Pussinen Annette Aigner Heiko Becher Florian Buggle Matthias F Bauer Caspar Grond-Ginsbach Anton Safer Christian Urbanek Armin J Grau

Atherosclerosis 2016 11 5;254:117-123. Epub 2016 Oct 5.

Department of Neurology, Klinikum Ludwigshafen, Germany.

Background And Aims: Infectious diseases contribute to stroke risk, and are associated with socioeconomic status (SES). We tested the hypotheses that the aggregate burden of infections increases the risk of ischemic stroke (IS) and partly explains the association between low SES and ischemic stroke.

Methods: In a case-control study with 470 ischemic stroke patients and 809 age- and sex-matched controls, randomly selected from the population, antibodies against the periodontal microbial agents Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis, against Chlamydia pneumonia, Mycoplasma pneumoniae (IgA and IgG), and CagA-positive Helicobacter pylori (IgG) were assessed.

Results: IgA seropositivity to two microbial agents was significantly associated with IS after adjustment for SES (OR 1.45 95% CI 1.01-2.08), but not in the fully adjusted model (OR 1.32 95% CI 0.86-2.02). By trend, cumulative IgA seropositivity was associated with stroke due to large vessel disease (LVD) after full adjustment (OR 1.88, 95% CI 0.96-3.69). Disadvantageous childhood SES was associated with higher cumulative seropositivity in univariable analyses, however, its strong impact on stroke risk was not influenced by seroepidemiological data in the multivariable model. The strong association between adulthood SES and stroke was rendered nonsignificant when factors of dental care were adjusted for.

Conclusions: Infectious burden assessed with five microbial agents did not independently contribute to ischemic stroke consistently, but may contribute to stroke due to LVD. High infectious burden may not explain the association between childhood SES and stroke risk. Lifestyle factors that include dental negligence may contribute to the association between disadvantageous adulthood SES and stroke.
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http://dx.doi.org/10.1016/j.atherosclerosis.2016.10.008DOI Listing
November 2016

Clinical Pregenetic Screening for Stroke Monogenic Diseases: Results From Lombardia GENS Registry.

Authors:
Anna Bersano Hugh Stephen Markus Silvana Quaglini Eloisa Arbustini Silvia Lanfranconi Giuseppe Micieli Giorgio B Boncoraglio Franco Taroni Cinzia Gellera Silvia Baratta Silvana Penco Lorena Mosca Maurizia Grasso Paola Carrera Maurizio Ferrari Cristina Cereda Gaetano Grieco Stefania Corti Dario Ronchi Maria Teresa Bassi Laura Obici Eugenio A Parati Alessando Pezzini Maria Luisa De Lodovici Elena P Verrengia Giorgio Bono Francesca Mazucchelli Davide Zarcone Maria Vittoria Calloni Patrizia Perrone

Stroke 2016 07 31;47(7):1702-9. Epub 2016 May 31.

From the Department of Cerebrovascular Disease, IRCCS Foundation Carlo Besta Neurological Institute, Milan, Italy (A.B., G.B.B., E.A.P., N.T.); Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (H.S.M.); Department of Bio-Medical Informatics, University of Pavia, Pavia, Italy (S.Q.); Department of Inherited Cardiovascular Disease, Foundation IRCCS Policlinico San Matteo, Pavia, Italy (E.A., M.G.); Neurology Unit, Department of Neuroscience and Sensory Organs, Maggiore Policlinico Hospital Foundation IRCCS Ca' Granda, Milan, Italy (S.L., L.C.); Neurology and Stroke Unit, Department of Urgency (G.M., A.C.), Department of Genetics (C.C., G.G.), and Brain MRI 3T Research Center (P.V.), IRCCS Foundation Casimiro Mondino Neurological Institute, Pavia, Italy; Department of Genetics of Neurodegenerative and Metabolic Diseases, IRCCS Foundation C, Besta Neurological Institute, Milan, Italy (F.T., C.G., S.B.); Department of Medical Genetics, Niguarda Ca' Granda Hospital, Milan, Italy (S.P., L.M.); Department of Genomics for Human Disease Diagnosis and Laboratory of Clinical Molecular Biology, IRCCS San Raffaele hospital, Milan, Italy (P.C., M.F.); University Vita-Salute, Milano, Italy (M.F.); Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Milan, Italy (S.C., D.R., G.P.C.); Neurology Unit, Department of Neuroscience and Sensory Organs, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico Milan, Milan, Italy (S.C., D.R., G.P.C.); Department of Molecular Biology, Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy (M.T.B.); Center for amyloidosis, Department of medical Thecnologies, IRCCS Foundation San Matteo Policlinico, Pavia, Italy (L.O., G.M.); Vascular Neurology - Spedali Civili, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy (A. Pezzini, A. Padovani); Stroke Unit, Departmen

Background And Purpose: Lombardia GENS is a multicentre prospective study aimed at diagnosing 5 single-gene disorders associated with stroke (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, Fabry disease, MELAS [mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes], hereditary cerebral amyloid angiopathy, and Marfan syndrome) by applying diagnostic algorithms specific for each clinically suspected disease

Methods: We enrolled a consecutive series of patients with ischemic or hemorrhagic stroke or transient ischemic attack admitted in stroke units in the Lombardia region participating in the project. Patients were defined as probable when presenting with stroke or transient ischemic attack of unknown etiopathogenic causes, or in the presence of <3 conventional vascular risk factors or young age at onset, or positive familial history or of specific clinical features. Patients fulfilling diagnostic algorithms specific for each monogenic disease (suspected) were referred for genetic analysis.

Results: In 209 patients (57.4±14.7 years), the application of the disease-specific algorithm identified 227 patients with possible monogenic disease. Genetic testing identified pathogenic mutations in 7% of these cases. Familial history of stroke was the only significant specific feature that distinguished mutated patients from nonmutated ones. The presence of cerebrovascular risk factors did not exclude a genetic disease.

Conclusions: In patients prescreened using a clinical algorithm for monogenic disorders, we identified monogenic causes of events in 7% of patients in comparison to the 1% to 5% prevalence reported in previous series.
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http://dx.doi.org/10.1161/STROKEAHA.115.012281DOI Listing
July 2016

Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2.

Authors:
Yu-Ching Cheng Tara M Stanne Anne-Katrin Giese Weang Kee Ho Matthew Traylor Philippe Amouyel Elizabeth G Holliday Rainer Malik Huichun Xu Steven J Kittner John W Cole Jeffrey R O'Connell John Danesh Asif Rasheed Wei Zhao Stefan Engelter Caspar Grond-Ginsbach Yoichiro Kamatani Mark Lathrop Didier Leys Vincent Thijs Tiina M Metso Turgut Tatlisumak Alessandro Pezzini Eugenio A Parati Bo Norrving Steve Bevan Peter M Rothwell Cathie Sudlow Agnieszka Slowik

Stroke 2016 Feb 5;47(2):307-16. Epub 2016 Jan 5.

From the Veterans Affairs Maryland Health Care System, Baltimore, MD (Y.-C.C., S.J.K., J.W.C., B.D.M.); University of Maryland School of Medicine, Baltimore (Y.-C.C., H.X., S.J.K., J.W.C., J.R.O., B.D.M.); The University of Gothenburg, Gothenburg, Sweden (T.M.S., C.J.); University of Rostock, Rostock, Germany (A.-K.G., A. Rolfs); University of Nottingham Malaysia Campus, Selangor Darul Ehsa, Malaysia (W.K.H.); University of Cambridge, Cambridge, UK (M.T., J.D., S.B., H.S.M., S.D., D.S.); Institut Pasteur de Lille, F-59000 Lille, France (P.A.); University of Newcastle, Australia (E.G.H.); Ludwig-Maximilians-Universität, Munich, Germany (R.M., K.S., M.D.); Wellcome Trust Sanger Institute, Cambridge, UK (J.D.); Center for Non-Communicable Diseases, Karachi, Pakistan (A. Rasheed, D.S.); University of Pennsylvania (W.Z., D.S.); Basel University Hospital, Switzerland (S.E.); Heidelberg University Hospital, Germany (C.G.-G.); Centre d'Étude du Polymorphisme Humain, Paris, France (Y.K.); RIKEN Center for Integrative Medical Sciences, Yokohama, Japan (Y.K.); National Genotyping Center, Evry, France (M.L.); Genome Quebec, McGill University, Montreal, Canada (M.L.); Lille University Hospital, France (D.L., S.D.); KU Leuven - University of Leuven, Leuven, Belgium (V.T.); Vesalius Research Center, VIB, Leuven, Belgium (V.T.); University Hospitals Leuven, Leuven, Belgium (V.T.); Helsinki University Central Hospital, Helsinki, Finland (T.M.M., T.T.); Università degli Studi di Brescia, Brescia, Italy (A. Pezzini); Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy (E.A.P., G.B.B.); University of Lund, Sweden (B.N.); University of Oxford, John Radcliffe Hospital (P.M.R.); University of Edinburgh, Edinburgh, UK (C.S.); Jagiellonian University Medical College, Krakow, Poland (A.S.); Lund University, Lund, Sweden (A.L.); Skåne University Hospital, Lund, Sweden (A.L.); University of Glasgow, Glasgow, UK (M.R.W.); University of Adelaide, Australia (J.J.); Mount Sinai Hos

Background And Purpose: Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset <60 years.

Methods: The discovery stage of our genome-wide association studies included 4505 cases and 21 968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5×10(-6) and performed in silico association analyses in an independent sample of ≤1003 cases and 7745 controls.

Results: One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10(-9)). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII-activating protease levels, a product of HABP2.

Conclusions: HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.
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http://dx.doi.org/10.1161/STROKEAHA.115.011328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729659PMC
February 2016
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