Genetic Insights on the Relation of Vascular Risk Factors and Cervical Artery Dissection

Quentin Le Grand; Leslie Ecker Ferreira; Tiina M Metso; Sabrina Schilling; Turgut Tatlisumak; Caspar Grond-Ginsbach; Stefan T Engelter; Philippe Lyrer; Jennifer J Majersik; Bradford B Worrall; Andrew M Southerland; Hugh S Markus; Mark Lathrop; Vincent Thijs; Didier Leys; Philippe Amouyel; Jean Dallongeville; Martin Dichgans; Alessandro Pezzini; Anna Bersano; Muralidharan Sargurupremraj; Stéphanie Debette; CADISP Consortium

doi:10.1016/j.jacc.2023.07.021

Genetic Insights on the Relation of Vascular Risk Factors and Cervical Artery Dissection

J Am Coll Cardiol. 2023 Oct 3;82(14):1411-1423. doi: 10.1016/j.jacc.2023.07.021.

Authors

Quentin Le Grand¹, Leslie Ecker Ferreira², Tiina M Metso³, Sabrina Schilling¹, Turgut Tatlisumak⁴, Caspar Grond-Ginsbach⁵, Stefan T Engelter⁶, Philippe Lyrer⁷, Jennifer J Majersik⁸, Bradford B Worrall⁹, Andrew M Southerland⁹, Hugh S Markus¹⁰, Mark Lathrop¹¹, Vincent Thijs¹², Didier Leys¹³, Philippe Amouyel¹⁴, Jean Dallongeville¹⁴, Martin Dichgans¹⁵, Alessandro Pezzini¹⁶, Anna Bersano¹⁷, Muralidharan Sargurupremraj¹⁸, Stéphanie Debette¹⁹; CADISP Consortium

Affiliations

¹ University of Bordeaux, Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux Population Health Center (BPH), Unité Mixte de Recherche (U) 1219, Bordeaux, France.
² Department of Medicine and Joinville Stroke Biobank, University of Region of Joinville, Joinville, Brazil.
³ Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
⁴ Department of Clinical Neurosciences/Neurology, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden.
⁵ Department of Vascular and Endovascular Surgery, University of Heidelberg, Heidelberg, Germany.
⁶ Neurology and Neurorehabilitation, University Department of Geriatric Medicine Felix Platter, University of Basel, Basel, Switzerland; Department of Neurology and Stroke Center, University Hospital Basel, University of Basel, Basel, Switzerland.
⁷ Department of Neurology and Stroke Center, University Hospital Basel, University of Basel, Basel, Switzerland.
⁸ Department of Neurology, University of Utah, Salt Lake City, Utah, USA.
⁹ Department of Neurology, University of Virginia, Charlottesville, Virginia, USA; Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia, USA.
¹⁰ Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.
¹¹ Department of Human Genetics, McGill University, Montreal, Quebec, Canada; Victor Phillip Dahdaleh Institute of Genomic Medicine at McGill University, Montreal, Quebec, Canada.
¹² Stroke Division, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia; Department of Neurology, Austin Health, Melbourne, Victoria, Australia.
¹³ INSERM U1172, Lille Neuroscience and Cognition, University of Lille, Lille, France.
¹⁴ Laboratory of Excellence Development of Innovative Strategies for a Transdisciplinary Approach to Alzheimer's Disease (LabEx DISTALZ), University of Lille, Lille, France; INSERM U1167 (Risk Factors and Molecular Determinants of Aging-Related Diseases - RID-AGE), Lille, France; Centre Hospitalier Universitaire Lille, Lille, France; Institut Pasteur de Lille, Lille, France.
¹⁵ Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilians University Munich, Munich, Germany; Munich Cluster for Systems Neurology, Munich, Germany; German Center for Neurodegenerative Diseases, Munich, Germany.
¹⁶ Department of Clinical and Experimental Sciences, Neurology Unit, University of Brescia, Brescia, Italy.
¹⁷ Cerebrovascular Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Neurologico Carlo Besta, Milan, Italy.
¹⁸ University of Bordeaux, Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux Population Health Center (BPH), Unité Mixte de Recherche (U) 1219, Bordeaux, France; Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, Texas.
¹⁹ University of Bordeaux, Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux Population Health Center (BPH), Unité Mixte de Recherche (U) 1219, Bordeaux, France; Department of Neurology, Institute of Neurodegenerative Diseases, Bordeaux University Hospital, Bordeaux, France. Electronic address: stephanie.debette@u-bordeaux.fr.

PMID: 37758436
DOI: 10.1016/j.jacc.2023.07.021

Abstract

Background: The association between vascular risk factors and cervical artery dissections (CeADs), a leading cause of ischemic stroke (IS) in the young, remains controversial.

Objectives: This study aimed to explore the causal relation of vascular risk factors with CeAD risk and recurrence and compare it to their relation with non-CeAD IS.

Methods: This study used 2-sample Mendelian randomization analyses to explore the association of blood pressure (BP), lipid levels, type 2 diabetes, waist-to-hip ratio, smoking, and body mass index with CeAD and non-CeAD IS. To simulate effects of the most frequently used BP-lowering drugs, this study constructed genetic proxies and tested their association with CeAD and non-CeAD IS. In analyses among patients with CeAD, the investigators studied the association between weighted genetic risk scores of vascular risk factors and the risk of multiple or early recurrent dissections.

Results: Genetically determined higher systolic BP (OR: 1.51; 95% CI: 1.32-1.72) and diastolic BP (OR: 2.40; 95% CI: 1.92-3.00) increased the risk of CeAD (P < 0.0001). Genetically determined higher body mass index was inconsistently associated with a lower risk of CeAD. Genetic proxies for β-blocker effects were associated with a lower risk of CeAD (OR: 0.65; 95% CI: 0.50-0.85), whereas calcium-channel blockers were associated with a lower risk of non-CeAD IS (OR: 0.75; 95% CI: 0.63-0.90). Weighted genetic risk scores for systolic BP and diastolic BP were associated with an increased risk of multiple or early recurrent CeAD.

Conclusions: These results are supportive of a causal association between higher BP and increased CeAD risk and recurrence and provide genetic evidence for lower CeAD risk under β-blockers. This may inform secondary prevention strategies and trial design for CeAD.

Keywords: Mendelian randomization; blood pressure; cervical artery dissection; drug effect; ischemic stroke; young adults.